The Future of Cancer Immunotherapy - Briacellbriacell.com/wp-content/uploads/2018/10/BriaCell... · The forward-looking statements in this presentation are also based on a number
42
OTCQB: BCTXF TSX-V: BCT Investor Presentation October 2018 The Future of Cancer Immunotherapy [email protected]BriaCell.com 1-888-485-6340 1
Except for historical information this presentation contains forward-looking statements which reflect BriaCellrsquoscurrent expectations regarding future events These forward-looking statements involve known and unknownrisks and uncertainties that could cause BriaCellrsquos actual results to differ materially from those statementsThose risks and uncertainties include but are not limited to our ability to access capital the successful andtimely completion of clinical trials the receipt of all regulatory approvals and other risks detailed from time totime in our ongoing quarterly and annual filings The forward-looking statements in this presentation are alsobased on a number of assumptions which may prove to be incorrect
Forward-looking statements contained in this presentation represent views only as of the date of thispresentation and are presented for the purpose of assisting potential investors in understanding BriaCellrsquosbusiness and may not be appropriate for other purposes BriaCell does not undertake to update forward-looking statements whether written or oral that may be made from time to time by or on its behalf except asrequired under applicable securities legislation
Investors are cautioned not to rely on these forward-looking statements and are encouraged to read BriaCellrsquoscontinuous disclosure documents including its financial statements which are available on SEDAR atwwwsedarcom
2
Cancer Immunotherapy Space
The Problems
Checkpoint Inhibitors Keytrudareg (anti-PD-1) Yervoyreg (anti-CTLA-4) and others reduce the tumorrsquos ability tosuppress immune system They only work in 20-30 of patients as they depend on a patientrsquos own weakenedimmune system to kill the tumor and can cause autoimmune disease
Therapeutic Cancer Vaccines Have not been successful in solid tumors or blood cancers as they are not specificenough to the patient
Personalized Immunotherapies Provengereg is effective for prostate cancer but must be individually manufactured for each patient and as a
result of the required manufacturing logistics has not been commercially successful CAR-T therapies are effective in blood cancers (but not in solid tumors) and must also be individually
manufactured in a complex process for each patient (launching in 2018)
BriaCellrsquos Solution
BriaCellrsquos Off-the-Shelf Personalized Immunotherapy BriaCell has been developing Bria-IMTtrade which is a targetedimmunotherapy for breast cancer Several remarkable responses in patients with late stage cancer have been seenin patients who match Bria-IMTtrade at certain HLA types This supports the development of Bria-OTStrade and BriaDXtradeBriaCellrsquos 15 HLA types (8 Class I amp 7 Class II) covermatch ~90 of the population This saves time and eliminatesthe complex manufacturing process associated with other personalized immunotherapies
3
These allele combinations covermatch with ~90 of the advanced breast cancer population
1 BriaDXtrade reveals the patientrsquos Class I andClass II HLA Alleles
2 The pre-manufactured Bria-OTStrade HLAAlleles are selected for the specificpatient
3 The selected Bria-OTStrade cell lines arethen shipped to the clinical site forpatient treatment
Pre-Manufactured Off-the-Shelf HLA Class II Alleles
Pre-Manufactured Off-the-Shelf HLA Class I Alleles
Bria-IMTtrade - First Product CandidateHuman Proof-of-Concept Trials in Advanced Breast Cancer
Bria-IMTtrade Non-Personalized Immunotherapy
First Proof-of-Concept Phase I (1999-2003) Used unmodified cell line + GM-CSF + cyclophosphamide N = 14 late stage treatment-refractory breast cancer patients Well tolerated no severe drug related AEs Median Overall Survival = 121 months
Second Proof-of-Concept Phase I (2005) Used GM-CSF-engineered cell line + cyclophosphamide + interferon-α N = 4 late stage treatment-refractory (3 breast cancer and 1 ovarian cancer) patients Well tolerated no life-threatening drug related adverse events One patient with transient urticaria reported as grade 3 responded to antihistamines Median Overall Survival = 35 months One robust responder with gt90 regression during treatment subsequent relapse (upon halting
treatment) responded to re-treatment
6
Bria-IMTtrade amp Bria-OTStradePotential Mechanisms of Action in Advanced Breast Cancer
Bria-IMTTM directly stimulates cancerfighting CD4+ and CD8+ T cells(further boosts the response)
Bria-IMTTM produces breastcancer antigens which aretaken up by dendritic cellsand ldquopresentedrdquo to CD4+and CD8+ T cells implicatedin tumor destruction
Bria-IMTTM secretes GM-CSF which further promotes dendritic cell-based antigen presentation (boosts the response) 7
Bria-IMTtradeHuman Proof-of-Concept Trials in Breast Cancer (Patient A002) Bria-IMTtrade Non-Personalized Immunotherapy ndash Given as Monotherapy
Second Proof-of-Concept Phase I (2005) 1 out of 4 patients responded with substantial tumor regression Patient A002 was the only patient with key HLA matches with Bria-IMTtrade
8
Bria-IMTtradeHuman Proof-of-Concept Trials in Breast Cancer (Patient A002) Approximately 3 months (106 days) after last inoculation Patient A002rsquos breast cancer returned and
spread to brain lung and other sites
Patient A002 was then re-treated with 10 inoculations of Bria-IMTtrade over 4 months
Repeat imaging studies showed normal findings on MRI and PET consistent with a completeremission of the previous multiple central nervous system metastases as shown in the brain scansbelow
Bria-IMTtrade and Bria-OTStrade shouldsynergize with existing approvedimmunotherapies as well as those stillunder development
This includes immune checkpointinhibitors such as antibodies to PD-1CTLA-4 GITR and CD73 inhibitors whicheliminate tumor immunosuppression Checkpoint Inhibitors were the
subject of the 2018 Nobel Prize inMedicine
In addition immunostimulatoryantibodies to molecules such as OX40should enhance responses to Bria-IMTtradeand Bria-OTStrade
13
Q3 2018 Data on first 20 Patients on Bria-IMTtrade Q3 2018 Initiate Combination Study of Bria-IMTtrade with Keytruda or Yervoy
Q4 2018 Switch to a novel frozen Bria-IMTtrade formulation Q4 2018 Safety Data (6 patients) of the Bria-IMTtrade - Keytrudareg Combination Study (SABC meeting) Q4 2018 Ongoing Corporate PartnershipCollaboration Discussions
Q1 2019 Efficacy Data (6 patients) of the Bria-IMTtrade - Keytrudareg Combination Study Q2 2019 Initiation of Bria-OTStrade GMP manufacturing (KBI BioPharma) Q2 2019 Additional Safety amp Efficacy data Monotherapy and Combination Studies (AACR meeting) Q2 2019 Final data for Monotherapy and Additional Data for the Combination Study (ASCO meeting) H1 2019 Candidate Selection for a PKCδ Inhibitor H1 2019 Initiate additional immunotherapy program H2 2019 Bria-OTStrade Authorization from FDA clearance for dosing H2 2019 Bria-OTStrade First Patient Dosed
Upcoming Milestones amp Catalysts
14
Involved in over 10 drugs brought to the market
Experienced Management Team
Management
William V Williams MD FACP President amp CEO VP Exploratory Development Incyte Corporation VP Experimental Medicine GlaxoSmithKline Head Rheumatology Research University of Pennsylvania Facilitated entry of over 20 compounds into the clinic including ruxolitinib (Jakafi)
baricitinib amp epacadostat NDAs including Jakafi Boniva Bexxar Author of over 120 peer-reviewed publications amp over 20 patents
Gadi Levin CA MBA CFO CFO of Labstyle Innovations Ltd VP of Finance for two Israeli investment houses in the fields of private equity
hedge funds and real estate Financial Consultant various firms Accountant Arthur Andersen
Markus Lacher PhD Senior Director RampD Founder T cell Therapeutics Inc an immuno-oncology company Sr Clinical Scientist Cesca Therapeutics Inc a clinical-stage autologous cell
therapy company Scientist at BioTime Inc and OncoCyte Corporation Editorial advisory board Recent Patents on Anti-Cancer Drug Discovery
Farrah Dean MSc MBA Manager Corp Development Investor relations CytRx Corporation amp CCG Investor Relations Senior Associate Equity Analyst Oppenheimer amp Co Rodman amp Renshaw amp
Brian Metcalf PhD Recently retired as CSO from Global Blood Therapeutics Former Head of Research amp Development Incyte Corporation Former Head of Medicinal Chemistry SmithKline Beecham
Douglas Faller MD PhD Professor of Medicine Pediatrics Biochemistry Microbiology Pathology and
Laboratory Medicine HematologistOncologist former Director of the Cancer Center Boston University School of Medicine
Founder of several successful biotechnology companies
Robert Williams PhD University Distinguished Professor of Chemistry Colorado State University Founder of several successful biotechnology companies including Microcide Xcyte
Therapies HemaQuest Arch Therapeutics and Cetya Therapeutics
Thomas Kieber-Emmons PhD Deputy Director University of Arkansas Cancer Center Expert in targeted cancer immunotherapies structural biology and computational
chemistry
Maria Trojanowska PhD Professor of Medicine Boston University School of Medicine Director The Arthritis Center
16
Veteran Board of Directors
Board of Directors
Saeid Babaei PhD MBA Chairman Entrepreneur 20 yrs of biotech leadership roles Current CEO AbCelex VP Bus Develop Lorus Therap Dir of Corp Develop Northern Therapeutics
Rahoul Sharan CA Director Chairman Potash Ridge Director of the Board Ansell Capital Corp Parallel Resources amp Galaxy Capital
Corporation
Martin Schmieg CPA Director CFO Sirna Therapeutics Inc amp Isolagen Inc CEO Freedom-2 Inc (now PharmaCyte Inc) Advisor Caladrius Biosciences Inc Beckman Coulter Genomics Calimmune
Charles Wiseman MD Co-Founder amp Director Director Immunotherapy Lab St Vincent Medical Center Chief Breast Cancer Basic Research Lab Univ of Texas MD Anderson Hospital amp
Tumour Institute Assist Prof Dept of Molecular Carcinogenesis amp Virology MD Anderson Acting Chief Div of Oncology White Memorial Medical Center LA
William V Williams MD FACP President amp CEO VP Exploratory Development Incyte Corporation VP Experimental Medicine GlaxoSmithKline Head Rheumatology Research University of Pennsylvania
Prior Affiliations
17
Drug Approvals by BriaCell Management Team
Bexxarreg (tositumomab and Iodine I131 tositumomab) Treatment of CD20 antigen-expressing relapsed or refractory low grade follicular or transformed non-Hodgkins lymphoma
Myleranreg (busulfan) for chronic myelogenous leukemia Defense of formulation change sNDA
Hycamtinreg (topotecan) for ovarian cancer Pediatric use sNDA
Navelbinereg (vinorelbine tartrate) for non-small cell lung cancer Pediatric use sNDA
Bonivareg (ibandronate) monthly oral treatment of osteoporosis
Bonivareg (ibandronate) quarterly intraveous treatment of osteoporosis
Zofranreg (ondansetron) for prevention of nausea and vomiting Pediatric use sNDA
Jakafireg (ruxolitinib) for myelofibrosis Jakafireg (ruxolitinib) for polycythemia vera
Olumiantreg (baricitinib) for rheumatoid arthritis Approved in USA Japan and Europe
18
Share Metrics
BCTV BCTXF 19
Data as of 1092018
Ticker TSX BCTV
US Ticker OTCQBBCTXF
Share Price (CAD) as of Oct 9 2018 $012
52-Week Range (CAD) $009-019
Shares Outstanding as of Oct 9 2018 1611M
Market Cap as of Oct 9 2018 (CAD) $193M
Cash and Short Term Investments as of July 31 2018 (CAD) $23M
Total Shareholders Equity as of July 31 2018 (CAD) $12M
Number of Warrants $014-$035 (CAD) as of Oct 9 2018 601M
Number of Compensation Warrants $014-$030 (CAD) as of Oct 9 2018 45M
Number of Options $014- $026 (CAD$) as of Oct 9 2018 93M
Developing Bria-OTStrade the First Off-the-Shelf Personalized Immunotherapy
Targeting Adv Breast Cancer Unmet medical need (42000 death in the US in 2017 ) $1 Bil- $5 Bil market opportunity depending on patient treatment stage
Impressive results in 2 proof-of-concept clinical trials Rapid Response Rate Repeated following re-treatment Excellent Safety Profile
Completed enrollment in Phase IIIa clinical trial of Bria-IMTtrade with outstanding safety amp efficacy data Initiated Phase IIa Combination Study of Bria-IMTtrade with Keytrudareg (Merck amp Co Inc)
Developing Bria-OTStrade along with BriaDXtrade its companion diagnostic test Ability to match and treat ~90 of patient population with Off-the-Shelf personalized immunotherapy
Experienced Management has been involved in over 10 drug approvals
Patient B001 Breast 70 No 1101 - 3501 4001 Negative -
Bria-IMTtradeHuman Proof-of-Concept Trials in Breast Cancer (Patient A002)
24
Proof-of-Concept Results Resulted in BriaCellrsquos Immunotherapy Strategy Use BriaDXtrade diagnostic to select only those patients matching Bria-IMTtrade Use BriaDXtrade diagnostic test to select Bria-OTStrade alleles matching ~90 of all patients
Bria-IMTtradeCurrent Phase IIIa Data Supports HLA Matching Hypothesis Six patients treated in 2017 Bria-IMTtrade was safe and well tolerated
Patient 01-002 73-year-old woman with breast cancer diagnosed in 1995 Developed liver metastases in2010 and lung metastases in 2017 Previously treated with 7 rounds of chemotherapy with 8 differentchemotherapy agents Received 5 cycles of Bria-IMTtrade over 3 months then monthly cycles (6 months total)Evaluated after 3 months and 6 months After 3 months despite the extensive prior therapy her scans notedthat ldquothere has been a clear response in the multiple bilateral pulmonary nodulesrdquo The response wasmaintained after 6 months of Bria-IMTtrade treatment She matches Bria-IMTtrade at 2 HLA alleles
The liver tumors were stable to slightly increased at 3 months and then progressed after 6 months
This supports our hypothesis of heightened anti-tumor activity in patients with a matched HLA types Clear path to develop BriaDXtrade to select the patients using HLA testing
1 RLL 29 Not Detectable Not Detectable2 LUL apical pleural based 34 tiny nodule lt 1mm scar tiny nodule lt 1mm scar3 xxx 39 Not Detectable Not Detectable4 40 Not Detectable Not Detectable5 RLL 45 Not Detectable Not Detectable6 LLL 49 Not Detectable Not Detectable7 xxx 52 Not Detectable Not Detectable8 RLL 52 Not Detectable Not Detectable9 RLL 56 Not Detectable Not Detectable
10 RLL costophrenic recess 56 Not Detectable Not Detectable11 XXX 58 Not Detectable Not Detectable12 LUL 60 Not Detectable Not Detectable13 XXX 67 15 1514 RUL 72 15 1515 LLL 76 Not Detectable Not Detectable16 RUL Noncalcified Nodule 77 Not Detectable Not Detectable17 RLL costophrenic recess 79 10 1018 RUL 82 Not Detectable Not Detectable19 RLL 90 Not Detectable Not Detectable20 RLL 91 lt 01 lt 0121 xxx xxx Not Detectable Not Detectable
27
Clinical Development Update ndash Summary 2018 September 26
Completed enrollment of Adv Breast cancer patients in the Phase IIIa ldquomonotherapyrdquo study of Bria-IMTtrade
We have confirmed our mechanism of action and achieved proof of concept
Initial safety data appears superior to that of the other advanced or approved drugs for breast cancer when they were at a similar clinical stage of development
Initial efficacy data is similar or superior to those of other advanced or approved drugs for breast cancer when they were at a similar clinical stage of development
Initiated Combination Study of Bria-IMTtrade with Keytrudareg or Yervoyreg in Adv breast cancer patients expecting even better response rates than those in the ldquomonotherapyrdquo study Initial safety data is expected in 4Q2018 Initial efficacy data is expected in 1Q2019
Bria-OTStrade the first off-the-shelf personalized treatment for advanced breast cancer is expected to enter the clinic in 2019
28
Bria-IMTtrade Excellent Safety Data - To Date
To date Bria-IMTtrade has been dosed in 24 patients (4 in 2004-2005 20 in 2017-2018)
Interim Data (20 patients)-Ongoing Phase IIIa Study (2017-2018)
Bria-IMTtrade has been very well tolerated (ge60 doses given to date) The majority of adverse events (AEs) were limited to expected minor local irritation at the
injection sites No related grade gt3 or unexpected AEs No related serious AEs No serious unexpected related AEs Most patients who have dropped out did so due to worsening of their underlying disease
Based on the current study Bria-IMTtrade has an excellent safety profile
29
Bria-IMTtrade - Efficacy as Predicted
Interim Data (19 patients)-Ongoing Phase IIIa Study (2017-2018) amp Original Study (2004-2005)
PD-L1 expression on circulating cancer cells amp cancer-associated cells in 100 of patients (to date) Strong rationale for combination with checkpoint inhibitors like Keytruda
30
Bria-IMTtrade appears to be most effective in patients who match with Bria-IMT trade at 2 HLA loci (types) further supporting our ldquoHLA Matching Hypothesisrdquo and the development of Bria-OTS trade to cover 90 of the patient population
Combination with immune checkpoint inhibitors may induce a more potent anti-cancer response leading to our strategy of combination studies of Bria-IMT trade with Keytruda or Yervoy
Patients (n) HLA Match
Tumor Shrinkage
Biological Response
4 ge2 50 7515 ge1 27 334 0 0 0
Biological response includes tumor shrinkage or lower circulating cancer associated cells
The confirmatory Bria-IMTtrade monotherapy Phase IIa trial has completed enrollment Additional Support for the HLA-matching hypothesis has been obtained
Bria-IMTtrade Combination Therapy study with immune checkpoint inhibitors Keytrudareg if PD-L12 positive (ge1) Yervoyreg if PD-L12 negative (lt1) Accepting patients from the monotherapy study who develop progressive disease Also enrolling patients directly into this study to enhance experience with the combination In discussion with other pharmaceutical companies to evaluate additional combinations with other
immunotherapies
Bria-OTStrade Off-the-Shelf Personalized Targeted Immunotherapy Developing Bria-OTStrade to co-express GM-CSF and interferon-α Pre-manufacture additional HLA alleles ndash Total of 15 alleles (8 Class I and 7 Class II) Co-development of BriaDXtrade companion diagnostic for HLA typing Combination therapy clinical trial with immune checkpoint inhibitors for non-responders using
information from the Bria-IMTtrade Combination Therapy Study
33
Development Timeline ndash Breast Cancer
20192018 2020 2021
Phase IIIaBria-IMTtrade
Monotherapy
Currently Enrolling Phase IIaBria-IMTtrade + Checkpoint
Currently in discussions with potential partnersPhase II Bria-IMTtrade plus Additional Combinations (1Q19 4Q22)(eg PD-1 Inhibitor PD-L1 inhibitor anti-CTLA4 anti-GITR anti-OX40)
1Q 2Q 3Q 4Q
2023
Bria-OTStrade Off-The-Shelf Personalized ImmunotherapyMonotherapy and Potential Partnered Combo Therapy
(2H19 Ongoing)
Bria-OTStradeOff-the-Shelf Cell Line cGMP Manufacturing
and BriaDXtrade(1Q18 1Q19)
Registration Studies (1Q20 2H22)Bria-IMTtrade with Checkpoint InhibitorsBria-OTStrade +- Checkpoint Inhibitors
34
Immuno-oncology Deals
Recent deals of small biotechs with big pharma in immuno-oncology
35
Date PartnershipDevelopment stage at the time of the deal Deal size
07122018 Immatics-Genmab Preclinical Up to $28B
04042018 OSE Immunotherapeutics-Boehringer Ingelheim Preclinical Up to euro113B ($139B)
02092018 Pieris Pharmaceuticals-Seattle Genetics Preclinical Up to $123B
2142018 Nektar-BMS Ph III Up to $36B
01222018 Juno-Celgene Ph II $9B (Acquisition)
11142017 Loxo-Bayer Larotrectinib (Ph II) LOXO-195 (Ph III) Up to $155B
1032017 CytomX-Amgen Preclinical Up to $15B
03202017 CytomX--BMS Ph III Up to $36B
6282016 Xencor-Novartis Preclinical Up to $24B
Early Stage Clinical Studies (Comparison)
We compared the interim data of Ph IIIa study of Bria-IMTtrade in advanced breast cancer with thedata in the early stage clinical studies of recently approved breast cancer drugs and one fasttracked product candidate
Apples to apples comparison Early Stage Clinical Studies in oncology are typically done in patientswith no other therapeutic options Thus the patients have very advanced disease and response ratesare typically quite low
The patients in our Ph IIIa study have been heavily pre-treated (median 45 prior regimens)Some recent studies of relevance in breast cancer are noted in the following slides
36
Breast Cancer Market Opportunity
Drug Technology Approved for Market (US)Ibrance (palbociclib) CDK 46 Inhibitor HR+HER2- MBC in combination with
fluvestrant or aromatase inhibitor$933M in 1Q2018 $3126M in 2017
Kisqali (ribociclib) CDK 46 Inhibitor 2017 HR+HER2- MBC in combination with fluvestrant or aromatase inhibitor
Peak sales projected at $25B
Verzenio (abemaciclib) CDK 46 Inhibitor 2017 HR+HER2- MBC in combination with fluvestrant or aromatase inhibitor
balixafortide CXCR4 antagonist Fast track designation in 2018 for HER2- MBC who have failed 2 prior regimens
The market for breast cancer drugs is a multibillion dollar market with new drugs being approvedon an ongoing basis indicating the shortage of safe and effective treatments for this deadly disease
37
Competitors- Phase III Clinical Data Bria-IMTtrade shows superior safety and similar to superior efficacy data compared with those of the multi-billion dollar drugs when they were at a similar early stage of clinical development
Injection site reactions No related SAEs or SUSARs
Tumor vol darr ampor darr circul tumor cellsAll Comers 21(419) 26(519)One or More HLA matches 27(415) 33(515)Two or More HLA matches 50 (24) 75 (34)
Sheet1 (3)
Comp -Slides
Data
HLA (2)
HLA
Data (Ph1-2+4Pt)
Competitors (2018)-Slide
Competitors (2018)
In the Pipeline Protein Kinase C delta (PKCδ) Inhibitors
30 of all human malignancies display activating RAS mutations Another 60 showing over-activity of Ras-signaling pathways
Ras has been termed ldquoundruggablerdquo (no one has been able to make a Ras inhibitor drug)
BriaCellrsquos novel proprietary PKCδ inhibitors have shown activity against multiple RAS transformed tumors Lung cancer Melanoma Breast cancer Neuroendocrine cancer Pancreatic cancer Colorectal cancer
This target has an attractive safety profile based on in vivo studies and knock out mouse studies
PKCδ inhibitors should qualify for an accelerated clinical development plan and regulatory pathway
Could be in clinic within 24 months
Cost-Effective Additional Shot-on-Goal and additional partnership opportunities
Early-Stage Preclinical Program
39
Protein Kinase C delta (PKCδ) Inhibitors
Activated PKCδ inhibits RAS degradation which in turn stimulates tumor growth
Koo et al Oncotarget 621328 2016
30 of all human malignancies display activating RASmutations with another 60 showing over-activity of Ras-signaling pathways
BriaCellrsquos novel proprietary PKCδ inhibitors have shownactivity against multiple RAS transformed tumors
This target has an attractive safety profile based on in vivostudies and knock out mouse studies
PKCδ also has potential activity as an immunotherapeuticby blocking TGFβ signaling
PKCδ inhibitors are applicable to specific niche tumor typeswhich provide an accelerated clinical development plan
Structural aspects of first generation inhibitor rottlerin and staurosporine (pan-PKC activator) were combined to create second generation inhibitor KAM1
Third generation inhibitors such as BJE6-106 have improved potency and selectivity Fourth generation inhibitors under development to optimize drug-like characteristics PKCδ inhibitors lack endothelial cell cytotoxicity amp PKCδ deficient mice develop normally and are fertile Potentially no marked intrinsic toxicity by inhibiting PKCδ
Mukai H Saeki T Shimada K Naito Y Matsubara N Nakanishi T Obaishi H Namiki M Sasaki Y Phase 1 combination study of eribulin mesylate with trastuzumab for advanced or recurrent human epidermal growth factor receptor 2 positive breast cancer Invest New Drugs 2015 Feb33(1)119-27
AstraZeneca
Lynparza (Olaparib) + Cediranib
PARP inhibitor + inhibitor of VEGF receptor tyrosine kinases
HR+ HER2- MBC
BC amp OC
2013
28 (8 BC)
3 for BC
Olaparib (a poly (ADP-ribose) polymerase (PARP) inhibitor) amp Cediranib (Vascular endothelial growth factor receptor (VEGFR) 1 2 and 3 tyrosine kinase inhibitor)3 at dose level (DL) 0 (cediranib 20mg olaparib 100mg) 3 at DL1 (cediranib 20mg olaparib 200mg) 7 at DL2 (cediranib 30mg olaparib 200mg) 6 at DL3 (cediranib 30mg olaparib 400mg)
Liu JF Tolaney SM Birrer M Fleming GF Buss MK Dahlberg SE Lee H Whalen C Tyburski K Winer E Ivy P Matulonis UA A Phase 1 trial of the poly(ADP-ribose) polymerase inhibitor olaparib (AZD2281) in combination with the anti-angiogenic cediranib (AZD2171) in recurrent epithelial ovarian or triple-negative breast cancer Eur J Cancer 2013 Sep49(14)2972-8
Reyon Pharmaceutical
VM206RY
Heterologous prime-boost with a truncated HER2 sequence
HER2+ Stage IIIampIV BC
2015
9
2 chemo
Plasmid DNA (pHM-GM-CSF expressing truncated HER2 amp GM-CSF) amp adenoviral vector (Ad-HM containing modified HER2) (2 4 and 8 mgpatientvisit) of pHM-GM-CSF 3x IM weeks 0 2 and 4 Ad-HM 3 times 109 virus particles at week 6
11 PR
4 pts showed 7 minor AEs
Unclear
Kim SB Ahn JH Kim J Jung KH A phase 1 study of a heterologous prime-boost vaccination involving a truncated HER2 sequence in patients with HER2-expressing breast cancer Mol Ther Methods Clin Dev 2015 Sep 30215031 doi 101038mtm201531 eCollection 2015
Rodon J Peacuterez-Fidalgo A Krop IE Burris H Guerrero-Zotano A Britten CD Becerra C Schellens J Richards DA Schuler M Abu-Khalaf M Johnson FM Ranson M Edenfield J Silva AP Hackl W Quadt C Demanse D Duval V Baselga J Phase 11b dose escalation and expansion study of BEZ235 a dual PI3KmTOR inhibitor in patients with advanced solid tumors including patients with advanced breast cancer Cancer Chemother Pharmacol 2018 Jun 7 doi 101007s00280-018-3610-z [Epub ahead of print]
Celgene (Abraxane)
Gemcitabine + Abraxane (nab-paclitaxel)
Chemo + Chemo
OC BC NSCLC amp Panc cancer + Lung OC BC Kaposi sarcoma
MBC
2016
9
Adjuvant chemo (100)chemo post-adjuvant (33)
Gem (nucleoside metabolic inhibitor 1250 mgm2) on days 1 and 8 nab-Pac (microtubule inhibitor) starting dose of 180 mgm2 (cohort 1) 220 mgm2 (cohort 2) and 260 mgm2 (cohort 3) on day 1 of the 21-day cycle using a 3 + 3 design
0
MTD not reached29 Gr3 Neutropenia59 Gr1 Peripheralneuropathy
Yoshitomi S Taira N Doihara H Mizoo T Nogami T Iwamoto T Motoki T Shien T Ogasawara Y Matsuoka J Tsuji H Mitsuhashi T A phase 1 dose-finding and pharmacokinetic study of gemcitabine with nab-paclitaxel in patients with metastatic breast cancer Cancer Chemother Pharmacol 2016 Aug78(2)289-94
Eli Lilly
Erbituxreg (cetuximab) + Taxane
EGFR inhibitor antineoplastic agent + Chemo
Headamp Neck Colorectal Cancer
TNBC
2007-2010
18
1 chemo
Cetuximab (epidermal growth factor receptor (EGFR) antagonist ) an initial loading dose of cetuximab 400 mgm2 followed by a weekly dose of 250 mgm2Paclitaxel (microtubule inhibitor) 80 mgm2 or Docetaxel at an initial dose of 30 mgm2 was administered weekly
56 CR 22 PR
83 Dermatologic toxicity11 Grade3+
Nechushtan H Vainer G Stainberg H Salmon AY Hamburger T Peretz T A phase 12 of a combination of cetuximab and taxane for triple negative breast cancer patients Breast 2014 Aug23(4)435-8
Polyphor
Balixafortide (POL6326) + eribulin
CXCR4 antagonist + tubulin-based antimitotic
Heavily pretreated Relapsed MBC
2014-2016
56
3rd line 3 chemo
3+3 dose escalation The highest dose was established as eribulin 14 mgmsup2 on days 2 and 9 and balixafortide 55 mgkg on days 1minus3 and 8minus10 of the 21-day cycle
30 PR
41 Gr34 Neutropenia11 Gr34 Leucopenia11 Gr34 Febrileneutropenia2 Related mortalities
Apr 2018 Fast Track for HER2-MBC who have failed 2prior regimens
Pernas S Martin M Kaufman PA Gil-Martin M Gomez Pardo P Lopez-Tarruella S Manso L Ciruelos E Perez-Fidalgo JA Hernando C Ademuyiwa FO Weilbaecher K Mayer I Pluard TJ Martinez Garcia M Vahdat L Perez-Garcia J Wach A Barker D Fung S Romagnoli B Cortes J Balixafortide plus eribulin in HER2-negative metastatic breast cancer a phase 1 single-arm dose-escalation trial Lancet Oncol 2018 Jun19(6)812-824
11 PRndashbut only + letrozole (No Resp on monotherapy)
61 Gr34 Neutropenia39 Gr34 Leucopenia
$933M in 1Q2018 $31B in 2017
Tamura K Mukai H Naito Y Yonemori K Kodaira M Tanabe Y Yamamoto N Osera S Sasaki M Mori Y Hashigaki S Nagasawa T Umeyama Y Yoshino T Phase I study of palbociclib a cyclin-dependent kinase 46 inhibitor in Japanese patients Cancer Sci 2016 Jun107(6)755-63 doi 101111cas12932 Epub 2016 May 11
Pfizer
Ibrancereg (palbociclib)
CDK 46 Inhibitor
HR+ HER2- MBC
Heavily pretreated Relapsed Metastatic Cancer
2004-2008
41 (5 BC)
chemo naiumlve (17) 1-2 (51)3 (29) 3+ (2)
Palbociclib 25-150 mg dose ranging
0
20 Gr34 Neutropenia23 Gr34 Leucopenia
$933M in 1Q2018 $31B in 2017
Flaherty KT Lorusso PM Demichele A Abramson VG Courtney R Randolph SS Shaik MN Wilner KD ODwyer PJ Schwartz GK Phase I dose-escalation trial of the oral cyclin-dependent kinase 46 inhibitor PD 0332991 administered using a 21-day schedule in patients with advanced cancer Clin Cancer Res 2012 Jan 1518(2)568-76 doi 1011581078-0432CCR-11-0509 Epub 2011 Nov 16
Novartis
Kisqalireg (ribociclib)
CDK 46 Inhibitors
Premenopausal HR+ HER2- MBC
Heavily pretreated Relapsed Metastatic Cancer
2016
132 (20 BC)
0-1 (25) 2-3 (42) 4+ (32)
Ribociclib 50 mg ranging up to 1200 mg dose escalation
23 PRndashincluded 1 in BC (5 of BC pts)
27 Gr34 Neutropenia17 Gr34 Leucopenia
Peak sales projected at $25B
Infante JR Cassier PA Gerecitano JF Witteveen PO Chugh R Ribrag V Chakraborty A Matano A Dobson JR Crystal AS Parasuraman S Shapiro GI A Phase I Study of the Cyclin-Dependent Kinase 46 Inhibitor Ribociclib (LEE011) in Patients with Advanced Solid Tumors and Lymphomas Clin Cancer Res 2016 Dec 122(23)5696-5705 Epub 2016 Aug 19
Eli Lilly
Verzenioreg (abemaciclib)
CDK 46 Inhibitors
HR+HER2minusMBC
Heavily pretreated Relapsed Metastatic Cancer
2016
12 (1 BC)
1 (312) 2 (212) 3+ (7)
Abemaciclib 100 mg ranging up to 200 mg dose escalation
17 PR (included 1 in BC)
17 Gr34 Neutropenia33 Gr34 Leucopenia
Peak sales projected at $2B
Fujiwara Y Tamura K Kondo S Tanabe Y Iwasa S Shimomura A Kitano S Ogasawara K Turner PK Mori J Asou H Chan EM Yamamoto N Phase 1 study of abemaciclib an inhibitor of CDK 4 and 6 as a single agent for Japanese patients with advanced cancer Cancer Chemother Pharmacol 2016 Aug78(2)281-8 doi 101007s00280-016-3085-8 Epub 2016 Jun 16
Mukai H Saeki T Shimada K Naito Y Matsubara N Nakanishi T Obaishi H Namiki M Sasaki Y Phase 1 combination study of eribulin mesylate with trastuzumab for advanced or recurrent human epidermal growth factor receptor 2 positive breast cancer Invest New Drugs 2015 Feb33(1)119-27
AstraZeneca
Lynparza (Olaparib)+ Cediranib
PARP inhibitor+ inhibitor of VEGF RTK
HR+ HER2- MBC
BC amp OC
13
28 (8 BC)
3 for BC
Olaparib (a poly (ADP-ribose) polymerase (PARP) inhibitor) amp Cediranib (Vascular endothelial growth factor receptor (VEGFR) 1 2 and 3 tyrosine kinase inhibitor)3 at dose level (DL) 0 (cediranib 20mg olaparib 100mg) 3 at DL1 (cediranib 20mg olaparib 200mg) 7 at DL2 (cediranib 30mg olaparib 200mg) 6 at DL3 (cediranib 30mg olaparib 400mg)
Liu JF Tolaney SM Birrer M Fleming GF Buss MK Dahlberg SE Lee H Whalen C Tyburski K Winer E Ivy P Matulonis UA A Phase 1 trial of the poly(ADP-ribose) polymerase inhibitor olaparib (AZD2281) in combination with the anti-angiogenic cediranib (AZD2171) in recurrent epithelial ovarian or triple-negative breast cancer Eur J Cancer 2013 Sep49(14)2972-8
ReyonPharma
VM206RY
Heterologous prime-boost with a truncated HER2 sequence
HER2+ Stg IIIampIV BC
15
9
2 chemo
Plasmid DNA (pHM-GM-CSF expressing truncated HER2 amp GM-CSF) amp adenoviral vector (Ad-HM containing modified HER2) (2 4 and 8 mgpatientvisit) of pHM-GM-CSF 3x IM weeks 0 2 and 4 Ad-HM 3 times 109 virus particles at week 6
11 PR
4 pts 7 minor AEs
Unclear
Kim SB Ahn JH Kim J Jung KH A phase 1 study of a heterologous prime-boost vaccination involving a truncated HER2 sequence in patients with HER2-expressing breast cancer Mol Ther Methods Clin Dev 2015 Sep 30215031 doi 101038mtm201531 eCollection 2015
Rodon J Peacuterez-Fidalgo A Krop IE Burris H Guerrero-Zotano A Britten CD Becerra C Schellens J Richards DA Schuler M Abu-Khalaf M Johnson FM Ranson M Edenfield J Silva AP Hackl W Quadt C Demanse D Duval V Baselga J Phase 11b dose escalation and expansion study of BEZ235 a dual PI3KmTOR inhibitor in patients with advanced solid tumors including patients with advanced breast cancer Cancer Chemother Pharmacol 2018 Jun 7 doi 101007s00280-018-3610-z [Epub ahead of print]
Celgene(Abraxane)
Gemcitabine + Abraxane (nab-paclitaxel)
Chemo+ Chemo
OC BC NSCLC PC + LC OC BC KS
MBC
16
9
Adjuv chemo (100)chemo post-adjuv (33)
Gem (nucleoside metabolic inhibitor 1250 mgm2) on days 1 and 8 nab-Pac (microtubule inhibitor) starting dose of 180 mgm2 (cohort 1) 220 mgm2 (cohort 2) and 260 mgm2 (cohort 3) on day 1 of the 21-day cycle using a 3 + 3 design
0
MTD not reached29 Gr3 Neutropenia59 Gr1 Peripheralneuropathy
Yoshitomi S Taira N Doihara H Mizoo T Nogami T Iwamoto T Motoki T Shien T Ogasawara Y Matsuoka J Tsuji H Mitsuhashi T A phase 1 dose-finding and pharmacokinetic study of gemcitabine with nab-paclitaxel in patients with metastatic breast cancer Cancer Chemother Pharmacol 2016 Aug78(2)289-94
Eli Lilly
Erbituxreg (cetuximab) + Taxane
EGFR inhibitor antineoplastic agent + Chemo
Head amp NeckColorectal
TNBC
07-10
18
1 chemo
Cetuximab (epidermal growth factor receptor (EGFR) antagonist ) an initial loading dose of cetuximab 400 mgm2 followed by a weekly dose of 250 mgm2Paclitaxel (microtubule inhibitor) 80 mgm2 or Docetaxel at an initial dose of 30 mgm2 was administered weekly
56 CR 22 PR
83 Dermatologic toxicity11 Grade3+
Nechushtan H Vainer G Stainberg H Salmon AY Hamburger T Peretz T A phase 12 of a combination of cetuximab and taxane for triple negative breast cancer patients Breast 2014 Aug23(4)435-8
Polyphor
Balixafortide (POL6326) + eribulin
CXCR4 antagonist + tubulin-based antimitotic
Heavily pretreatedRelapsed MBC
14-16
56
3rd line 3 chemo
3+3 dose escalation The highest dose was established as eribulin 14 mgmsup2 on days 2 and 9 and balixafortide 55 mgkg on days 1minus3 and 8minus10 of the 21-day cycle
30 PR
41 Gr34 Neutropenia11 Gr34 Leucopenia11 Gr34 Febrileneutropenia2 Related mortalities
42018 Fast Track (HER2-MBC failed 2 prior regimens)
Pernas S Martin M Kaufman PA Gil-Martin M Gomez Pardo P Lopez-Tarruella S Manso L Ciruelos E Perez-Fidalgo JA Hernando C Ademuyiwa FO Weilbaecher K Mayer I Pluard TJ Martinez Garcia M Vahdat L Perez-Garcia J Wach A Barker D Fung S Romagnoli B Cortes J Balixafortide plus eribulin in HER2-negative metastatic breast cancer a phase 1 single-arm dose-escalation trial Lancet Oncol 2018 Jun19(6)812-824
1 PRndashbut only + letrozoleNo Resp on monotherapy
61 Gr34 Neutropenia39 Gr34 Leucopenia
$933M (1Q18)$31B (2017)
Tamura K Mukai H Naito Y Yonemori K Kodaira M Tanabe Y Yamamoto N Osera S Sasaki M Mori Y Hashigaki S Nagasawa T Umeyama Y Yoshino T Phase I study of palbociclib a cyclin-dependent kinase 46 inhibitor in Japanese patients Cancer Sci 2016 Jun107(6)755-63 doi 101111cas12932 Epub 2016 May 11
Pfizer
Ibrancereg (palbociclib)
CDK 46 Inhibitor
HR+ HER2- MBC
Heavily pretreatedRelapsed Met Cancer
04-08
41 (5 BC)
chemo naiumlve (17)1-2(51) 3(29) 3+(2)
Palbociclib 25-150 mg dose ranging
0
20 Gr34 Neutropenia23 Gr34 Leucopenia
$933M (1Q18)$31B (2017)
Flaherty KT Lorusso PM Demichele A Abramson VG Courtney R Randolph SS Shaik MN Wilner KD ODwyer PJ Schwartz GK Phase I dose-escalation trial of the oral cyclin-dependent kinase 46 inhibitor PD 0332991 administered using a 21-day schedule in patients with advanced cancer Clin Cancer Res 2012 Jan 1518(2)568-76 doi 1011581078-0432CCR-11-0509 Epub 2011 Nov 16
Novartis
Kisqalireg (ribociclib)
CDK 46 Inhibitor
Premenopausal HR+ HER2- MBC
Heavily pretreatedRelapsed Met Cancer
16
132 (20 BC)
0-1 (25) 2-3 (42)4+ (32)
Ribociclib 50 mg ranging up to 1200 mg dose escalation
23 PR-included 1 BC (5 of BC pts)
27 Gr34 Neutropenia17 Gr34 Leucopenia
Peak sales est at $25B
Infante JR Cassier PA Gerecitano JF Witteveen PO Chugh R Ribrag V Chakraborty A Matano A Dobson JR Crystal AS Parasuraman S Shapiro GI A Phase I Study of the Cyclin-Dependent Kinase 46 Inhibitor Ribociclib (LEE011) in Patients with Advanced Solid Tumors and Lymphomas Clin Cancer Res 2016 Dec 122(23)5696-5705 Epub 2016 Aug 19
Eli Lilly
Verzenioreg (abemaciclib)
CDK 46 Inhibitor
HR+HER2minusMBC
Heavily pretreatedRelapsed Met Cancer
16
12 (1 BC)
1 (312) 2 (212) 3+(7)
Abemaciclib 100 mg ranging up to 200 mg dose escalation
17 PR (included 1 BC)
17 Gr34 Neutropenia33 Gr34 Leucopenia
Peak sales est at $2B
Fujiwara Y Tamura K Kondo S Tanabe Y Iwasa S Shimomura A Kitano S Ogasawara K Turner PK Mori J Asou H Chan EM Yamamoto N Phase 1 study of abemaciclib an inhibitor of CDK 4 and 6 as a single agent for Japanese patients with advanced cancer Cancer Chemother Pharmacol 2016 Aug78(2)281-8 doi 101007s00280-016-3085-8 Epub 2016 Jun 16
Mukai H Saeki T Shimada K Naito Y Matsubara N Nakanishi T Obaishi H Namiki M Sasaki Y Phase 1 combination study of eribulin mesylate with trastuzumab for advanced or recurrent human epidermal growth factor receptor 2 positive breast cancer Invest New Drugs 2015 Feb33(1)119-27
AstraZeneca
Lynparza (Olaparib) + Cediranib
PARP inhibitor + inhibitor of VEGF receptor tyrosine kinases
HR+ HER2- MBC
BC amp OC
2013
28 (8 BC)
3 for BC
Olaparib (a poly (ADP-ribose) polymerase (PARP) inhibitor) amp Cediranib (Vascular endothelial growth factor receptor (VEGFR) 1 2 and 3 tyrosine kinase inhibitor)3 at dose level (DL) 0 (cediranib 20mg olaparib 100mg) 3 at DL1 (cediranib 20mg olaparib 200mg) 7 at DL2 (cediranib 30mg olaparib 200mg) 6 at DL3 (cediranib 30mg olaparib 400mg)
Liu JF Tolaney SM Birrer M Fleming GF Buss MK Dahlberg SE Lee H Whalen C Tyburski K Winer E Ivy P Matulonis UA A Phase 1 trial of the poly(ADP-ribose) polymerase inhibitor olaparib (AZD2281) in combination with the anti-angiogenic cediranib (AZD2171) in recurrent epithelial ovarian or triple-negative breast cancer Eur J Cancer 2013 Sep49(14)2972-8
Reyon Pharmaceutical
VM206RY
Heterologous prime-boost with a truncated HER2 sequence
HER2+ Stage IIIampIV BC
2015
9
2 chemo
Plasmid DNA (pHM-GM-CSF expressing truncated HER2 amp GM-CSF) amp adenoviral vector (Ad-HM containing modified HER2) (2 4 and 8 mgpatientvisit) of pHM-GM-CSF 3x IM weeks 0 2 and 4 Ad-HM 3 times 109 virus particles at week 6
11 PR
4 pts showed 7 minor AEs
Unclear
Kim SB Ahn JH Kim J Jung KH A phase 1 study of a heterologous prime-boost vaccination involving a truncated HER2 sequence in patients with HER2-expressing breast cancer Mol Ther Methods Clin Dev 2015 Sep 30215031 doi 101038mtm201531 eCollection 2015
Rodon J Peacuterez-Fidalgo A Krop IE Burris H Guerrero-Zotano A Britten CD Becerra C Schellens J Richards DA Schuler M Abu-Khalaf M Johnson FM Ranson M Edenfield J Silva AP Hackl W Quadt C Demanse D Duval V Baselga J Phase 11b dose escalation and expansion study of BEZ235 a dual PI3KmTOR inhibitor in patients with advanced solid tumors including patients with advanced breast cancer Cancer Chemother Pharmacol 2018 Jun 7 doi 101007s00280-018-3610-z [Epub ahead of print]
Celgene (Abraxane)
Gemcitabine + Abraxane (nab-paclitaxel)
Chemo + Chemo
OC BC NSCLC amp Panc cancer + Lung OC BC Kaposi sarcoma
MBC
2016
9
Adjuvant chemo (100)chemo post-adjuvant (33)
Gem (nucleoside metabolic inhibitor 1250 mgm2) on days 1 and 8 nab-Pac (microtubule inhibitor) starting dose of 180 mgm2 (cohort 1) 220 mgm2 (cohort 2) and 260 mgm2 (cohort 3) on day 1 of the 21-day cycle using a 3 + 3 design
0
MTD not reached29 Gr3 Neutropenia59 Gr1 Peripheralneuropathy
Yoshitomi S Taira N Doihara H Mizoo T Nogami T Iwamoto T Motoki T Shien T Ogasawara Y Matsuoka J Tsuji H Mitsuhashi T A phase 1 dose-finding and pharmacokinetic study of gemcitabine with nab-paclitaxel in patients with metastatic breast cancer Cancer Chemother Pharmacol 2016 Aug78(2)289-94
Eli Lilly
Erbituxreg (cetuximab) + Taxane
EGFR inhibitor antineoplastic agent + Chemo
Headamp Neck Colorectal Cancer
TNBC
2007-2010
18
1 chemo
Cetuximab (epidermal growth factor receptor (EGFR) antagonist ) an initial loading dose of cetuximab 400 mgm2 followed by a weekly dose of 250 mgm2Paclitaxel (microtubule inhibitor) 80 mgm2 or Docetaxel at an initial dose of 30 mgm2 was administered weekly
56 CR 22 PR
83 Dermatologic toxicity11 Grade3+
Nechushtan H Vainer G Stainberg H Salmon AY Hamburger T Peretz T A phase 12 of a combination of cetuximab and taxane for triple negative breast cancer patients Breast 2014 Aug23(4)435-8
Polyphor
Balixafortide (POL6326) + eribulin
CXCR4 antagonist + tubulin-based antimitotic
Heavily pretreated Relapsed MBC
2014-2016
56
3rd line 3 chemo
3+3 dose escalation The highest dose was established as eribulin 14 mgmsup2 on days 2 and 9 and balixafortide 55 mgkg on days 1minus3 and 8minus10 of the 21-day cycle
30 PR
41 Gr34 Neutropenia11 Gr34 Leucopenia11 Gr34 Febrileneutropenia2 Related mortalities
Apr 2018 Fast Track for HER2-MBC who have failed 2prior regimens
Pernas S Martin M Kaufman PA Gil-Martin M Gomez Pardo P Lopez-Tarruella S Manso L Ciruelos E Perez-Fidalgo JA Hernando C Ademuyiwa FO Weilbaecher K Mayer I Pluard TJ Martinez Garcia M Vahdat L Perez-Garcia J Wach A Barker D Fung S Romagnoli B Cortes J Balixafortide plus eribulin in HER2-negative metastatic breast cancer a phase 1 single-arm dose-escalation trial Lancet Oncol 2018 Jun19(6)812-824
11 PRndashbut only + letrozole (No Resp on monotherapy)
61 Gr34 Neutropenia39 Gr34 Leucopenia
$933M in 1Q2018 $31B in 2017
Tamura K Mukai H Naito Y Yonemori K Kodaira M Tanabe Y Yamamoto N Osera S Sasaki M Mori Y Hashigaki S Nagasawa T Umeyama Y Yoshino T Phase I study of palbociclib a cyclin-dependent kinase 46 inhibitor in Japanese patients Cancer Sci 2016 Jun107(6)755-63 doi 101111cas12932 Epub 2016 May 11
Pfizer
Ibrancereg (palbociclib)
CDK 46 Inhibitor
HR+ HER2- MBC
Heavily pretreated Relapsed Metastatic Cancer
2004-2008
41 (5 BC)
chemo naiumlve (17) 1-2 (51)3 (29) 3+ (2)
Palbociclib 25-150 mg dose ranging
0
20 Gr34 Neutropenia23 Gr34 Leucopenia
$933M in 1Q2018 $31B in 2017
Flaherty KT Lorusso PM Demichele A Abramson VG Courtney R Randolph SS Shaik MN Wilner KD ODwyer PJ Schwartz GK Phase I dose-escalation trial of the oral cyclin-dependent kinase 46 inhibitor PD 0332991 administered using a 21-day schedule in patients with advanced cancer Clin Cancer Res 2012 Jan 1518(2)568-76 doi 1011581078-0432CCR-11-0509 Epub 2011 Nov 16
Novartis
Kisqalireg (ribociclib)
CDK 46 Inhibitors
Premenopausal HR+ HER2- MBC
Heavily pretreated Relapsed Metastatic Cancer
2016
132 (20 BC)
0-1 (25) 2-3 (42) 4+ (32)
Ribociclib 50 mg ranging up to 1200 mg dose escalation
23 PRndashincluded 1 in BC (5 of BC pts)
27 Gr34 Neutropenia17 Gr34 Leucopenia
Peak sales projected at $25B
Infante JR Cassier PA Gerecitano JF Witteveen PO Chugh R Ribrag V Chakraborty A Matano A Dobson JR Crystal AS Parasuraman S Shapiro GI A Phase I Study of the Cyclin-Dependent Kinase 46 Inhibitor Ribociclib (LEE011) in Patients with Advanced Solid Tumors and Lymphomas Clin Cancer Res 2016 Dec 122(23)5696-5705 Epub 2016 Aug 19
Eli Lilly
Verzenioreg (abemaciclib)
CDK 46 Inhibitors
HR+HER2minusMBC
Heavily pretreated Relapsed Metastatic Cancer
2016
12 (1 BC)
1 (312) 2 (212) 3+ (7)
Abemaciclib 100 mg ranging up to 200 mg dose escalation
17 PR (included 1 in BC)
17 Gr34 Neutropenia33 Gr34 Leucopenia
Peak sales projected at $2B
Fujiwara Y Tamura K Kondo S Tanabe Y Iwasa S Shimomura A Kitano S Ogasawara K Turner PK Mori J Asou H Chan EM Yamamoto N Phase 1 study of abemaciclib an inhibitor of CDK 4 and 6 as a single agent for Japanese patients with advanced cancer Cancer Chemother Pharmacol 2016 Aug78(2)281-8 doi 101007s00280-016-3085-8 Epub 2016 Jun 16
Mukai H Saeki T Shimada K Naito Y Matsubara N Nakanishi T Obaishi H Namiki M Sasaki Y Phase 1 combination study of eribulin mesylate with trastuzumab for advanced or recurrent human epidermal growth factor receptor 2 positive breast cancer Invest New Drugs 2015 Feb33(1)119-27
AstraZeneca
Lynparza (Olaparib)+ Cediranib
PARP inhibitor+ inhibitor of VEGF RTK
HR+ HER2- MBC
BC amp OC
13
28 (8 BC)
3 for BC
Olaparib (a poly (ADP-ribose) polymerase (PARP) inhibitor) amp Cediranib (Vascular endothelial growth factor receptor (VEGFR) 1 2 and 3 tyrosine kinase inhibitor)3 at dose level (DL) 0 (cediranib 20mg olaparib 100mg) 3 at DL1 (cediranib 20mg olaparib 200mg) 7 at DL2 (cediranib 30mg olaparib 200mg) 6 at DL3 (cediranib 30mg olaparib 400mg)
Liu JF Tolaney SM Birrer M Fleming GF Buss MK Dahlberg SE Lee H Whalen C Tyburski K Winer E Ivy P Matulonis UA A Phase 1 trial of the poly(ADP-ribose) polymerase inhibitor olaparib (AZD2281) in combination with the anti-angiogenic cediranib (AZD2171) in recurrent epithelial ovarian or triple-negative breast cancer Eur J Cancer 2013 Sep49(14)2972-8
ReyonPharma
VM206RY
Heterologous prime-boost with a truncated HER2 sequence
HER2+ Stg IIIampIV BC
15
9
2 chemo
Plasmid DNA (pHM-GM-CSF expressing truncated HER2 amp GM-CSF) amp adenoviral vector (Ad-HM containing modified HER2) (2 4 and 8 mgpatientvisit) of pHM-GM-CSF 3x IM weeks 0 2 and 4 Ad-HM 3 times 109 virus particles at week 6
11 PR
4 pts 7 minor AEs
Unclear
Kim SB Ahn JH Kim J Jung KH A phase 1 study of a heterologous prime-boost vaccination involving a truncated HER2 sequence in patients with HER2-expressing breast cancer Mol Ther Methods Clin Dev 2015 Sep 30215031 doi 101038mtm201531 eCollection 2015
Rodon J Peacuterez-Fidalgo A Krop IE Burris H Guerrero-Zotano A Britten CD Becerra C Schellens J Richards DA Schuler M Abu-Khalaf M Johnson FM Ranson M Edenfield J Silva AP Hackl W Quadt C Demanse D Duval V Baselga J Phase 11b dose escalation and expansion study of BEZ235 a dual PI3KmTOR inhibitor in patients with advanced solid tumors including patients with advanced breast cancer Cancer Chemother Pharmacol 2018 Jun 7 doi 101007s00280-018-3610-z [Epub ahead of print]
Celgene(Abraxane)
Gemcitabine + Abraxane (nab-paclitaxel)
Chemo+ Chemo
OC BC NSCLC PC + LC OC BC KS
MBC
16
9
Adjuv chemo (100)chemo post-adjuv (33)
Gem (nucleoside metabolic inhibitor 1250 mgm2) on days 1 and 8 nab-Pac (microtubule inhibitor) starting dose of 180 mgm2 (cohort 1) 220 mgm2 (cohort 2) and 260 mgm2 (cohort 3) on day 1 of the 21-day cycle using a 3 + 3 design
0
MTD not reached29 Gr3 Neutropenia59 Gr1 Peripheralneuropathy
Yoshitomi S Taira N Doihara H Mizoo T Nogami T Iwamoto T Motoki T Shien T Ogasawara Y Matsuoka J Tsuji H Mitsuhashi T A phase 1 dose-finding and pharmacokinetic study of gemcitabine with nab-paclitaxel in patients with metastatic breast cancer Cancer Chemother Pharmacol 2016 Aug78(2)289-94
Eli Lilly
Erbituxreg (cetuximab) + Taxane
EGFR inhibitor antineoplastic agent + Chemo
Head amp NeckColorectal
TNBC
07-10
18
1 chemo
Cetuximab (epidermal growth factor receptor (EGFR) antagonist ) an initial loading dose of cetuximab 400 mgm2 followed by a weekly dose of 250 mgm2Paclitaxel (microtubule inhibitor) 80 mgm2 or Docetaxel at an initial dose of 30 mgm2 was administered weekly
56 CR 22 PR
83 Dermatologic toxicity11 Grade3+
Nechushtan H Vainer G Stainberg H Salmon AY Hamburger T Peretz T A phase 12 of a combination of cetuximab and taxane for triple negative breast cancer patients Breast 2014 Aug23(4)435-8
Polyphor
Balixafortide (POL6326) + eribulin
CXCR4 antagonist + tubulin-based antimitotic
Heavily pretreatedRelapsed MBC
14-16
56
3rd line 3 chemo
3+3 dose escalation The highest dose was established as eribulin 14 mgmsup2 on days 2 and 9 and balixafortide 55 mgkg on days 1minus3 and 8minus10 of the 21-day cycle
30 PR
41 Gr34 Neutropenia11 Gr34 Leucopenia11 Gr34 Febrileneutropenia2 Related mortalities
42018 Fast Track (HER2-MBC failed 2 prior regimens)
Pernas S Martin M Kaufman PA Gil-Martin M Gomez Pardo P Lopez-Tarruella S Manso L Ciruelos E Perez-Fidalgo JA Hernando C Ademuyiwa FO Weilbaecher K Mayer I Pluard TJ Martinez Garcia M Vahdat L Perez-Garcia J Wach A Barker D Fung S Romagnoli B Cortes J Balixafortide plus eribulin in HER2-negative metastatic breast cancer a phase 1 single-arm dose-escalation trial Lancet Oncol 2018 Jun19(6)812-824
1 PRndashbut only + letrozoleNo Resp on monotherapy
61 Gr34 Neutropenia39 Gr34 Leucopenia
$933M (1Q18)$31B (2017)
Tamura K Mukai H Naito Y Yonemori K Kodaira M Tanabe Y Yamamoto N Osera S Sasaki M Mori Y Hashigaki S Nagasawa T Umeyama Y Yoshino T Phase I study of palbociclib a cyclin-dependent kinase 46 inhibitor in Japanese patients Cancer Sci 2016 Jun107(6)755-63 doi 101111cas12932 Epub 2016 May 11
Pfizer
Ibrancereg (palbociclib)
CDK 46 Inhibitor
HR+ HER2- MBC
Heavily pretreatedRelapsed Met Cancer
04-08
41 (5 BC)
chemo naiumlve (17)1-2(51) 3(29) 3+(2)
Palbociclib 25-150 mg dose ranging
0
20 Gr34 Neutropenia23 Gr34 Leucopenia
$933M (1Q18)$31B (2017)
Flaherty KT Lorusso PM Demichele A Abramson VG Courtney R Randolph SS Shaik MN Wilner KD ODwyer PJ Schwartz GK Phase I dose-escalation trial of the oral cyclin-dependent kinase 46 inhibitor PD 0332991 administered using a 21-day schedule in patients with advanced cancer Clin Cancer Res 2012 Jan 1518(2)568-76 doi 1011581078-0432CCR-11-0509 Epub 2011 Nov 16
Novartis
Kisqalireg (ribociclib)
CDK 46 Inhibitor
Premenopausal HR+ HER2- MBC
Heavily pretreatedRelapsed Met Cancer
16
132 (20 BC)
0-1 (25) 2-3 (42)4+ (32)
Ribociclib 50 mg ranging up to 1200 mg dose escalation
23 PR-included 1 BC (5 of BC pts)
27 Gr34 Neutropenia17 Gr34 Leucopenia
Peak sales est at $25B
Infante JR Cassier PA Gerecitano JF Witteveen PO Chugh R Ribrag V Chakraborty A Matano A Dobson JR Crystal AS Parasuraman S Shapiro GI A Phase I Study of the Cyclin-Dependent Kinase 46 Inhibitor Ribociclib (LEE011) in Patients with Advanced Solid Tumors and Lymphomas Clin Cancer Res 2016 Dec 122(23)5696-5705 Epub 2016 Aug 19
Eli Lilly
Verzenioreg (abemaciclib)
CDK 46 Inhibitor
HR+HER2minusMBC
Heavily pretreatedRelapsed Met Cancer
16
12 (1 BC)
1 (312) 2 (212) 3+(7)
Abemaciclib 100 mg ranging up to 200 mg dose escalation
17 PR (included 1 BC)
17 Gr34 Neutropenia33 Gr34 Leucopenia
Peak sales est at $2B
Fujiwara Y Tamura K Kondo S Tanabe Y Iwasa S Shimomura A Kitano S Ogasawara K Turner PK Mori J Asou H Chan EM Yamamoto N Phase 1 study of abemaciclib an inhibitor of CDK 4 and 6 as a single agent for Japanese patients with advanced cancer Cancer Chemother Pharmacol 2016 Aug78(2)281-8 doi 101007s00280-016-3085-8 Epub 2016 Jun 16
41 Gr34 Neutropenia11 Gr34 Leucopenia11 Gr34 Febrileneutropenia2 Related mortalities
30 PRs in combination with Halaven
Bria-IMTTM
20
Injection site reactions No related SAEs or SUSARs
Tumor vol darr ampor darr circul tumor cells)All Comers 21(419) 26(519)One or More HLA matches 27(415) 33(515)Two or More HLA matches 50 (24) 75 (34))
Drug
Technology
Approved for
Market (US)
Ibrance (palbociclib)
CDK 46 Inhibitor
HR+HER2- MBC in combination with fluvestrant or aromatase inhibitor
$933M in 1Q2018 $3126M in 2017
Kisqali (ribociclib)
CDK 46 Inhibitor
2017 HR+HER2- MBC in combination with fluvestrant or aromatase inhibitor
Peak sales projected at $25B
Verzenio (abemaciclib)
CDK 46 Inhibitor
2017 HR+HER2- MBC in combination with fluvestrant or aromatase inhibitor
Peak sales projected at $2B
Lynparza (olaparib)
Poly (ADP-ribose) polymerase (PARP) inhibitor
2017 ovarian amp breast cancer
$997M in 2017
Halaven (eribulin mesylate)
Tubulin-based antimitotic
2H2017 3rd line MBC amp liposarcoma
$181M in 2017
balixafortide
CXCR4 antagonist
Fast track designation in 2018 for HER2- MBC who have failed 2 prior regimens
Forward-Looking Statements
Except for historical information this presentation contains forward-looking statements which reflect BriaCellrsquoscurrent expectations regarding future events These forward-looking statements involve known and unknownrisks and uncertainties that could cause BriaCellrsquos actual results to differ materially from those statementsThose risks and uncertainties include but are not limited to our ability to access capital the successful andtimely completion of clinical trials the receipt of all regulatory approvals and other risks detailed from time totime in our ongoing quarterly and annual filings The forward-looking statements in this presentation are alsobased on a number of assumptions which may prove to be incorrect
Forward-looking statements contained in this presentation represent views only as of the date of thispresentation and are presented for the purpose of assisting potential investors in understanding BriaCellrsquosbusiness and may not be appropriate for other purposes BriaCell does not undertake to update forward-looking statements whether written or oral that may be made from time to time by or on its behalf except asrequired under applicable securities legislation
Investors are cautioned not to rely on these forward-looking statements and are encouraged to read BriaCellrsquoscontinuous disclosure documents including its financial statements which are available on SEDAR atwwwsedarcom
2
Cancer Immunotherapy Space
The Problems
Checkpoint Inhibitors Keytrudareg (anti-PD-1) Yervoyreg (anti-CTLA-4) and others reduce the tumorrsquos ability tosuppress immune system They only work in 20-30 of patients as they depend on a patientrsquos own weakenedimmune system to kill the tumor and can cause autoimmune disease
Therapeutic Cancer Vaccines Have not been successful in solid tumors or blood cancers as they are not specificenough to the patient
Personalized Immunotherapies Provengereg is effective for prostate cancer but must be individually manufactured for each patient and as a
result of the required manufacturing logistics has not been commercially successful CAR-T therapies are effective in blood cancers (but not in solid tumors) and must also be individually
manufactured in a complex process for each patient (launching in 2018)
BriaCellrsquos Solution
BriaCellrsquos Off-the-Shelf Personalized Immunotherapy BriaCell has been developing Bria-IMTtrade which is a targetedimmunotherapy for breast cancer Several remarkable responses in patients with late stage cancer have been seenin patients who match Bria-IMTtrade at certain HLA types This supports the development of Bria-OTStrade and BriaDXtradeBriaCellrsquos 15 HLA types (8 Class I amp 7 Class II) covermatch ~90 of the population This saves time and eliminatesthe complex manufacturing process associated with other personalized immunotherapies
3
These allele combinations covermatch with ~90 of the advanced breast cancer population
1 BriaDXtrade reveals the patientrsquos Class I andClass II HLA Alleles
2 The pre-manufactured Bria-OTStrade HLAAlleles are selected for the specificpatient
3 The selected Bria-OTStrade cell lines arethen shipped to the clinical site forpatient treatment
Pre-Manufactured Off-the-Shelf HLA Class II Alleles
Pre-Manufactured Off-the-Shelf HLA Class I Alleles
Bria-IMTtrade - First Product CandidateHuman Proof-of-Concept Trials in Advanced Breast Cancer
Bria-IMTtrade Non-Personalized Immunotherapy
First Proof-of-Concept Phase I (1999-2003) Used unmodified cell line + GM-CSF + cyclophosphamide N = 14 late stage treatment-refractory breast cancer patients Well tolerated no severe drug related AEs Median Overall Survival = 121 months
Second Proof-of-Concept Phase I (2005) Used GM-CSF-engineered cell line + cyclophosphamide + interferon-α N = 4 late stage treatment-refractory (3 breast cancer and 1 ovarian cancer) patients Well tolerated no life-threatening drug related adverse events One patient with transient urticaria reported as grade 3 responded to antihistamines Median Overall Survival = 35 months One robust responder with gt90 regression during treatment subsequent relapse (upon halting
treatment) responded to re-treatment
6
Bria-IMTtrade amp Bria-OTStradePotential Mechanisms of Action in Advanced Breast Cancer
Bria-IMTTM directly stimulates cancerfighting CD4+ and CD8+ T cells(further boosts the response)
Bria-IMTTM produces breastcancer antigens which aretaken up by dendritic cellsand ldquopresentedrdquo to CD4+and CD8+ T cells implicatedin tumor destruction
Bria-IMTTM secretes GM-CSF which further promotes dendritic cell-based antigen presentation (boosts the response) 7
Bria-IMTtradeHuman Proof-of-Concept Trials in Breast Cancer (Patient A002) Bria-IMTtrade Non-Personalized Immunotherapy ndash Given as Monotherapy
Second Proof-of-Concept Phase I (2005) 1 out of 4 patients responded with substantial tumor regression Patient A002 was the only patient with key HLA matches with Bria-IMTtrade
8
Bria-IMTtradeHuman Proof-of-Concept Trials in Breast Cancer (Patient A002) Approximately 3 months (106 days) after last inoculation Patient A002rsquos breast cancer returned and
spread to brain lung and other sites
Patient A002 was then re-treated with 10 inoculations of Bria-IMTtrade over 4 months
Repeat imaging studies showed normal findings on MRI and PET consistent with a completeremission of the previous multiple central nervous system metastases as shown in the brain scansbelow
Bria-IMTtrade and Bria-OTStrade shouldsynergize with existing approvedimmunotherapies as well as those stillunder development
This includes immune checkpointinhibitors such as antibodies to PD-1CTLA-4 GITR and CD73 inhibitors whicheliminate tumor immunosuppression Checkpoint Inhibitors were the
subject of the 2018 Nobel Prize inMedicine
In addition immunostimulatoryantibodies to molecules such as OX40should enhance responses to Bria-IMTtradeand Bria-OTStrade
13
Q3 2018 Data on first 20 Patients on Bria-IMTtrade Q3 2018 Initiate Combination Study of Bria-IMTtrade with Keytruda or Yervoy
Q4 2018 Switch to a novel frozen Bria-IMTtrade formulation Q4 2018 Safety Data (6 patients) of the Bria-IMTtrade - Keytrudareg Combination Study (SABC meeting) Q4 2018 Ongoing Corporate PartnershipCollaboration Discussions
Q1 2019 Efficacy Data (6 patients) of the Bria-IMTtrade - Keytrudareg Combination Study Q2 2019 Initiation of Bria-OTStrade GMP manufacturing (KBI BioPharma) Q2 2019 Additional Safety amp Efficacy data Monotherapy and Combination Studies (AACR meeting) Q2 2019 Final data for Monotherapy and Additional Data for the Combination Study (ASCO meeting) H1 2019 Candidate Selection for a PKCδ Inhibitor H1 2019 Initiate additional immunotherapy program H2 2019 Bria-OTStrade Authorization from FDA clearance for dosing H2 2019 Bria-OTStrade First Patient Dosed
Upcoming Milestones amp Catalysts
14
Involved in over 10 drugs brought to the market
Experienced Management Team
Management
William V Williams MD FACP President amp CEO VP Exploratory Development Incyte Corporation VP Experimental Medicine GlaxoSmithKline Head Rheumatology Research University of Pennsylvania Facilitated entry of over 20 compounds into the clinic including ruxolitinib (Jakafi)
baricitinib amp epacadostat NDAs including Jakafi Boniva Bexxar Author of over 120 peer-reviewed publications amp over 20 patents
Gadi Levin CA MBA CFO CFO of Labstyle Innovations Ltd VP of Finance for two Israeli investment houses in the fields of private equity
hedge funds and real estate Financial Consultant various firms Accountant Arthur Andersen
Markus Lacher PhD Senior Director RampD Founder T cell Therapeutics Inc an immuno-oncology company Sr Clinical Scientist Cesca Therapeutics Inc a clinical-stage autologous cell
therapy company Scientist at BioTime Inc and OncoCyte Corporation Editorial advisory board Recent Patents on Anti-Cancer Drug Discovery
Farrah Dean MSc MBA Manager Corp Development Investor relations CytRx Corporation amp CCG Investor Relations Senior Associate Equity Analyst Oppenheimer amp Co Rodman amp Renshaw amp
Brian Metcalf PhD Recently retired as CSO from Global Blood Therapeutics Former Head of Research amp Development Incyte Corporation Former Head of Medicinal Chemistry SmithKline Beecham
Douglas Faller MD PhD Professor of Medicine Pediatrics Biochemistry Microbiology Pathology and
Laboratory Medicine HematologistOncologist former Director of the Cancer Center Boston University School of Medicine
Founder of several successful biotechnology companies
Robert Williams PhD University Distinguished Professor of Chemistry Colorado State University Founder of several successful biotechnology companies including Microcide Xcyte
Therapies HemaQuest Arch Therapeutics and Cetya Therapeutics
Thomas Kieber-Emmons PhD Deputy Director University of Arkansas Cancer Center Expert in targeted cancer immunotherapies structural biology and computational
chemistry
Maria Trojanowska PhD Professor of Medicine Boston University School of Medicine Director The Arthritis Center
16
Veteran Board of Directors
Board of Directors
Saeid Babaei PhD MBA Chairman Entrepreneur 20 yrs of biotech leadership roles Current CEO AbCelex VP Bus Develop Lorus Therap Dir of Corp Develop Northern Therapeutics
Rahoul Sharan CA Director Chairman Potash Ridge Director of the Board Ansell Capital Corp Parallel Resources amp Galaxy Capital
Corporation
Martin Schmieg CPA Director CFO Sirna Therapeutics Inc amp Isolagen Inc CEO Freedom-2 Inc (now PharmaCyte Inc) Advisor Caladrius Biosciences Inc Beckman Coulter Genomics Calimmune
Charles Wiseman MD Co-Founder amp Director Director Immunotherapy Lab St Vincent Medical Center Chief Breast Cancer Basic Research Lab Univ of Texas MD Anderson Hospital amp
Tumour Institute Assist Prof Dept of Molecular Carcinogenesis amp Virology MD Anderson Acting Chief Div of Oncology White Memorial Medical Center LA
William V Williams MD FACP President amp CEO VP Exploratory Development Incyte Corporation VP Experimental Medicine GlaxoSmithKline Head Rheumatology Research University of Pennsylvania
Prior Affiliations
17
Drug Approvals by BriaCell Management Team
Bexxarreg (tositumomab and Iodine I131 tositumomab) Treatment of CD20 antigen-expressing relapsed or refractory low grade follicular or transformed non-Hodgkins lymphoma
Myleranreg (busulfan) for chronic myelogenous leukemia Defense of formulation change sNDA
Hycamtinreg (topotecan) for ovarian cancer Pediatric use sNDA
Navelbinereg (vinorelbine tartrate) for non-small cell lung cancer Pediatric use sNDA
Bonivareg (ibandronate) monthly oral treatment of osteoporosis
Bonivareg (ibandronate) quarterly intraveous treatment of osteoporosis
Zofranreg (ondansetron) for prevention of nausea and vomiting Pediatric use sNDA
Jakafireg (ruxolitinib) for myelofibrosis Jakafireg (ruxolitinib) for polycythemia vera
Olumiantreg (baricitinib) for rheumatoid arthritis Approved in USA Japan and Europe
18
Share Metrics
BCTV BCTXF 19
Data as of 1092018
Ticker TSX BCTV
US Ticker OTCQBBCTXF
Share Price (CAD) as of Oct 9 2018 $012
52-Week Range (CAD) $009-019
Shares Outstanding as of Oct 9 2018 1611M
Market Cap as of Oct 9 2018 (CAD) $193M
Cash and Short Term Investments as of July 31 2018 (CAD) $23M
Total Shareholders Equity as of July 31 2018 (CAD) $12M
Number of Warrants $014-$035 (CAD) as of Oct 9 2018 601M
Number of Compensation Warrants $014-$030 (CAD) as of Oct 9 2018 45M
Number of Options $014- $026 (CAD$) as of Oct 9 2018 93M
Developing Bria-OTStrade the First Off-the-Shelf Personalized Immunotherapy
Targeting Adv Breast Cancer Unmet medical need (42000 death in the US in 2017 ) $1 Bil- $5 Bil market opportunity depending on patient treatment stage
Impressive results in 2 proof-of-concept clinical trials Rapid Response Rate Repeated following re-treatment Excellent Safety Profile
Completed enrollment in Phase IIIa clinical trial of Bria-IMTtrade with outstanding safety amp efficacy data Initiated Phase IIa Combination Study of Bria-IMTtrade with Keytrudareg (Merck amp Co Inc)
Developing Bria-OTStrade along with BriaDXtrade its companion diagnostic test Ability to match and treat ~90 of patient population with Off-the-Shelf personalized immunotherapy
Experienced Management has been involved in over 10 drug approvals
Patient B001 Breast 70 No 1101 - 3501 4001 Negative -
Bria-IMTtradeHuman Proof-of-Concept Trials in Breast Cancer (Patient A002)
24
Proof-of-Concept Results Resulted in BriaCellrsquos Immunotherapy Strategy Use BriaDXtrade diagnostic to select only those patients matching Bria-IMTtrade Use BriaDXtrade diagnostic test to select Bria-OTStrade alleles matching ~90 of all patients
Bria-IMTtradeCurrent Phase IIIa Data Supports HLA Matching Hypothesis Six patients treated in 2017 Bria-IMTtrade was safe and well tolerated
Patient 01-002 73-year-old woman with breast cancer diagnosed in 1995 Developed liver metastases in2010 and lung metastases in 2017 Previously treated with 7 rounds of chemotherapy with 8 differentchemotherapy agents Received 5 cycles of Bria-IMTtrade over 3 months then monthly cycles (6 months total)Evaluated after 3 months and 6 months After 3 months despite the extensive prior therapy her scans notedthat ldquothere has been a clear response in the multiple bilateral pulmonary nodulesrdquo The response wasmaintained after 6 months of Bria-IMTtrade treatment She matches Bria-IMTtrade at 2 HLA alleles
The liver tumors were stable to slightly increased at 3 months and then progressed after 6 months
This supports our hypothesis of heightened anti-tumor activity in patients with a matched HLA types Clear path to develop BriaDXtrade to select the patients using HLA testing
1 RLL 29 Not Detectable Not Detectable2 LUL apical pleural based 34 tiny nodule lt 1mm scar tiny nodule lt 1mm scar3 xxx 39 Not Detectable Not Detectable4 40 Not Detectable Not Detectable5 RLL 45 Not Detectable Not Detectable6 LLL 49 Not Detectable Not Detectable7 xxx 52 Not Detectable Not Detectable8 RLL 52 Not Detectable Not Detectable9 RLL 56 Not Detectable Not Detectable
10 RLL costophrenic recess 56 Not Detectable Not Detectable11 XXX 58 Not Detectable Not Detectable12 LUL 60 Not Detectable Not Detectable13 XXX 67 15 1514 RUL 72 15 1515 LLL 76 Not Detectable Not Detectable16 RUL Noncalcified Nodule 77 Not Detectable Not Detectable17 RLL costophrenic recess 79 10 1018 RUL 82 Not Detectable Not Detectable19 RLL 90 Not Detectable Not Detectable20 RLL 91 lt 01 lt 0121 xxx xxx Not Detectable Not Detectable
27
Clinical Development Update ndash Summary 2018 September 26
Completed enrollment of Adv Breast cancer patients in the Phase IIIa ldquomonotherapyrdquo study of Bria-IMTtrade
We have confirmed our mechanism of action and achieved proof of concept
Initial safety data appears superior to that of the other advanced or approved drugs for breast cancer when they were at a similar clinical stage of development
Initial efficacy data is similar or superior to those of other advanced or approved drugs for breast cancer when they were at a similar clinical stage of development
Initiated Combination Study of Bria-IMTtrade with Keytrudareg or Yervoyreg in Adv breast cancer patients expecting even better response rates than those in the ldquomonotherapyrdquo study Initial safety data is expected in 4Q2018 Initial efficacy data is expected in 1Q2019
Bria-OTStrade the first off-the-shelf personalized treatment for advanced breast cancer is expected to enter the clinic in 2019
28
Bria-IMTtrade Excellent Safety Data - To Date
To date Bria-IMTtrade has been dosed in 24 patients (4 in 2004-2005 20 in 2017-2018)
Interim Data (20 patients)-Ongoing Phase IIIa Study (2017-2018)
Bria-IMTtrade has been very well tolerated (ge60 doses given to date) The majority of adverse events (AEs) were limited to expected minor local irritation at the
injection sites No related grade gt3 or unexpected AEs No related serious AEs No serious unexpected related AEs Most patients who have dropped out did so due to worsening of their underlying disease
Based on the current study Bria-IMTtrade has an excellent safety profile
29
Bria-IMTtrade - Efficacy as Predicted
Interim Data (19 patients)-Ongoing Phase IIIa Study (2017-2018) amp Original Study (2004-2005)
PD-L1 expression on circulating cancer cells amp cancer-associated cells in 100 of patients (to date) Strong rationale for combination with checkpoint inhibitors like Keytruda
30
Bria-IMTtrade appears to be most effective in patients who match with Bria-IMT trade at 2 HLA loci (types) further supporting our ldquoHLA Matching Hypothesisrdquo and the development of Bria-OTS trade to cover 90 of the patient population
Combination with immune checkpoint inhibitors may induce a more potent anti-cancer response leading to our strategy of combination studies of Bria-IMT trade with Keytruda or Yervoy
Patients (n) HLA Match
Tumor Shrinkage
Biological Response
4 ge2 50 7515 ge1 27 334 0 0 0
Biological response includes tumor shrinkage or lower circulating cancer associated cells
The confirmatory Bria-IMTtrade monotherapy Phase IIa trial has completed enrollment Additional Support for the HLA-matching hypothesis has been obtained
Bria-IMTtrade Combination Therapy study with immune checkpoint inhibitors Keytrudareg if PD-L12 positive (ge1) Yervoyreg if PD-L12 negative (lt1) Accepting patients from the monotherapy study who develop progressive disease Also enrolling patients directly into this study to enhance experience with the combination In discussion with other pharmaceutical companies to evaluate additional combinations with other
immunotherapies
Bria-OTStrade Off-the-Shelf Personalized Targeted Immunotherapy Developing Bria-OTStrade to co-express GM-CSF and interferon-α Pre-manufacture additional HLA alleles ndash Total of 15 alleles (8 Class I and 7 Class II) Co-development of BriaDXtrade companion diagnostic for HLA typing Combination therapy clinical trial with immune checkpoint inhibitors for non-responders using
information from the Bria-IMTtrade Combination Therapy Study
33
Development Timeline ndash Breast Cancer
20192018 2020 2021
Phase IIIaBria-IMTtrade
Monotherapy
Currently Enrolling Phase IIaBria-IMTtrade + Checkpoint
Currently in discussions with potential partnersPhase II Bria-IMTtrade plus Additional Combinations (1Q19 4Q22)(eg PD-1 Inhibitor PD-L1 inhibitor anti-CTLA4 anti-GITR anti-OX40)
1Q 2Q 3Q 4Q
2023
Bria-OTStrade Off-The-Shelf Personalized ImmunotherapyMonotherapy and Potential Partnered Combo Therapy
(2H19 Ongoing)
Bria-OTStradeOff-the-Shelf Cell Line cGMP Manufacturing
and BriaDXtrade(1Q18 1Q19)
Registration Studies (1Q20 2H22)Bria-IMTtrade with Checkpoint InhibitorsBria-OTStrade +- Checkpoint Inhibitors
34
Immuno-oncology Deals
Recent deals of small biotechs with big pharma in immuno-oncology
35
Date PartnershipDevelopment stage at the time of the deal Deal size
07122018 Immatics-Genmab Preclinical Up to $28B
04042018 OSE Immunotherapeutics-Boehringer Ingelheim Preclinical Up to euro113B ($139B)
02092018 Pieris Pharmaceuticals-Seattle Genetics Preclinical Up to $123B
2142018 Nektar-BMS Ph III Up to $36B
01222018 Juno-Celgene Ph II $9B (Acquisition)
11142017 Loxo-Bayer Larotrectinib (Ph II) LOXO-195 (Ph III) Up to $155B
1032017 CytomX-Amgen Preclinical Up to $15B
03202017 CytomX--BMS Ph III Up to $36B
6282016 Xencor-Novartis Preclinical Up to $24B
Early Stage Clinical Studies (Comparison)
We compared the interim data of Ph IIIa study of Bria-IMTtrade in advanced breast cancer with thedata in the early stage clinical studies of recently approved breast cancer drugs and one fasttracked product candidate
Apples to apples comparison Early Stage Clinical Studies in oncology are typically done in patientswith no other therapeutic options Thus the patients have very advanced disease and response ratesare typically quite low
The patients in our Ph IIIa study have been heavily pre-treated (median 45 prior regimens)Some recent studies of relevance in breast cancer are noted in the following slides
36
Breast Cancer Market Opportunity
Drug Technology Approved for Market (US)Ibrance (palbociclib) CDK 46 Inhibitor HR+HER2- MBC in combination with
fluvestrant or aromatase inhibitor$933M in 1Q2018 $3126M in 2017
Kisqali (ribociclib) CDK 46 Inhibitor 2017 HR+HER2- MBC in combination with fluvestrant or aromatase inhibitor
Peak sales projected at $25B
Verzenio (abemaciclib) CDK 46 Inhibitor 2017 HR+HER2- MBC in combination with fluvestrant or aromatase inhibitor
balixafortide CXCR4 antagonist Fast track designation in 2018 for HER2- MBC who have failed 2 prior regimens
The market for breast cancer drugs is a multibillion dollar market with new drugs being approvedon an ongoing basis indicating the shortage of safe and effective treatments for this deadly disease
37
Competitors- Phase III Clinical Data Bria-IMTtrade shows superior safety and similar to superior efficacy data compared with those of the multi-billion dollar drugs when they were at a similar early stage of clinical development
Injection site reactions No related SAEs or SUSARs
Tumor vol darr ampor darr circul tumor cellsAll Comers 21(419) 26(519)One or More HLA matches 27(415) 33(515)Two or More HLA matches 50 (24) 75 (34)
Sheet1 (3)
Comp -Slides
Data
HLA (2)
HLA
Data (Ph1-2+4Pt)
Competitors (2018)-Slide
Competitors (2018)
In the Pipeline Protein Kinase C delta (PKCδ) Inhibitors
30 of all human malignancies display activating RAS mutations Another 60 showing over-activity of Ras-signaling pathways
Ras has been termed ldquoundruggablerdquo (no one has been able to make a Ras inhibitor drug)
BriaCellrsquos novel proprietary PKCδ inhibitors have shown activity against multiple RAS transformed tumors Lung cancer Melanoma Breast cancer Neuroendocrine cancer Pancreatic cancer Colorectal cancer
This target has an attractive safety profile based on in vivo studies and knock out mouse studies
PKCδ inhibitors should qualify for an accelerated clinical development plan and regulatory pathway
Could be in clinic within 24 months
Cost-Effective Additional Shot-on-Goal and additional partnership opportunities
Early-Stage Preclinical Program
39
Protein Kinase C delta (PKCδ) Inhibitors
Activated PKCδ inhibits RAS degradation which in turn stimulates tumor growth
Koo et al Oncotarget 621328 2016
30 of all human malignancies display activating RASmutations with another 60 showing over-activity of Ras-signaling pathways
BriaCellrsquos novel proprietary PKCδ inhibitors have shownactivity against multiple RAS transformed tumors
This target has an attractive safety profile based on in vivostudies and knock out mouse studies
PKCδ also has potential activity as an immunotherapeuticby blocking TGFβ signaling
PKCδ inhibitors are applicable to specific niche tumor typeswhich provide an accelerated clinical development plan
Structural aspects of first generation inhibitor rottlerin and staurosporine (pan-PKC activator) were combined to create second generation inhibitor KAM1
Third generation inhibitors such as BJE6-106 have improved potency and selectivity Fourth generation inhibitors under development to optimize drug-like characteristics PKCδ inhibitors lack endothelial cell cytotoxicity amp PKCδ deficient mice develop normally and are fertile Potentially no marked intrinsic toxicity by inhibiting PKCδ
Mukai H Saeki T Shimada K Naito Y Matsubara N Nakanishi T Obaishi H Namiki M Sasaki Y Phase 1 combination study of eribulin mesylate with trastuzumab for advanced or recurrent human epidermal growth factor receptor 2 positive breast cancer Invest New Drugs 2015 Feb33(1)119-27
AstraZeneca
Lynparza (Olaparib) + Cediranib
PARP inhibitor + inhibitor of VEGF receptor tyrosine kinases
HR+ HER2- MBC
BC amp OC
2013
28 (8 BC)
3 for BC
Olaparib (a poly (ADP-ribose) polymerase (PARP) inhibitor) amp Cediranib (Vascular endothelial growth factor receptor (VEGFR) 1 2 and 3 tyrosine kinase inhibitor)3 at dose level (DL) 0 (cediranib 20mg olaparib 100mg) 3 at DL1 (cediranib 20mg olaparib 200mg) 7 at DL2 (cediranib 30mg olaparib 200mg) 6 at DL3 (cediranib 30mg olaparib 400mg)
Liu JF Tolaney SM Birrer M Fleming GF Buss MK Dahlberg SE Lee H Whalen C Tyburski K Winer E Ivy P Matulonis UA A Phase 1 trial of the poly(ADP-ribose) polymerase inhibitor olaparib (AZD2281) in combination with the anti-angiogenic cediranib (AZD2171) in recurrent epithelial ovarian or triple-negative breast cancer Eur J Cancer 2013 Sep49(14)2972-8
Reyon Pharmaceutical
VM206RY
Heterologous prime-boost with a truncated HER2 sequence
HER2+ Stage IIIampIV BC
2015
9
2 chemo
Plasmid DNA (pHM-GM-CSF expressing truncated HER2 amp GM-CSF) amp adenoviral vector (Ad-HM containing modified HER2) (2 4 and 8 mgpatientvisit) of pHM-GM-CSF 3x IM weeks 0 2 and 4 Ad-HM 3 times 109 virus particles at week 6
11 PR
4 pts showed 7 minor AEs
Unclear
Kim SB Ahn JH Kim J Jung KH A phase 1 study of a heterologous prime-boost vaccination involving a truncated HER2 sequence in patients with HER2-expressing breast cancer Mol Ther Methods Clin Dev 2015 Sep 30215031 doi 101038mtm201531 eCollection 2015
Rodon J Peacuterez-Fidalgo A Krop IE Burris H Guerrero-Zotano A Britten CD Becerra C Schellens J Richards DA Schuler M Abu-Khalaf M Johnson FM Ranson M Edenfield J Silva AP Hackl W Quadt C Demanse D Duval V Baselga J Phase 11b dose escalation and expansion study of BEZ235 a dual PI3KmTOR inhibitor in patients with advanced solid tumors including patients with advanced breast cancer Cancer Chemother Pharmacol 2018 Jun 7 doi 101007s00280-018-3610-z [Epub ahead of print]
Celgene (Abraxane)
Gemcitabine + Abraxane (nab-paclitaxel)
Chemo + Chemo
OC BC NSCLC amp Panc cancer + Lung OC BC Kaposi sarcoma
MBC
2016
9
Adjuvant chemo (100)chemo post-adjuvant (33)
Gem (nucleoside metabolic inhibitor 1250 mgm2) on days 1 and 8 nab-Pac (microtubule inhibitor) starting dose of 180 mgm2 (cohort 1) 220 mgm2 (cohort 2) and 260 mgm2 (cohort 3) on day 1 of the 21-day cycle using a 3 + 3 design
0
MTD not reached29 Gr3 Neutropenia59 Gr1 Peripheralneuropathy
Yoshitomi S Taira N Doihara H Mizoo T Nogami T Iwamoto T Motoki T Shien T Ogasawara Y Matsuoka J Tsuji H Mitsuhashi T A phase 1 dose-finding and pharmacokinetic study of gemcitabine with nab-paclitaxel in patients with metastatic breast cancer Cancer Chemother Pharmacol 2016 Aug78(2)289-94
Eli Lilly
Erbituxreg (cetuximab) + Taxane
EGFR inhibitor antineoplastic agent + Chemo
Headamp Neck Colorectal Cancer
TNBC
2007-2010
18
1 chemo
Cetuximab (epidermal growth factor receptor (EGFR) antagonist ) an initial loading dose of cetuximab 400 mgm2 followed by a weekly dose of 250 mgm2Paclitaxel (microtubule inhibitor) 80 mgm2 or Docetaxel at an initial dose of 30 mgm2 was administered weekly
56 CR 22 PR
83 Dermatologic toxicity11 Grade3+
Nechushtan H Vainer G Stainberg H Salmon AY Hamburger T Peretz T A phase 12 of a combination of cetuximab and taxane for triple negative breast cancer patients Breast 2014 Aug23(4)435-8
Polyphor
Balixafortide (POL6326) + eribulin
CXCR4 antagonist + tubulin-based antimitotic
Heavily pretreated Relapsed MBC
2014-2016
56
3rd line 3 chemo
3+3 dose escalation The highest dose was established as eribulin 14 mgmsup2 on days 2 and 9 and balixafortide 55 mgkg on days 1minus3 and 8minus10 of the 21-day cycle
30 PR
41 Gr34 Neutropenia11 Gr34 Leucopenia11 Gr34 Febrileneutropenia2 Related mortalities
Apr 2018 Fast Track for HER2-MBC who have failed 2prior regimens
Pernas S Martin M Kaufman PA Gil-Martin M Gomez Pardo P Lopez-Tarruella S Manso L Ciruelos E Perez-Fidalgo JA Hernando C Ademuyiwa FO Weilbaecher K Mayer I Pluard TJ Martinez Garcia M Vahdat L Perez-Garcia J Wach A Barker D Fung S Romagnoli B Cortes J Balixafortide plus eribulin in HER2-negative metastatic breast cancer a phase 1 single-arm dose-escalation trial Lancet Oncol 2018 Jun19(6)812-824
11 PRndashbut only + letrozole (No Resp on monotherapy)
61 Gr34 Neutropenia39 Gr34 Leucopenia
$933M in 1Q2018 $31B in 2017
Tamura K Mukai H Naito Y Yonemori K Kodaira M Tanabe Y Yamamoto N Osera S Sasaki M Mori Y Hashigaki S Nagasawa T Umeyama Y Yoshino T Phase I study of palbociclib a cyclin-dependent kinase 46 inhibitor in Japanese patients Cancer Sci 2016 Jun107(6)755-63 doi 101111cas12932 Epub 2016 May 11
Pfizer
Ibrancereg (palbociclib)
CDK 46 Inhibitor
HR+ HER2- MBC
Heavily pretreated Relapsed Metastatic Cancer
2004-2008
41 (5 BC)
chemo naiumlve (17) 1-2 (51)3 (29) 3+ (2)
Palbociclib 25-150 mg dose ranging
0
20 Gr34 Neutropenia23 Gr34 Leucopenia
$933M in 1Q2018 $31B in 2017
Flaherty KT Lorusso PM Demichele A Abramson VG Courtney R Randolph SS Shaik MN Wilner KD ODwyer PJ Schwartz GK Phase I dose-escalation trial of the oral cyclin-dependent kinase 46 inhibitor PD 0332991 administered using a 21-day schedule in patients with advanced cancer Clin Cancer Res 2012 Jan 1518(2)568-76 doi 1011581078-0432CCR-11-0509 Epub 2011 Nov 16
Novartis
Kisqalireg (ribociclib)
CDK 46 Inhibitors
Premenopausal HR+ HER2- MBC
Heavily pretreated Relapsed Metastatic Cancer
2016
132 (20 BC)
0-1 (25) 2-3 (42) 4+ (32)
Ribociclib 50 mg ranging up to 1200 mg dose escalation
23 PRndashincluded 1 in BC (5 of BC pts)
27 Gr34 Neutropenia17 Gr34 Leucopenia
Peak sales projected at $25B
Infante JR Cassier PA Gerecitano JF Witteveen PO Chugh R Ribrag V Chakraborty A Matano A Dobson JR Crystal AS Parasuraman S Shapiro GI A Phase I Study of the Cyclin-Dependent Kinase 46 Inhibitor Ribociclib (LEE011) in Patients with Advanced Solid Tumors and Lymphomas Clin Cancer Res 2016 Dec 122(23)5696-5705 Epub 2016 Aug 19
Eli Lilly
Verzenioreg (abemaciclib)
CDK 46 Inhibitors
HR+HER2minusMBC
Heavily pretreated Relapsed Metastatic Cancer
2016
12 (1 BC)
1 (312) 2 (212) 3+ (7)
Abemaciclib 100 mg ranging up to 200 mg dose escalation
17 PR (included 1 in BC)
17 Gr34 Neutropenia33 Gr34 Leucopenia
Peak sales projected at $2B
Fujiwara Y Tamura K Kondo S Tanabe Y Iwasa S Shimomura A Kitano S Ogasawara K Turner PK Mori J Asou H Chan EM Yamamoto N Phase 1 study of abemaciclib an inhibitor of CDK 4 and 6 as a single agent for Japanese patients with advanced cancer Cancer Chemother Pharmacol 2016 Aug78(2)281-8 doi 101007s00280-016-3085-8 Epub 2016 Jun 16
Mukai H Saeki T Shimada K Naito Y Matsubara N Nakanishi T Obaishi H Namiki M Sasaki Y Phase 1 combination study of eribulin mesylate with trastuzumab for advanced or recurrent human epidermal growth factor receptor 2 positive breast cancer Invest New Drugs 2015 Feb33(1)119-27
AstraZeneca
Lynparza (Olaparib)+ Cediranib
PARP inhibitor+ inhibitor of VEGF RTK
HR+ HER2- MBC
BC amp OC
13
28 (8 BC)
3 for BC
Olaparib (a poly (ADP-ribose) polymerase (PARP) inhibitor) amp Cediranib (Vascular endothelial growth factor receptor (VEGFR) 1 2 and 3 tyrosine kinase inhibitor)3 at dose level (DL) 0 (cediranib 20mg olaparib 100mg) 3 at DL1 (cediranib 20mg olaparib 200mg) 7 at DL2 (cediranib 30mg olaparib 200mg) 6 at DL3 (cediranib 30mg olaparib 400mg)
Liu JF Tolaney SM Birrer M Fleming GF Buss MK Dahlberg SE Lee H Whalen C Tyburski K Winer E Ivy P Matulonis UA A Phase 1 trial of the poly(ADP-ribose) polymerase inhibitor olaparib (AZD2281) in combination with the anti-angiogenic cediranib (AZD2171) in recurrent epithelial ovarian or triple-negative breast cancer Eur J Cancer 2013 Sep49(14)2972-8
ReyonPharma
VM206RY
Heterologous prime-boost with a truncated HER2 sequence
HER2+ Stg IIIampIV BC
15
9
2 chemo
Plasmid DNA (pHM-GM-CSF expressing truncated HER2 amp GM-CSF) amp adenoviral vector (Ad-HM containing modified HER2) (2 4 and 8 mgpatientvisit) of pHM-GM-CSF 3x IM weeks 0 2 and 4 Ad-HM 3 times 109 virus particles at week 6
11 PR
4 pts 7 minor AEs
Unclear
Kim SB Ahn JH Kim J Jung KH A phase 1 study of a heterologous prime-boost vaccination involving a truncated HER2 sequence in patients with HER2-expressing breast cancer Mol Ther Methods Clin Dev 2015 Sep 30215031 doi 101038mtm201531 eCollection 2015
Rodon J Peacuterez-Fidalgo A Krop IE Burris H Guerrero-Zotano A Britten CD Becerra C Schellens J Richards DA Schuler M Abu-Khalaf M Johnson FM Ranson M Edenfield J Silva AP Hackl W Quadt C Demanse D Duval V Baselga J Phase 11b dose escalation and expansion study of BEZ235 a dual PI3KmTOR inhibitor in patients with advanced solid tumors including patients with advanced breast cancer Cancer Chemother Pharmacol 2018 Jun 7 doi 101007s00280-018-3610-z [Epub ahead of print]
Celgene(Abraxane)
Gemcitabine + Abraxane (nab-paclitaxel)
Chemo+ Chemo
OC BC NSCLC PC + LC OC BC KS
MBC
16
9
Adjuv chemo (100)chemo post-adjuv (33)
Gem (nucleoside metabolic inhibitor 1250 mgm2) on days 1 and 8 nab-Pac (microtubule inhibitor) starting dose of 180 mgm2 (cohort 1) 220 mgm2 (cohort 2) and 260 mgm2 (cohort 3) on day 1 of the 21-day cycle using a 3 + 3 design
0
MTD not reached29 Gr3 Neutropenia59 Gr1 Peripheralneuropathy
Yoshitomi S Taira N Doihara H Mizoo T Nogami T Iwamoto T Motoki T Shien T Ogasawara Y Matsuoka J Tsuji H Mitsuhashi T A phase 1 dose-finding and pharmacokinetic study of gemcitabine with nab-paclitaxel in patients with metastatic breast cancer Cancer Chemother Pharmacol 2016 Aug78(2)289-94
Eli Lilly
Erbituxreg (cetuximab) + Taxane
EGFR inhibitor antineoplastic agent + Chemo
Head amp NeckColorectal
TNBC
07-10
18
1 chemo
Cetuximab (epidermal growth factor receptor (EGFR) antagonist ) an initial loading dose of cetuximab 400 mgm2 followed by a weekly dose of 250 mgm2Paclitaxel (microtubule inhibitor) 80 mgm2 or Docetaxel at an initial dose of 30 mgm2 was administered weekly
56 CR 22 PR
83 Dermatologic toxicity11 Grade3+
Nechushtan H Vainer G Stainberg H Salmon AY Hamburger T Peretz T A phase 12 of a combination of cetuximab and taxane for triple negative breast cancer patients Breast 2014 Aug23(4)435-8
Polyphor
Balixafortide (POL6326) + eribulin
CXCR4 antagonist + tubulin-based antimitotic
Heavily pretreatedRelapsed MBC
14-16
56
3rd line 3 chemo
3+3 dose escalation The highest dose was established as eribulin 14 mgmsup2 on days 2 and 9 and balixafortide 55 mgkg on days 1minus3 and 8minus10 of the 21-day cycle
30 PR
41 Gr34 Neutropenia11 Gr34 Leucopenia11 Gr34 Febrileneutropenia2 Related mortalities
42018 Fast Track (HER2-MBC failed 2 prior regimens)
Pernas S Martin M Kaufman PA Gil-Martin M Gomez Pardo P Lopez-Tarruella S Manso L Ciruelos E Perez-Fidalgo JA Hernando C Ademuyiwa FO Weilbaecher K Mayer I Pluard TJ Martinez Garcia M Vahdat L Perez-Garcia J Wach A Barker D Fung S Romagnoli B Cortes J Balixafortide plus eribulin in HER2-negative metastatic breast cancer a phase 1 single-arm dose-escalation trial Lancet Oncol 2018 Jun19(6)812-824
1 PRndashbut only + letrozoleNo Resp on monotherapy
61 Gr34 Neutropenia39 Gr34 Leucopenia
$933M (1Q18)$31B (2017)
Tamura K Mukai H Naito Y Yonemori K Kodaira M Tanabe Y Yamamoto N Osera S Sasaki M Mori Y Hashigaki S Nagasawa T Umeyama Y Yoshino T Phase I study of palbociclib a cyclin-dependent kinase 46 inhibitor in Japanese patients Cancer Sci 2016 Jun107(6)755-63 doi 101111cas12932 Epub 2016 May 11
Pfizer
Ibrancereg (palbociclib)
CDK 46 Inhibitor
HR+ HER2- MBC
Heavily pretreatedRelapsed Met Cancer
04-08
41 (5 BC)
chemo naiumlve (17)1-2(51) 3(29) 3+(2)
Palbociclib 25-150 mg dose ranging
0
20 Gr34 Neutropenia23 Gr34 Leucopenia
$933M (1Q18)$31B (2017)
Flaherty KT Lorusso PM Demichele A Abramson VG Courtney R Randolph SS Shaik MN Wilner KD ODwyer PJ Schwartz GK Phase I dose-escalation trial of the oral cyclin-dependent kinase 46 inhibitor PD 0332991 administered using a 21-day schedule in patients with advanced cancer Clin Cancer Res 2012 Jan 1518(2)568-76 doi 1011581078-0432CCR-11-0509 Epub 2011 Nov 16
Novartis
Kisqalireg (ribociclib)
CDK 46 Inhibitor
Premenopausal HR+ HER2- MBC
Heavily pretreatedRelapsed Met Cancer
16
132 (20 BC)
0-1 (25) 2-3 (42)4+ (32)
Ribociclib 50 mg ranging up to 1200 mg dose escalation
23 PR-included 1 BC (5 of BC pts)
27 Gr34 Neutropenia17 Gr34 Leucopenia
Peak sales est at $25B
Infante JR Cassier PA Gerecitano JF Witteveen PO Chugh R Ribrag V Chakraborty A Matano A Dobson JR Crystal AS Parasuraman S Shapiro GI A Phase I Study of the Cyclin-Dependent Kinase 46 Inhibitor Ribociclib (LEE011) in Patients with Advanced Solid Tumors and Lymphomas Clin Cancer Res 2016 Dec 122(23)5696-5705 Epub 2016 Aug 19
Eli Lilly
Verzenioreg (abemaciclib)
CDK 46 Inhibitor
HR+HER2minusMBC
Heavily pretreatedRelapsed Met Cancer
16
12 (1 BC)
1 (312) 2 (212) 3+(7)
Abemaciclib 100 mg ranging up to 200 mg dose escalation
17 PR (included 1 BC)
17 Gr34 Neutropenia33 Gr34 Leucopenia
Peak sales est at $2B
Fujiwara Y Tamura K Kondo S Tanabe Y Iwasa S Shimomura A Kitano S Ogasawara K Turner PK Mori J Asou H Chan EM Yamamoto N Phase 1 study of abemaciclib an inhibitor of CDK 4 and 6 as a single agent for Japanese patients with advanced cancer Cancer Chemother Pharmacol 2016 Aug78(2)281-8 doi 101007s00280-016-3085-8 Epub 2016 Jun 16
Mukai H Saeki T Shimada K Naito Y Matsubara N Nakanishi T Obaishi H Namiki M Sasaki Y Phase 1 combination study of eribulin mesylate with trastuzumab for advanced or recurrent human epidermal growth factor receptor 2 positive breast cancer Invest New Drugs 2015 Feb33(1)119-27
AstraZeneca
Lynparza (Olaparib) + Cediranib
PARP inhibitor + inhibitor of VEGF receptor tyrosine kinases
HR+ HER2- MBC
BC amp OC
2013
28 (8 BC)
3 for BC
Olaparib (a poly (ADP-ribose) polymerase (PARP) inhibitor) amp Cediranib (Vascular endothelial growth factor receptor (VEGFR) 1 2 and 3 tyrosine kinase inhibitor)3 at dose level (DL) 0 (cediranib 20mg olaparib 100mg) 3 at DL1 (cediranib 20mg olaparib 200mg) 7 at DL2 (cediranib 30mg olaparib 200mg) 6 at DL3 (cediranib 30mg olaparib 400mg)
Liu JF Tolaney SM Birrer M Fleming GF Buss MK Dahlberg SE Lee H Whalen C Tyburski K Winer E Ivy P Matulonis UA A Phase 1 trial of the poly(ADP-ribose) polymerase inhibitor olaparib (AZD2281) in combination with the anti-angiogenic cediranib (AZD2171) in recurrent epithelial ovarian or triple-negative breast cancer Eur J Cancer 2013 Sep49(14)2972-8
Reyon Pharmaceutical
VM206RY
Heterologous prime-boost with a truncated HER2 sequence
HER2+ Stage IIIampIV BC
2015
9
2 chemo
Plasmid DNA (pHM-GM-CSF expressing truncated HER2 amp GM-CSF) amp adenoviral vector (Ad-HM containing modified HER2) (2 4 and 8 mgpatientvisit) of pHM-GM-CSF 3x IM weeks 0 2 and 4 Ad-HM 3 times 109 virus particles at week 6
11 PR
4 pts showed 7 minor AEs
Unclear
Kim SB Ahn JH Kim J Jung KH A phase 1 study of a heterologous prime-boost vaccination involving a truncated HER2 sequence in patients with HER2-expressing breast cancer Mol Ther Methods Clin Dev 2015 Sep 30215031 doi 101038mtm201531 eCollection 2015
Rodon J Peacuterez-Fidalgo A Krop IE Burris H Guerrero-Zotano A Britten CD Becerra C Schellens J Richards DA Schuler M Abu-Khalaf M Johnson FM Ranson M Edenfield J Silva AP Hackl W Quadt C Demanse D Duval V Baselga J Phase 11b dose escalation and expansion study of BEZ235 a dual PI3KmTOR inhibitor in patients with advanced solid tumors including patients with advanced breast cancer Cancer Chemother Pharmacol 2018 Jun 7 doi 101007s00280-018-3610-z [Epub ahead of print]
Celgene (Abraxane)
Gemcitabine + Abraxane (nab-paclitaxel)
Chemo + Chemo
OC BC NSCLC amp Panc cancer + Lung OC BC Kaposi sarcoma
MBC
2016
9
Adjuvant chemo (100)chemo post-adjuvant (33)
Gem (nucleoside metabolic inhibitor 1250 mgm2) on days 1 and 8 nab-Pac (microtubule inhibitor) starting dose of 180 mgm2 (cohort 1) 220 mgm2 (cohort 2) and 260 mgm2 (cohort 3) on day 1 of the 21-day cycle using a 3 + 3 design
0
MTD not reached29 Gr3 Neutropenia59 Gr1 Peripheralneuropathy
Yoshitomi S Taira N Doihara H Mizoo T Nogami T Iwamoto T Motoki T Shien T Ogasawara Y Matsuoka J Tsuji H Mitsuhashi T A phase 1 dose-finding and pharmacokinetic study of gemcitabine with nab-paclitaxel in patients with metastatic breast cancer Cancer Chemother Pharmacol 2016 Aug78(2)289-94
Eli Lilly
Erbituxreg (cetuximab) + Taxane
EGFR inhibitor antineoplastic agent + Chemo
Headamp Neck Colorectal Cancer
TNBC
2007-2010
18
1 chemo
Cetuximab (epidermal growth factor receptor (EGFR) antagonist ) an initial loading dose of cetuximab 400 mgm2 followed by a weekly dose of 250 mgm2Paclitaxel (microtubule inhibitor) 80 mgm2 or Docetaxel at an initial dose of 30 mgm2 was administered weekly
56 CR 22 PR
83 Dermatologic toxicity11 Grade3+
Nechushtan H Vainer G Stainberg H Salmon AY Hamburger T Peretz T A phase 12 of a combination of cetuximab and taxane for triple negative breast cancer patients Breast 2014 Aug23(4)435-8
Polyphor
Balixafortide (POL6326) + eribulin
CXCR4 antagonist + tubulin-based antimitotic
Heavily pretreated Relapsed MBC
2014-2016
56
3rd line 3 chemo
3+3 dose escalation The highest dose was established as eribulin 14 mgmsup2 on days 2 and 9 and balixafortide 55 mgkg on days 1minus3 and 8minus10 of the 21-day cycle
30 PR
41 Gr34 Neutropenia11 Gr34 Leucopenia11 Gr34 Febrileneutropenia2 Related mortalities
Apr 2018 Fast Track for HER2-MBC who have failed 2prior regimens
Pernas S Martin M Kaufman PA Gil-Martin M Gomez Pardo P Lopez-Tarruella S Manso L Ciruelos E Perez-Fidalgo JA Hernando C Ademuyiwa FO Weilbaecher K Mayer I Pluard TJ Martinez Garcia M Vahdat L Perez-Garcia J Wach A Barker D Fung S Romagnoli B Cortes J Balixafortide plus eribulin in HER2-negative metastatic breast cancer a phase 1 single-arm dose-escalation trial Lancet Oncol 2018 Jun19(6)812-824
11 PRndashbut only + letrozole (No Resp on monotherapy)
61 Gr34 Neutropenia39 Gr34 Leucopenia
$933M in 1Q2018 $31B in 2017
Tamura K Mukai H Naito Y Yonemori K Kodaira M Tanabe Y Yamamoto N Osera S Sasaki M Mori Y Hashigaki S Nagasawa T Umeyama Y Yoshino T Phase I study of palbociclib a cyclin-dependent kinase 46 inhibitor in Japanese patients Cancer Sci 2016 Jun107(6)755-63 doi 101111cas12932 Epub 2016 May 11
Pfizer
Ibrancereg (palbociclib)
CDK 46 Inhibitor
HR+ HER2- MBC
Heavily pretreated Relapsed Metastatic Cancer
2004-2008
41 (5 BC)
chemo naiumlve (17) 1-2 (51)3 (29) 3+ (2)
Palbociclib 25-150 mg dose ranging
0
20 Gr34 Neutropenia23 Gr34 Leucopenia
$933M in 1Q2018 $31B in 2017
Flaherty KT Lorusso PM Demichele A Abramson VG Courtney R Randolph SS Shaik MN Wilner KD ODwyer PJ Schwartz GK Phase I dose-escalation trial of the oral cyclin-dependent kinase 46 inhibitor PD 0332991 administered using a 21-day schedule in patients with advanced cancer Clin Cancer Res 2012 Jan 1518(2)568-76 doi 1011581078-0432CCR-11-0509 Epub 2011 Nov 16
Novartis
Kisqalireg (ribociclib)
CDK 46 Inhibitors
Premenopausal HR+ HER2- MBC
Heavily pretreated Relapsed Metastatic Cancer
2016
132 (20 BC)
0-1 (25) 2-3 (42) 4+ (32)
Ribociclib 50 mg ranging up to 1200 mg dose escalation
23 PRndashincluded 1 in BC (5 of BC pts)
27 Gr34 Neutropenia17 Gr34 Leucopenia
Peak sales projected at $25B
Infante JR Cassier PA Gerecitano JF Witteveen PO Chugh R Ribrag V Chakraborty A Matano A Dobson JR Crystal AS Parasuraman S Shapiro GI A Phase I Study of the Cyclin-Dependent Kinase 46 Inhibitor Ribociclib (LEE011) in Patients with Advanced Solid Tumors and Lymphomas Clin Cancer Res 2016 Dec 122(23)5696-5705 Epub 2016 Aug 19
Eli Lilly
Verzenioreg (abemaciclib)
CDK 46 Inhibitors
HR+HER2minusMBC
Heavily pretreated Relapsed Metastatic Cancer
2016
12 (1 BC)
1 (312) 2 (212) 3+ (7)
Abemaciclib 100 mg ranging up to 200 mg dose escalation
17 PR (included 1 in BC)
17 Gr34 Neutropenia33 Gr34 Leucopenia
Peak sales projected at $2B
Fujiwara Y Tamura K Kondo S Tanabe Y Iwasa S Shimomura A Kitano S Ogasawara K Turner PK Mori J Asou H Chan EM Yamamoto N Phase 1 study of abemaciclib an inhibitor of CDK 4 and 6 as a single agent for Japanese patients with advanced cancer Cancer Chemother Pharmacol 2016 Aug78(2)281-8 doi 101007s00280-016-3085-8 Epub 2016 Jun 16
Mukai H Saeki T Shimada K Naito Y Matsubara N Nakanishi T Obaishi H Namiki M Sasaki Y Phase 1 combination study of eribulin mesylate with trastuzumab for advanced or recurrent human epidermal growth factor receptor 2 positive breast cancer Invest New Drugs 2015 Feb33(1)119-27
AstraZeneca
Lynparza (Olaparib)+ Cediranib
PARP inhibitor+ inhibitor of VEGF RTK
HR+ HER2- MBC
BC amp OC
13
28 (8 BC)
3 for BC
Olaparib (a poly (ADP-ribose) polymerase (PARP) inhibitor) amp Cediranib (Vascular endothelial growth factor receptor (VEGFR) 1 2 and 3 tyrosine kinase inhibitor)3 at dose level (DL) 0 (cediranib 20mg olaparib 100mg) 3 at DL1 (cediranib 20mg olaparib 200mg) 7 at DL2 (cediranib 30mg olaparib 200mg) 6 at DL3 (cediranib 30mg olaparib 400mg)
Liu JF Tolaney SM Birrer M Fleming GF Buss MK Dahlberg SE Lee H Whalen C Tyburski K Winer E Ivy P Matulonis UA A Phase 1 trial of the poly(ADP-ribose) polymerase inhibitor olaparib (AZD2281) in combination with the anti-angiogenic cediranib (AZD2171) in recurrent epithelial ovarian or triple-negative breast cancer Eur J Cancer 2013 Sep49(14)2972-8
ReyonPharma
VM206RY
Heterologous prime-boost with a truncated HER2 sequence
HER2+ Stg IIIampIV BC
15
9
2 chemo
Plasmid DNA (pHM-GM-CSF expressing truncated HER2 amp GM-CSF) amp adenoviral vector (Ad-HM containing modified HER2) (2 4 and 8 mgpatientvisit) of pHM-GM-CSF 3x IM weeks 0 2 and 4 Ad-HM 3 times 109 virus particles at week 6
11 PR
4 pts 7 minor AEs
Unclear
Kim SB Ahn JH Kim J Jung KH A phase 1 study of a heterologous prime-boost vaccination involving a truncated HER2 sequence in patients with HER2-expressing breast cancer Mol Ther Methods Clin Dev 2015 Sep 30215031 doi 101038mtm201531 eCollection 2015
Rodon J Peacuterez-Fidalgo A Krop IE Burris H Guerrero-Zotano A Britten CD Becerra C Schellens J Richards DA Schuler M Abu-Khalaf M Johnson FM Ranson M Edenfield J Silva AP Hackl W Quadt C Demanse D Duval V Baselga J Phase 11b dose escalation and expansion study of BEZ235 a dual PI3KmTOR inhibitor in patients with advanced solid tumors including patients with advanced breast cancer Cancer Chemother Pharmacol 2018 Jun 7 doi 101007s00280-018-3610-z [Epub ahead of print]
Celgene(Abraxane)
Gemcitabine + Abraxane (nab-paclitaxel)
Chemo+ Chemo
OC BC NSCLC PC + LC OC BC KS
MBC
16
9
Adjuv chemo (100)chemo post-adjuv (33)
Gem (nucleoside metabolic inhibitor 1250 mgm2) on days 1 and 8 nab-Pac (microtubule inhibitor) starting dose of 180 mgm2 (cohort 1) 220 mgm2 (cohort 2) and 260 mgm2 (cohort 3) on day 1 of the 21-day cycle using a 3 + 3 design
0
MTD not reached29 Gr3 Neutropenia59 Gr1 Peripheralneuropathy
Yoshitomi S Taira N Doihara H Mizoo T Nogami T Iwamoto T Motoki T Shien T Ogasawara Y Matsuoka J Tsuji H Mitsuhashi T A phase 1 dose-finding and pharmacokinetic study of gemcitabine with nab-paclitaxel in patients with metastatic breast cancer Cancer Chemother Pharmacol 2016 Aug78(2)289-94
Eli Lilly
Erbituxreg (cetuximab) + Taxane
EGFR inhibitor antineoplastic agent + Chemo
Head amp NeckColorectal
TNBC
07-10
18
1 chemo
Cetuximab (epidermal growth factor receptor (EGFR) antagonist ) an initial loading dose of cetuximab 400 mgm2 followed by a weekly dose of 250 mgm2Paclitaxel (microtubule inhibitor) 80 mgm2 or Docetaxel at an initial dose of 30 mgm2 was administered weekly
56 CR 22 PR
83 Dermatologic toxicity11 Grade3+
Nechushtan H Vainer G Stainberg H Salmon AY Hamburger T Peretz T A phase 12 of a combination of cetuximab and taxane for triple negative breast cancer patients Breast 2014 Aug23(4)435-8
Polyphor
Balixafortide (POL6326) + eribulin
CXCR4 antagonist + tubulin-based antimitotic
Heavily pretreatedRelapsed MBC
14-16
56
3rd line 3 chemo
3+3 dose escalation The highest dose was established as eribulin 14 mgmsup2 on days 2 and 9 and balixafortide 55 mgkg on days 1minus3 and 8minus10 of the 21-day cycle
30 PR
41 Gr34 Neutropenia11 Gr34 Leucopenia11 Gr34 Febrileneutropenia2 Related mortalities
42018 Fast Track (HER2-MBC failed 2 prior regimens)
Pernas S Martin M Kaufman PA Gil-Martin M Gomez Pardo P Lopez-Tarruella S Manso L Ciruelos E Perez-Fidalgo JA Hernando C Ademuyiwa FO Weilbaecher K Mayer I Pluard TJ Martinez Garcia M Vahdat L Perez-Garcia J Wach A Barker D Fung S Romagnoli B Cortes J Balixafortide plus eribulin in HER2-negative metastatic breast cancer a phase 1 single-arm dose-escalation trial Lancet Oncol 2018 Jun19(6)812-824
1 PRndashbut only + letrozoleNo Resp on monotherapy
61 Gr34 Neutropenia39 Gr34 Leucopenia
$933M (1Q18)$31B (2017)
Tamura K Mukai H Naito Y Yonemori K Kodaira M Tanabe Y Yamamoto N Osera S Sasaki M Mori Y Hashigaki S Nagasawa T Umeyama Y Yoshino T Phase I study of palbociclib a cyclin-dependent kinase 46 inhibitor in Japanese patients Cancer Sci 2016 Jun107(6)755-63 doi 101111cas12932 Epub 2016 May 11
Pfizer
Ibrancereg (palbociclib)
CDK 46 Inhibitor
HR+ HER2- MBC
Heavily pretreatedRelapsed Met Cancer
04-08
41 (5 BC)
chemo naiumlve (17)1-2(51) 3(29) 3+(2)
Palbociclib 25-150 mg dose ranging
0
20 Gr34 Neutropenia23 Gr34 Leucopenia
$933M (1Q18)$31B (2017)
Flaherty KT Lorusso PM Demichele A Abramson VG Courtney R Randolph SS Shaik MN Wilner KD ODwyer PJ Schwartz GK Phase I dose-escalation trial of the oral cyclin-dependent kinase 46 inhibitor PD 0332991 administered using a 21-day schedule in patients with advanced cancer Clin Cancer Res 2012 Jan 1518(2)568-76 doi 1011581078-0432CCR-11-0509 Epub 2011 Nov 16
Novartis
Kisqalireg (ribociclib)
CDK 46 Inhibitor
Premenopausal HR+ HER2- MBC
Heavily pretreatedRelapsed Met Cancer
16
132 (20 BC)
0-1 (25) 2-3 (42)4+ (32)
Ribociclib 50 mg ranging up to 1200 mg dose escalation
23 PR-included 1 BC (5 of BC pts)
27 Gr34 Neutropenia17 Gr34 Leucopenia
Peak sales est at $25B
Infante JR Cassier PA Gerecitano JF Witteveen PO Chugh R Ribrag V Chakraborty A Matano A Dobson JR Crystal AS Parasuraman S Shapiro GI A Phase I Study of the Cyclin-Dependent Kinase 46 Inhibitor Ribociclib (LEE011) in Patients with Advanced Solid Tumors and Lymphomas Clin Cancer Res 2016 Dec 122(23)5696-5705 Epub 2016 Aug 19
Eli Lilly
Verzenioreg (abemaciclib)
CDK 46 Inhibitor
HR+HER2minusMBC
Heavily pretreatedRelapsed Met Cancer
16
12 (1 BC)
1 (312) 2 (212) 3+(7)
Abemaciclib 100 mg ranging up to 200 mg dose escalation
17 PR (included 1 BC)
17 Gr34 Neutropenia33 Gr34 Leucopenia
Peak sales est at $2B
Fujiwara Y Tamura K Kondo S Tanabe Y Iwasa S Shimomura A Kitano S Ogasawara K Turner PK Mori J Asou H Chan EM Yamamoto N Phase 1 study of abemaciclib an inhibitor of CDK 4 and 6 as a single agent for Japanese patients with advanced cancer Cancer Chemother Pharmacol 2016 Aug78(2)281-8 doi 101007s00280-016-3085-8 Epub 2016 Jun 16
41 Gr34 Neutropenia11 Gr34 Leucopenia11 Gr34 Febrileneutropenia2 Related mortalities
30 PRs in combination with Halaven
Bria-IMTTM
20
Injection site reactions No related SAEs or SUSARs
Tumor vol darr ampor darr circul tumor cells)All Comers 21(419) 26(519)One or More HLA matches 27(415) 33(515)Two or More HLA matches 50 (24) 75 (34))
Drug
Technology
Approved for
Market (US)
Ibrance (palbociclib)
CDK 46 Inhibitor
HR+HER2- MBC in combination with fluvestrant or aromatase inhibitor
$933M in 1Q2018 $3126M in 2017
Kisqali (ribociclib)
CDK 46 Inhibitor
2017 HR+HER2- MBC in combination with fluvestrant or aromatase inhibitor
Peak sales projected at $25B
Verzenio (abemaciclib)
CDK 46 Inhibitor
2017 HR+HER2- MBC in combination with fluvestrant or aromatase inhibitor
Peak sales projected at $2B
Lynparza (olaparib)
Poly (ADP-ribose) polymerase (PARP) inhibitor
2017 ovarian amp breast cancer
$997M in 2017
Halaven (eribulin mesylate)
Tubulin-based antimitotic
2H2017 3rd line MBC amp liposarcoma
$181M in 2017
balixafortide
CXCR4 antagonist
Fast track designation in 2018 for HER2- MBC who have failed 2 prior regimens
Cancer Immunotherapy Space
The Problems
Checkpoint Inhibitors Keytrudareg (anti-PD-1) Yervoyreg (anti-CTLA-4) and others reduce the tumorrsquos ability tosuppress immune system They only work in 20-30 of patients as they depend on a patientrsquos own weakenedimmune system to kill the tumor and can cause autoimmune disease
Therapeutic Cancer Vaccines Have not been successful in solid tumors or blood cancers as they are not specificenough to the patient
Personalized Immunotherapies Provengereg is effective for prostate cancer but must be individually manufactured for each patient and as a
result of the required manufacturing logistics has not been commercially successful CAR-T therapies are effective in blood cancers (but not in solid tumors) and must also be individually
manufactured in a complex process for each patient (launching in 2018)
BriaCellrsquos Solution
BriaCellrsquos Off-the-Shelf Personalized Immunotherapy BriaCell has been developing Bria-IMTtrade which is a targetedimmunotherapy for breast cancer Several remarkable responses in patients with late stage cancer have been seenin patients who match Bria-IMTtrade at certain HLA types This supports the development of Bria-OTStrade and BriaDXtradeBriaCellrsquos 15 HLA types (8 Class I amp 7 Class II) covermatch ~90 of the population This saves time and eliminatesthe complex manufacturing process associated with other personalized immunotherapies
3
These allele combinations covermatch with ~90 of the advanced breast cancer population
1 BriaDXtrade reveals the patientrsquos Class I andClass II HLA Alleles
2 The pre-manufactured Bria-OTStrade HLAAlleles are selected for the specificpatient
3 The selected Bria-OTStrade cell lines arethen shipped to the clinical site forpatient treatment
Pre-Manufactured Off-the-Shelf HLA Class II Alleles
Pre-Manufactured Off-the-Shelf HLA Class I Alleles
Bria-IMTtrade - First Product CandidateHuman Proof-of-Concept Trials in Advanced Breast Cancer
Bria-IMTtrade Non-Personalized Immunotherapy
First Proof-of-Concept Phase I (1999-2003) Used unmodified cell line + GM-CSF + cyclophosphamide N = 14 late stage treatment-refractory breast cancer patients Well tolerated no severe drug related AEs Median Overall Survival = 121 months
Second Proof-of-Concept Phase I (2005) Used GM-CSF-engineered cell line + cyclophosphamide + interferon-α N = 4 late stage treatment-refractory (3 breast cancer and 1 ovarian cancer) patients Well tolerated no life-threatening drug related adverse events One patient with transient urticaria reported as grade 3 responded to antihistamines Median Overall Survival = 35 months One robust responder with gt90 regression during treatment subsequent relapse (upon halting
treatment) responded to re-treatment
6
Bria-IMTtrade amp Bria-OTStradePotential Mechanisms of Action in Advanced Breast Cancer
Bria-IMTTM directly stimulates cancerfighting CD4+ and CD8+ T cells(further boosts the response)
Bria-IMTTM produces breastcancer antigens which aretaken up by dendritic cellsand ldquopresentedrdquo to CD4+and CD8+ T cells implicatedin tumor destruction
Bria-IMTTM secretes GM-CSF which further promotes dendritic cell-based antigen presentation (boosts the response) 7
Bria-IMTtradeHuman Proof-of-Concept Trials in Breast Cancer (Patient A002) Bria-IMTtrade Non-Personalized Immunotherapy ndash Given as Monotherapy
Second Proof-of-Concept Phase I (2005) 1 out of 4 patients responded with substantial tumor regression Patient A002 was the only patient with key HLA matches with Bria-IMTtrade
8
Bria-IMTtradeHuman Proof-of-Concept Trials in Breast Cancer (Patient A002) Approximately 3 months (106 days) after last inoculation Patient A002rsquos breast cancer returned and
spread to brain lung and other sites
Patient A002 was then re-treated with 10 inoculations of Bria-IMTtrade over 4 months
Repeat imaging studies showed normal findings on MRI and PET consistent with a completeremission of the previous multiple central nervous system metastases as shown in the brain scansbelow
Bria-IMTtrade and Bria-OTStrade shouldsynergize with existing approvedimmunotherapies as well as those stillunder development
This includes immune checkpointinhibitors such as antibodies to PD-1CTLA-4 GITR and CD73 inhibitors whicheliminate tumor immunosuppression Checkpoint Inhibitors were the
subject of the 2018 Nobel Prize inMedicine
In addition immunostimulatoryantibodies to molecules such as OX40should enhance responses to Bria-IMTtradeand Bria-OTStrade
13
Q3 2018 Data on first 20 Patients on Bria-IMTtrade Q3 2018 Initiate Combination Study of Bria-IMTtrade with Keytruda or Yervoy
Q4 2018 Switch to a novel frozen Bria-IMTtrade formulation Q4 2018 Safety Data (6 patients) of the Bria-IMTtrade - Keytrudareg Combination Study (SABC meeting) Q4 2018 Ongoing Corporate PartnershipCollaboration Discussions
Q1 2019 Efficacy Data (6 patients) of the Bria-IMTtrade - Keytrudareg Combination Study Q2 2019 Initiation of Bria-OTStrade GMP manufacturing (KBI BioPharma) Q2 2019 Additional Safety amp Efficacy data Monotherapy and Combination Studies (AACR meeting) Q2 2019 Final data for Monotherapy and Additional Data for the Combination Study (ASCO meeting) H1 2019 Candidate Selection for a PKCδ Inhibitor H1 2019 Initiate additional immunotherapy program H2 2019 Bria-OTStrade Authorization from FDA clearance for dosing H2 2019 Bria-OTStrade First Patient Dosed
Upcoming Milestones amp Catalysts
14
Involved in over 10 drugs brought to the market
Experienced Management Team
Management
William V Williams MD FACP President amp CEO VP Exploratory Development Incyte Corporation VP Experimental Medicine GlaxoSmithKline Head Rheumatology Research University of Pennsylvania Facilitated entry of over 20 compounds into the clinic including ruxolitinib (Jakafi)
baricitinib amp epacadostat NDAs including Jakafi Boniva Bexxar Author of over 120 peer-reviewed publications amp over 20 patents
Gadi Levin CA MBA CFO CFO of Labstyle Innovations Ltd VP of Finance for two Israeli investment houses in the fields of private equity
hedge funds and real estate Financial Consultant various firms Accountant Arthur Andersen
Markus Lacher PhD Senior Director RampD Founder T cell Therapeutics Inc an immuno-oncology company Sr Clinical Scientist Cesca Therapeutics Inc a clinical-stage autologous cell
therapy company Scientist at BioTime Inc and OncoCyte Corporation Editorial advisory board Recent Patents on Anti-Cancer Drug Discovery
Farrah Dean MSc MBA Manager Corp Development Investor relations CytRx Corporation amp CCG Investor Relations Senior Associate Equity Analyst Oppenheimer amp Co Rodman amp Renshaw amp
Brian Metcalf PhD Recently retired as CSO from Global Blood Therapeutics Former Head of Research amp Development Incyte Corporation Former Head of Medicinal Chemistry SmithKline Beecham
Douglas Faller MD PhD Professor of Medicine Pediatrics Biochemistry Microbiology Pathology and
Laboratory Medicine HematologistOncologist former Director of the Cancer Center Boston University School of Medicine
Founder of several successful biotechnology companies
Robert Williams PhD University Distinguished Professor of Chemistry Colorado State University Founder of several successful biotechnology companies including Microcide Xcyte
Therapies HemaQuest Arch Therapeutics and Cetya Therapeutics
Thomas Kieber-Emmons PhD Deputy Director University of Arkansas Cancer Center Expert in targeted cancer immunotherapies structural biology and computational
chemistry
Maria Trojanowska PhD Professor of Medicine Boston University School of Medicine Director The Arthritis Center
16
Veteran Board of Directors
Board of Directors
Saeid Babaei PhD MBA Chairman Entrepreneur 20 yrs of biotech leadership roles Current CEO AbCelex VP Bus Develop Lorus Therap Dir of Corp Develop Northern Therapeutics
Rahoul Sharan CA Director Chairman Potash Ridge Director of the Board Ansell Capital Corp Parallel Resources amp Galaxy Capital
Corporation
Martin Schmieg CPA Director CFO Sirna Therapeutics Inc amp Isolagen Inc CEO Freedom-2 Inc (now PharmaCyte Inc) Advisor Caladrius Biosciences Inc Beckman Coulter Genomics Calimmune
Charles Wiseman MD Co-Founder amp Director Director Immunotherapy Lab St Vincent Medical Center Chief Breast Cancer Basic Research Lab Univ of Texas MD Anderson Hospital amp
Tumour Institute Assist Prof Dept of Molecular Carcinogenesis amp Virology MD Anderson Acting Chief Div of Oncology White Memorial Medical Center LA
William V Williams MD FACP President amp CEO VP Exploratory Development Incyte Corporation VP Experimental Medicine GlaxoSmithKline Head Rheumatology Research University of Pennsylvania
Prior Affiliations
17
Drug Approvals by BriaCell Management Team
Bexxarreg (tositumomab and Iodine I131 tositumomab) Treatment of CD20 antigen-expressing relapsed or refractory low grade follicular or transformed non-Hodgkins lymphoma
Myleranreg (busulfan) for chronic myelogenous leukemia Defense of formulation change sNDA
Hycamtinreg (topotecan) for ovarian cancer Pediatric use sNDA
Navelbinereg (vinorelbine tartrate) for non-small cell lung cancer Pediatric use sNDA
Bonivareg (ibandronate) monthly oral treatment of osteoporosis
Bonivareg (ibandronate) quarterly intraveous treatment of osteoporosis
Zofranreg (ondansetron) for prevention of nausea and vomiting Pediatric use sNDA
Jakafireg (ruxolitinib) for myelofibrosis Jakafireg (ruxolitinib) for polycythemia vera
Olumiantreg (baricitinib) for rheumatoid arthritis Approved in USA Japan and Europe
18
Share Metrics
BCTV BCTXF 19
Data as of 1092018
Ticker TSX BCTV
US Ticker OTCQBBCTXF
Share Price (CAD) as of Oct 9 2018 $012
52-Week Range (CAD) $009-019
Shares Outstanding as of Oct 9 2018 1611M
Market Cap as of Oct 9 2018 (CAD) $193M
Cash and Short Term Investments as of July 31 2018 (CAD) $23M
Total Shareholders Equity as of July 31 2018 (CAD) $12M
Number of Warrants $014-$035 (CAD) as of Oct 9 2018 601M
Number of Compensation Warrants $014-$030 (CAD) as of Oct 9 2018 45M
Number of Options $014- $026 (CAD$) as of Oct 9 2018 93M
Developing Bria-OTStrade the First Off-the-Shelf Personalized Immunotherapy
Targeting Adv Breast Cancer Unmet medical need (42000 death in the US in 2017 ) $1 Bil- $5 Bil market opportunity depending on patient treatment stage
Impressive results in 2 proof-of-concept clinical trials Rapid Response Rate Repeated following re-treatment Excellent Safety Profile
Completed enrollment in Phase IIIa clinical trial of Bria-IMTtrade with outstanding safety amp efficacy data Initiated Phase IIa Combination Study of Bria-IMTtrade with Keytrudareg (Merck amp Co Inc)
Developing Bria-OTStrade along with BriaDXtrade its companion diagnostic test Ability to match and treat ~90 of patient population with Off-the-Shelf personalized immunotherapy
Experienced Management has been involved in over 10 drug approvals
Patient B001 Breast 70 No 1101 - 3501 4001 Negative -
Bria-IMTtradeHuman Proof-of-Concept Trials in Breast Cancer (Patient A002)
24
Proof-of-Concept Results Resulted in BriaCellrsquos Immunotherapy Strategy Use BriaDXtrade diagnostic to select only those patients matching Bria-IMTtrade Use BriaDXtrade diagnostic test to select Bria-OTStrade alleles matching ~90 of all patients
Bria-IMTtradeCurrent Phase IIIa Data Supports HLA Matching Hypothesis Six patients treated in 2017 Bria-IMTtrade was safe and well tolerated
Patient 01-002 73-year-old woman with breast cancer diagnosed in 1995 Developed liver metastases in2010 and lung metastases in 2017 Previously treated with 7 rounds of chemotherapy with 8 differentchemotherapy agents Received 5 cycles of Bria-IMTtrade over 3 months then monthly cycles (6 months total)Evaluated after 3 months and 6 months After 3 months despite the extensive prior therapy her scans notedthat ldquothere has been a clear response in the multiple bilateral pulmonary nodulesrdquo The response wasmaintained after 6 months of Bria-IMTtrade treatment She matches Bria-IMTtrade at 2 HLA alleles
The liver tumors were stable to slightly increased at 3 months and then progressed after 6 months
This supports our hypothesis of heightened anti-tumor activity in patients with a matched HLA types Clear path to develop BriaDXtrade to select the patients using HLA testing
1 RLL 29 Not Detectable Not Detectable2 LUL apical pleural based 34 tiny nodule lt 1mm scar tiny nodule lt 1mm scar3 xxx 39 Not Detectable Not Detectable4 40 Not Detectable Not Detectable5 RLL 45 Not Detectable Not Detectable6 LLL 49 Not Detectable Not Detectable7 xxx 52 Not Detectable Not Detectable8 RLL 52 Not Detectable Not Detectable9 RLL 56 Not Detectable Not Detectable
10 RLL costophrenic recess 56 Not Detectable Not Detectable11 XXX 58 Not Detectable Not Detectable12 LUL 60 Not Detectable Not Detectable13 XXX 67 15 1514 RUL 72 15 1515 LLL 76 Not Detectable Not Detectable16 RUL Noncalcified Nodule 77 Not Detectable Not Detectable17 RLL costophrenic recess 79 10 1018 RUL 82 Not Detectable Not Detectable19 RLL 90 Not Detectable Not Detectable20 RLL 91 lt 01 lt 0121 xxx xxx Not Detectable Not Detectable
27
Clinical Development Update ndash Summary 2018 September 26
Completed enrollment of Adv Breast cancer patients in the Phase IIIa ldquomonotherapyrdquo study of Bria-IMTtrade
We have confirmed our mechanism of action and achieved proof of concept
Initial safety data appears superior to that of the other advanced or approved drugs for breast cancer when they were at a similar clinical stage of development
Initial efficacy data is similar or superior to those of other advanced or approved drugs for breast cancer when they were at a similar clinical stage of development
Initiated Combination Study of Bria-IMTtrade with Keytrudareg or Yervoyreg in Adv breast cancer patients expecting even better response rates than those in the ldquomonotherapyrdquo study Initial safety data is expected in 4Q2018 Initial efficacy data is expected in 1Q2019
Bria-OTStrade the first off-the-shelf personalized treatment for advanced breast cancer is expected to enter the clinic in 2019
28
Bria-IMTtrade Excellent Safety Data - To Date
To date Bria-IMTtrade has been dosed in 24 patients (4 in 2004-2005 20 in 2017-2018)
Interim Data (20 patients)-Ongoing Phase IIIa Study (2017-2018)
Bria-IMTtrade has been very well tolerated (ge60 doses given to date) The majority of adverse events (AEs) were limited to expected minor local irritation at the
injection sites No related grade gt3 or unexpected AEs No related serious AEs No serious unexpected related AEs Most patients who have dropped out did so due to worsening of their underlying disease
Based on the current study Bria-IMTtrade has an excellent safety profile
29
Bria-IMTtrade - Efficacy as Predicted
Interim Data (19 patients)-Ongoing Phase IIIa Study (2017-2018) amp Original Study (2004-2005)
PD-L1 expression on circulating cancer cells amp cancer-associated cells in 100 of patients (to date) Strong rationale for combination with checkpoint inhibitors like Keytruda
30
Bria-IMTtrade appears to be most effective in patients who match with Bria-IMT trade at 2 HLA loci (types) further supporting our ldquoHLA Matching Hypothesisrdquo and the development of Bria-OTS trade to cover 90 of the patient population
Combination with immune checkpoint inhibitors may induce a more potent anti-cancer response leading to our strategy of combination studies of Bria-IMT trade with Keytruda or Yervoy
Patients (n) HLA Match
Tumor Shrinkage
Biological Response
4 ge2 50 7515 ge1 27 334 0 0 0
Biological response includes tumor shrinkage or lower circulating cancer associated cells
The confirmatory Bria-IMTtrade monotherapy Phase IIa trial has completed enrollment Additional Support for the HLA-matching hypothesis has been obtained
Bria-IMTtrade Combination Therapy study with immune checkpoint inhibitors Keytrudareg if PD-L12 positive (ge1) Yervoyreg if PD-L12 negative (lt1) Accepting patients from the monotherapy study who develop progressive disease Also enrolling patients directly into this study to enhance experience with the combination In discussion with other pharmaceutical companies to evaluate additional combinations with other
immunotherapies
Bria-OTStrade Off-the-Shelf Personalized Targeted Immunotherapy Developing Bria-OTStrade to co-express GM-CSF and interferon-α Pre-manufacture additional HLA alleles ndash Total of 15 alleles (8 Class I and 7 Class II) Co-development of BriaDXtrade companion diagnostic for HLA typing Combination therapy clinical trial with immune checkpoint inhibitors for non-responders using
information from the Bria-IMTtrade Combination Therapy Study
33
Development Timeline ndash Breast Cancer
20192018 2020 2021
Phase IIIaBria-IMTtrade
Monotherapy
Currently Enrolling Phase IIaBria-IMTtrade + Checkpoint
Currently in discussions with potential partnersPhase II Bria-IMTtrade plus Additional Combinations (1Q19 4Q22)(eg PD-1 Inhibitor PD-L1 inhibitor anti-CTLA4 anti-GITR anti-OX40)
1Q 2Q 3Q 4Q
2023
Bria-OTStrade Off-The-Shelf Personalized ImmunotherapyMonotherapy and Potential Partnered Combo Therapy
(2H19 Ongoing)
Bria-OTStradeOff-the-Shelf Cell Line cGMP Manufacturing
and BriaDXtrade(1Q18 1Q19)
Registration Studies (1Q20 2H22)Bria-IMTtrade with Checkpoint InhibitorsBria-OTStrade +- Checkpoint Inhibitors
34
Immuno-oncology Deals
Recent deals of small biotechs with big pharma in immuno-oncology
35
Date PartnershipDevelopment stage at the time of the deal Deal size
07122018 Immatics-Genmab Preclinical Up to $28B
04042018 OSE Immunotherapeutics-Boehringer Ingelheim Preclinical Up to euro113B ($139B)
02092018 Pieris Pharmaceuticals-Seattle Genetics Preclinical Up to $123B
2142018 Nektar-BMS Ph III Up to $36B
01222018 Juno-Celgene Ph II $9B (Acquisition)
11142017 Loxo-Bayer Larotrectinib (Ph II) LOXO-195 (Ph III) Up to $155B
1032017 CytomX-Amgen Preclinical Up to $15B
03202017 CytomX--BMS Ph III Up to $36B
6282016 Xencor-Novartis Preclinical Up to $24B
Early Stage Clinical Studies (Comparison)
We compared the interim data of Ph IIIa study of Bria-IMTtrade in advanced breast cancer with thedata in the early stage clinical studies of recently approved breast cancer drugs and one fasttracked product candidate
Apples to apples comparison Early Stage Clinical Studies in oncology are typically done in patientswith no other therapeutic options Thus the patients have very advanced disease and response ratesare typically quite low
The patients in our Ph IIIa study have been heavily pre-treated (median 45 prior regimens)Some recent studies of relevance in breast cancer are noted in the following slides
36
Breast Cancer Market Opportunity
Drug Technology Approved for Market (US)Ibrance (palbociclib) CDK 46 Inhibitor HR+HER2- MBC in combination with
fluvestrant or aromatase inhibitor$933M in 1Q2018 $3126M in 2017
Kisqali (ribociclib) CDK 46 Inhibitor 2017 HR+HER2- MBC in combination with fluvestrant or aromatase inhibitor
Peak sales projected at $25B
Verzenio (abemaciclib) CDK 46 Inhibitor 2017 HR+HER2- MBC in combination with fluvestrant or aromatase inhibitor
balixafortide CXCR4 antagonist Fast track designation in 2018 for HER2- MBC who have failed 2 prior regimens
The market for breast cancer drugs is a multibillion dollar market with new drugs being approvedon an ongoing basis indicating the shortage of safe and effective treatments for this deadly disease
37
Competitors- Phase III Clinical Data Bria-IMTtrade shows superior safety and similar to superior efficacy data compared with those of the multi-billion dollar drugs when they were at a similar early stage of clinical development
Injection site reactions No related SAEs or SUSARs
Tumor vol darr ampor darr circul tumor cellsAll Comers 21(419) 26(519)One or More HLA matches 27(415) 33(515)Two or More HLA matches 50 (24) 75 (34)
Sheet1 (3)
Comp -Slides
Data
HLA (2)
HLA
Data (Ph1-2+4Pt)
Competitors (2018)-Slide
Competitors (2018)
In the Pipeline Protein Kinase C delta (PKCδ) Inhibitors
30 of all human malignancies display activating RAS mutations Another 60 showing over-activity of Ras-signaling pathways
Ras has been termed ldquoundruggablerdquo (no one has been able to make a Ras inhibitor drug)
BriaCellrsquos novel proprietary PKCδ inhibitors have shown activity against multiple RAS transformed tumors Lung cancer Melanoma Breast cancer Neuroendocrine cancer Pancreatic cancer Colorectal cancer
This target has an attractive safety profile based on in vivo studies and knock out mouse studies
PKCδ inhibitors should qualify for an accelerated clinical development plan and regulatory pathway
Could be in clinic within 24 months
Cost-Effective Additional Shot-on-Goal and additional partnership opportunities
Early-Stage Preclinical Program
39
Protein Kinase C delta (PKCδ) Inhibitors
Activated PKCδ inhibits RAS degradation which in turn stimulates tumor growth
Koo et al Oncotarget 621328 2016
30 of all human malignancies display activating RASmutations with another 60 showing over-activity of Ras-signaling pathways
BriaCellrsquos novel proprietary PKCδ inhibitors have shownactivity against multiple RAS transformed tumors
This target has an attractive safety profile based on in vivostudies and knock out mouse studies
PKCδ also has potential activity as an immunotherapeuticby blocking TGFβ signaling
PKCδ inhibitors are applicable to specific niche tumor typeswhich provide an accelerated clinical development plan
Structural aspects of first generation inhibitor rottlerin and staurosporine (pan-PKC activator) were combined to create second generation inhibitor KAM1
Third generation inhibitors such as BJE6-106 have improved potency and selectivity Fourth generation inhibitors under development to optimize drug-like characteristics PKCδ inhibitors lack endothelial cell cytotoxicity amp PKCδ deficient mice develop normally and are fertile Potentially no marked intrinsic toxicity by inhibiting PKCδ
Mukai H Saeki T Shimada K Naito Y Matsubara N Nakanishi T Obaishi H Namiki M Sasaki Y Phase 1 combination study of eribulin mesylate with trastuzumab for advanced or recurrent human epidermal growth factor receptor 2 positive breast cancer Invest New Drugs 2015 Feb33(1)119-27
AstraZeneca
Lynparza (Olaparib) + Cediranib
PARP inhibitor + inhibitor of VEGF receptor tyrosine kinases
HR+ HER2- MBC
BC amp OC
2013
28 (8 BC)
3 for BC
Olaparib (a poly (ADP-ribose) polymerase (PARP) inhibitor) amp Cediranib (Vascular endothelial growth factor receptor (VEGFR) 1 2 and 3 tyrosine kinase inhibitor)3 at dose level (DL) 0 (cediranib 20mg olaparib 100mg) 3 at DL1 (cediranib 20mg olaparib 200mg) 7 at DL2 (cediranib 30mg olaparib 200mg) 6 at DL3 (cediranib 30mg olaparib 400mg)
Liu JF Tolaney SM Birrer M Fleming GF Buss MK Dahlberg SE Lee H Whalen C Tyburski K Winer E Ivy P Matulonis UA A Phase 1 trial of the poly(ADP-ribose) polymerase inhibitor olaparib (AZD2281) in combination with the anti-angiogenic cediranib (AZD2171) in recurrent epithelial ovarian or triple-negative breast cancer Eur J Cancer 2013 Sep49(14)2972-8
Reyon Pharmaceutical
VM206RY
Heterologous prime-boost with a truncated HER2 sequence
HER2+ Stage IIIampIV BC
2015
9
2 chemo
Plasmid DNA (pHM-GM-CSF expressing truncated HER2 amp GM-CSF) amp adenoviral vector (Ad-HM containing modified HER2) (2 4 and 8 mgpatientvisit) of pHM-GM-CSF 3x IM weeks 0 2 and 4 Ad-HM 3 times 109 virus particles at week 6
11 PR
4 pts showed 7 minor AEs
Unclear
Kim SB Ahn JH Kim J Jung KH A phase 1 study of a heterologous prime-boost vaccination involving a truncated HER2 sequence in patients with HER2-expressing breast cancer Mol Ther Methods Clin Dev 2015 Sep 30215031 doi 101038mtm201531 eCollection 2015
Rodon J Peacuterez-Fidalgo A Krop IE Burris H Guerrero-Zotano A Britten CD Becerra C Schellens J Richards DA Schuler M Abu-Khalaf M Johnson FM Ranson M Edenfield J Silva AP Hackl W Quadt C Demanse D Duval V Baselga J Phase 11b dose escalation and expansion study of BEZ235 a dual PI3KmTOR inhibitor in patients with advanced solid tumors including patients with advanced breast cancer Cancer Chemother Pharmacol 2018 Jun 7 doi 101007s00280-018-3610-z [Epub ahead of print]
Celgene (Abraxane)
Gemcitabine + Abraxane (nab-paclitaxel)
Chemo + Chemo
OC BC NSCLC amp Panc cancer + Lung OC BC Kaposi sarcoma
MBC
2016
9
Adjuvant chemo (100)chemo post-adjuvant (33)
Gem (nucleoside metabolic inhibitor 1250 mgm2) on days 1 and 8 nab-Pac (microtubule inhibitor) starting dose of 180 mgm2 (cohort 1) 220 mgm2 (cohort 2) and 260 mgm2 (cohort 3) on day 1 of the 21-day cycle using a 3 + 3 design
0
MTD not reached29 Gr3 Neutropenia59 Gr1 Peripheralneuropathy
Yoshitomi S Taira N Doihara H Mizoo T Nogami T Iwamoto T Motoki T Shien T Ogasawara Y Matsuoka J Tsuji H Mitsuhashi T A phase 1 dose-finding and pharmacokinetic study of gemcitabine with nab-paclitaxel in patients with metastatic breast cancer Cancer Chemother Pharmacol 2016 Aug78(2)289-94
Eli Lilly
Erbituxreg (cetuximab) + Taxane
EGFR inhibitor antineoplastic agent + Chemo
Headamp Neck Colorectal Cancer
TNBC
2007-2010
18
1 chemo
Cetuximab (epidermal growth factor receptor (EGFR) antagonist ) an initial loading dose of cetuximab 400 mgm2 followed by a weekly dose of 250 mgm2Paclitaxel (microtubule inhibitor) 80 mgm2 or Docetaxel at an initial dose of 30 mgm2 was administered weekly
56 CR 22 PR
83 Dermatologic toxicity11 Grade3+
Nechushtan H Vainer G Stainberg H Salmon AY Hamburger T Peretz T A phase 12 of a combination of cetuximab and taxane for triple negative breast cancer patients Breast 2014 Aug23(4)435-8
Polyphor
Balixafortide (POL6326) + eribulin
CXCR4 antagonist + tubulin-based antimitotic
Heavily pretreated Relapsed MBC
2014-2016
56
3rd line 3 chemo
3+3 dose escalation The highest dose was established as eribulin 14 mgmsup2 on days 2 and 9 and balixafortide 55 mgkg on days 1minus3 and 8minus10 of the 21-day cycle
30 PR
41 Gr34 Neutropenia11 Gr34 Leucopenia11 Gr34 Febrileneutropenia2 Related mortalities
Apr 2018 Fast Track for HER2-MBC who have failed 2prior regimens
Pernas S Martin M Kaufman PA Gil-Martin M Gomez Pardo P Lopez-Tarruella S Manso L Ciruelos E Perez-Fidalgo JA Hernando C Ademuyiwa FO Weilbaecher K Mayer I Pluard TJ Martinez Garcia M Vahdat L Perez-Garcia J Wach A Barker D Fung S Romagnoli B Cortes J Balixafortide plus eribulin in HER2-negative metastatic breast cancer a phase 1 single-arm dose-escalation trial Lancet Oncol 2018 Jun19(6)812-824
11 PRndashbut only + letrozole (No Resp on monotherapy)
61 Gr34 Neutropenia39 Gr34 Leucopenia
$933M in 1Q2018 $31B in 2017
Tamura K Mukai H Naito Y Yonemori K Kodaira M Tanabe Y Yamamoto N Osera S Sasaki M Mori Y Hashigaki S Nagasawa T Umeyama Y Yoshino T Phase I study of palbociclib a cyclin-dependent kinase 46 inhibitor in Japanese patients Cancer Sci 2016 Jun107(6)755-63 doi 101111cas12932 Epub 2016 May 11
Pfizer
Ibrancereg (palbociclib)
CDK 46 Inhibitor
HR+ HER2- MBC
Heavily pretreated Relapsed Metastatic Cancer
2004-2008
41 (5 BC)
chemo naiumlve (17) 1-2 (51)3 (29) 3+ (2)
Palbociclib 25-150 mg dose ranging
0
20 Gr34 Neutropenia23 Gr34 Leucopenia
$933M in 1Q2018 $31B in 2017
Flaherty KT Lorusso PM Demichele A Abramson VG Courtney R Randolph SS Shaik MN Wilner KD ODwyer PJ Schwartz GK Phase I dose-escalation trial of the oral cyclin-dependent kinase 46 inhibitor PD 0332991 administered using a 21-day schedule in patients with advanced cancer Clin Cancer Res 2012 Jan 1518(2)568-76 doi 1011581078-0432CCR-11-0509 Epub 2011 Nov 16
Novartis
Kisqalireg (ribociclib)
CDK 46 Inhibitors
Premenopausal HR+ HER2- MBC
Heavily pretreated Relapsed Metastatic Cancer
2016
132 (20 BC)
0-1 (25) 2-3 (42) 4+ (32)
Ribociclib 50 mg ranging up to 1200 mg dose escalation
23 PRndashincluded 1 in BC (5 of BC pts)
27 Gr34 Neutropenia17 Gr34 Leucopenia
Peak sales projected at $25B
Infante JR Cassier PA Gerecitano JF Witteveen PO Chugh R Ribrag V Chakraborty A Matano A Dobson JR Crystal AS Parasuraman S Shapiro GI A Phase I Study of the Cyclin-Dependent Kinase 46 Inhibitor Ribociclib (LEE011) in Patients with Advanced Solid Tumors and Lymphomas Clin Cancer Res 2016 Dec 122(23)5696-5705 Epub 2016 Aug 19
Eli Lilly
Verzenioreg (abemaciclib)
CDK 46 Inhibitors
HR+HER2minusMBC
Heavily pretreated Relapsed Metastatic Cancer
2016
12 (1 BC)
1 (312) 2 (212) 3+ (7)
Abemaciclib 100 mg ranging up to 200 mg dose escalation
17 PR (included 1 in BC)
17 Gr34 Neutropenia33 Gr34 Leucopenia
Peak sales projected at $2B
Fujiwara Y Tamura K Kondo S Tanabe Y Iwasa S Shimomura A Kitano S Ogasawara K Turner PK Mori J Asou H Chan EM Yamamoto N Phase 1 study of abemaciclib an inhibitor of CDK 4 and 6 as a single agent for Japanese patients with advanced cancer Cancer Chemother Pharmacol 2016 Aug78(2)281-8 doi 101007s00280-016-3085-8 Epub 2016 Jun 16
Mukai H Saeki T Shimada K Naito Y Matsubara N Nakanishi T Obaishi H Namiki M Sasaki Y Phase 1 combination study of eribulin mesylate with trastuzumab for advanced or recurrent human epidermal growth factor receptor 2 positive breast cancer Invest New Drugs 2015 Feb33(1)119-27
AstraZeneca
Lynparza (Olaparib)+ Cediranib
PARP inhibitor+ inhibitor of VEGF RTK
HR+ HER2- MBC
BC amp OC
13
28 (8 BC)
3 for BC
Olaparib (a poly (ADP-ribose) polymerase (PARP) inhibitor) amp Cediranib (Vascular endothelial growth factor receptor (VEGFR) 1 2 and 3 tyrosine kinase inhibitor)3 at dose level (DL) 0 (cediranib 20mg olaparib 100mg) 3 at DL1 (cediranib 20mg olaparib 200mg) 7 at DL2 (cediranib 30mg olaparib 200mg) 6 at DL3 (cediranib 30mg olaparib 400mg)
Liu JF Tolaney SM Birrer M Fleming GF Buss MK Dahlberg SE Lee H Whalen C Tyburski K Winer E Ivy P Matulonis UA A Phase 1 trial of the poly(ADP-ribose) polymerase inhibitor olaparib (AZD2281) in combination with the anti-angiogenic cediranib (AZD2171) in recurrent epithelial ovarian or triple-negative breast cancer Eur J Cancer 2013 Sep49(14)2972-8
ReyonPharma
VM206RY
Heterologous prime-boost with a truncated HER2 sequence
HER2+ Stg IIIampIV BC
15
9
2 chemo
Plasmid DNA (pHM-GM-CSF expressing truncated HER2 amp GM-CSF) amp adenoviral vector (Ad-HM containing modified HER2) (2 4 and 8 mgpatientvisit) of pHM-GM-CSF 3x IM weeks 0 2 and 4 Ad-HM 3 times 109 virus particles at week 6
11 PR
4 pts 7 minor AEs
Unclear
Kim SB Ahn JH Kim J Jung KH A phase 1 study of a heterologous prime-boost vaccination involving a truncated HER2 sequence in patients with HER2-expressing breast cancer Mol Ther Methods Clin Dev 2015 Sep 30215031 doi 101038mtm201531 eCollection 2015
Rodon J Peacuterez-Fidalgo A Krop IE Burris H Guerrero-Zotano A Britten CD Becerra C Schellens J Richards DA Schuler M Abu-Khalaf M Johnson FM Ranson M Edenfield J Silva AP Hackl W Quadt C Demanse D Duval V Baselga J Phase 11b dose escalation and expansion study of BEZ235 a dual PI3KmTOR inhibitor in patients with advanced solid tumors including patients with advanced breast cancer Cancer Chemother Pharmacol 2018 Jun 7 doi 101007s00280-018-3610-z [Epub ahead of print]
Celgene(Abraxane)
Gemcitabine + Abraxane (nab-paclitaxel)
Chemo+ Chemo
OC BC NSCLC PC + LC OC BC KS
MBC
16
9
Adjuv chemo (100)chemo post-adjuv (33)
Gem (nucleoside metabolic inhibitor 1250 mgm2) on days 1 and 8 nab-Pac (microtubule inhibitor) starting dose of 180 mgm2 (cohort 1) 220 mgm2 (cohort 2) and 260 mgm2 (cohort 3) on day 1 of the 21-day cycle using a 3 + 3 design
0
MTD not reached29 Gr3 Neutropenia59 Gr1 Peripheralneuropathy
Yoshitomi S Taira N Doihara H Mizoo T Nogami T Iwamoto T Motoki T Shien T Ogasawara Y Matsuoka J Tsuji H Mitsuhashi T A phase 1 dose-finding and pharmacokinetic study of gemcitabine with nab-paclitaxel in patients with metastatic breast cancer Cancer Chemother Pharmacol 2016 Aug78(2)289-94
Eli Lilly
Erbituxreg (cetuximab) + Taxane
EGFR inhibitor antineoplastic agent + Chemo
Head amp NeckColorectal
TNBC
07-10
18
1 chemo
Cetuximab (epidermal growth factor receptor (EGFR) antagonist ) an initial loading dose of cetuximab 400 mgm2 followed by a weekly dose of 250 mgm2Paclitaxel (microtubule inhibitor) 80 mgm2 or Docetaxel at an initial dose of 30 mgm2 was administered weekly
56 CR 22 PR
83 Dermatologic toxicity11 Grade3+
Nechushtan H Vainer G Stainberg H Salmon AY Hamburger T Peretz T A phase 12 of a combination of cetuximab and taxane for triple negative breast cancer patients Breast 2014 Aug23(4)435-8
Polyphor
Balixafortide (POL6326) + eribulin
CXCR4 antagonist + tubulin-based antimitotic
Heavily pretreatedRelapsed MBC
14-16
56
3rd line 3 chemo
3+3 dose escalation The highest dose was established as eribulin 14 mgmsup2 on days 2 and 9 and balixafortide 55 mgkg on days 1minus3 and 8minus10 of the 21-day cycle
30 PR
41 Gr34 Neutropenia11 Gr34 Leucopenia11 Gr34 Febrileneutropenia2 Related mortalities
42018 Fast Track (HER2-MBC failed 2 prior regimens)
Pernas S Martin M Kaufman PA Gil-Martin M Gomez Pardo P Lopez-Tarruella S Manso L Ciruelos E Perez-Fidalgo JA Hernando C Ademuyiwa FO Weilbaecher K Mayer I Pluard TJ Martinez Garcia M Vahdat L Perez-Garcia J Wach A Barker D Fung S Romagnoli B Cortes J Balixafortide plus eribulin in HER2-negative metastatic breast cancer a phase 1 single-arm dose-escalation trial Lancet Oncol 2018 Jun19(6)812-824
1 PRndashbut only + letrozoleNo Resp on monotherapy
61 Gr34 Neutropenia39 Gr34 Leucopenia
$933M (1Q18)$31B (2017)
Tamura K Mukai H Naito Y Yonemori K Kodaira M Tanabe Y Yamamoto N Osera S Sasaki M Mori Y Hashigaki S Nagasawa T Umeyama Y Yoshino T Phase I study of palbociclib a cyclin-dependent kinase 46 inhibitor in Japanese patients Cancer Sci 2016 Jun107(6)755-63 doi 101111cas12932 Epub 2016 May 11
Pfizer
Ibrancereg (palbociclib)
CDK 46 Inhibitor
HR+ HER2- MBC
Heavily pretreatedRelapsed Met Cancer
04-08
41 (5 BC)
chemo naiumlve (17)1-2(51) 3(29) 3+(2)
Palbociclib 25-150 mg dose ranging
0
20 Gr34 Neutropenia23 Gr34 Leucopenia
$933M (1Q18)$31B (2017)
Flaherty KT Lorusso PM Demichele A Abramson VG Courtney R Randolph SS Shaik MN Wilner KD ODwyer PJ Schwartz GK Phase I dose-escalation trial of the oral cyclin-dependent kinase 46 inhibitor PD 0332991 administered using a 21-day schedule in patients with advanced cancer Clin Cancer Res 2012 Jan 1518(2)568-76 doi 1011581078-0432CCR-11-0509 Epub 2011 Nov 16
Novartis
Kisqalireg (ribociclib)
CDK 46 Inhibitor
Premenopausal HR+ HER2- MBC
Heavily pretreatedRelapsed Met Cancer
16
132 (20 BC)
0-1 (25) 2-3 (42)4+ (32)
Ribociclib 50 mg ranging up to 1200 mg dose escalation
23 PR-included 1 BC (5 of BC pts)
27 Gr34 Neutropenia17 Gr34 Leucopenia
Peak sales est at $25B
Infante JR Cassier PA Gerecitano JF Witteveen PO Chugh R Ribrag V Chakraborty A Matano A Dobson JR Crystal AS Parasuraman S Shapiro GI A Phase I Study of the Cyclin-Dependent Kinase 46 Inhibitor Ribociclib (LEE011) in Patients with Advanced Solid Tumors and Lymphomas Clin Cancer Res 2016 Dec 122(23)5696-5705 Epub 2016 Aug 19
Eli Lilly
Verzenioreg (abemaciclib)
CDK 46 Inhibitor
HR+HER2minusMBC
Heavily pretreatedRelapsed Met Cancer
16
12 (1 BC)
1 (312) 2 (212) 3+(7)
Abemaciclib 100 mg ranging up to 200 mg dose escalation
17 PR (included 1 BC)
17 Gr34 Neutropenia33 Gr34 Leucopenia
Peak sales est at $2B
Fujiwara Y Tamura K Kondo S Tanabe Y Iwasa S Shimomura A Kitano S Ogasawara K Turner PK Mori J Asou H Chan EM Yamamoto N Phase 1 study of abemaciclib an inhibitor of CDK 4 and 6 as a single agent for Japanese patients with advanced cancer Cancer Chemother Pharmacol 2016 Aug78(2)281-8 doi 101007s00280-016-3085-8 Epub 2016 Jun 16
Mukai H Saeki T Shimada K Naito Y Matsubara N Nakanishi T Obaishi H Namiki M Sasaki Y Phase 1 combination study of eribulin mesylate with trastuzumab for advanced or recurrent human epidermal growth factor receptor 2 positive breast cancer Invest New Drugs 2015 Feb33(1)119-27
AstraZeneca
Lynparza (Olaparib) + Cediranib
PARP inhibitor + inhibitor of VEGF receptor tyrosine kinases
HR+ HER2- MBC
BC amp OC
2013
28 (8 BC)
3 for BC
Olaparib (a poly (ADP-ribose) polymerase (PARP) inhibitor) amp Cediranib (Vascular endothelial growth factor receptor (VEGFR) 1 2 and 3 tyrosine kinase inhibitor)3 at dose level (DL) 0 (cediranib 20mg olaparib 100mg) 3 at DL1 (cediranib 20mg olaparib 200mg) 7 at DL2 (cediranib 30mg olaparib 200mg) 6 at DL3 (cediranib 30mg olaparib 400mg)
Liu JF Tolaney SM Birrer M Fleming GF Buss MK Dahlberg SE Lee H Whalen C Tyburski K Winer E Ivy P Matulonis UA A Phase 1 trial of the poly(ADP-ribose) polymerase inhibitor olaparib (AZD2281) in combination with the anti-angiogenic cediranib (AZD2171) in recurrent epithelial ovarian or triple-negative breast cancer Eur J Cancer 2013 Sep49(14)2972-8
Reyon Pharmaceutical
VM206RY
Heterologous prime-boost with a truncated HER2 sequence
HER2+ Stage IIIampIV BC
2015
9
2 chemo
Plasmid DNA (pHM-GM-CSF expressing truncated HER2 amp GM-CSF) amp adenoviral vector (Ad-HM containing modified HER2) (2 4 and 8 mgpatientvisit) of pHM-GM-CSF 3x IM weeks 0 2 and 4 Ad-HM 3 times 109 virus particles at week 6
11 PR
4 pts showed 7 minor AEs
Unclear
Kim SB Ahn JH Kim J Jung KH A phase 1 study of a heterologous prime-boost vaccination involving a truncated HER2 sequence in patients with HER2-expressing breast cancer Mol Ther Methods Clin Dev 2015 Sep 30215031 doi 101038mtm201531 eCollection 2015
Rodon J Peacuterez-Fidalgo A Krop IE Burris H Guerrero-Zotano A Britten CD Becerra C Schellens J Richards DA Schuler M Abu-Khalaf M Johnson FM Ranson M Edenfield J Silva AP Hackl W Quadt C Demanse D Duval V Baselga J Phase 11b dose escalation and expansion study of BEZ235 a dual PI3KmTOR inhibitor in patients with advanced solid tumors including patients with advanced breast cancer Cancer Chemother Pharmacol 2018 Jun 7 doi 101007s00280-018-3610-z [Epub ahead of print]
Celgene (Abraxane)
Gemcitabine + Abraxane (nab-paclitaxel)
Chemo + Chemo
OC BC NSCLC amp Panc cancer + Lung OC BC Kaposi sarcoma
MBC
2016
9
Adjuvant chemo (100)chemo post-adjuvant (33)
Gem (nucleoside metabolic inhibitor 1250 mgm2) on days 1 and 8 nab-Pac (microtubule inhibitor) starting dose of 180 mgm2 (cohort 1) 220 mgm2 (cohort 2) and 260 mgm2 (cohort 3) on day 1 of the 21-day cycle using a 3 + 3 design
0
MTD not reached29 Gr3 Neutropenia59 Gr1 Peripheralneuropathy
Yoshitomi S Taira N Doihara H Mizoo T Nogami T Iwamoto T Motoki T Shien T Ogasawara Y Matsuoka J Tsuji H Mitsuhashi T A phase 1 dose-finding and pharmacokinetic study of gemcitabine with nab-paclitaxel in patients with metastatic breast cancer Cancer Chemother Pharmacol 2016 Aug78(2)289-94
Eli Lilly
Erbituxreg (cetuximab) + Taxane
EGFR inhibitor antineoplastic agent + Chemo
Headamp Neck Colorectal Cancer
TNBC
2007-2010
18
1 chemo
Cetuximab (epidermal growth factor receptor (EGFR) antagonist ) an initial loading dose of cetuximab 400 mgm2 followed by a weekly dose of 250 mgm2Paclitaxel (microtubule inhibitor) 80 mgm2 or Docetaxel at an initial dose of 30 mgm2 was administered weekly
56 CR 22 PR
83 Dermatologic toxicity11 Grade3+
Nechushtan H Vainer G Stainberg H Salmon AY Hamburger T Peretz T A phase 12 of a combination of cetuximab and taxane for triple negative breast cancer patients Breast 2014 Aug23(4)435-8
Polyphor
Balixafortide (POL6326) + eribulin
CXCR4 antagonist + tubulin-based antimitotic
Heavily pretreated Relapsed MBC
2014-2016
56
3rd line 3 chemo
3+3 dose escalation The highest dose was established as eribulin 14 mgmsup2 on days 2 and 9 and balixafortide 55 mgkg on days 1minus3 and 8minus10 of the 21-day cycle
30 PR
41 Gr34 Neutropenia11 Gr34 Leucopenia11 Gr34 Febrileneutropenia2 Related mortalities
Apr 2018 Fast Track for HER2-MBC who have failed 2prior regimens
Pernas S Martin M Kaufman PA Gil-Martin M Gomez Pardo P Lopez-Tarruella S Manso L Ciruelos E Perez-Fidalgo JA Hernando C Ademuyiwa FO Weilbaecher K Mayer I Pluard TJ Martinez Garcia M Vahdat L Perez-Garcia J Wach A Barker D Fung S Romagnoli B Cortes J Balixafortide plus eribulin in HER2-negative metastatic breast cancer a phase 1 single-arm dose-escalation trial Lancet Oncol 2018 Jun19(6)812-824
11 PRndashbut only + letrozole (No Resp on monotherapy)
61 Gr34 Neutropenia39 Gr34 Leucopenia
$933M in 1Q2018 $31B in 2017
Tamura K Mukai H Naito Y Yonemori K Kodaira M Tanabe Y Yamamoto N Osera S Sasaki M Mori Y Hashigaki S Nagasawa T Umeyama Y Yoshino T Phase I study of palbociclib a cyclin-dependent kinase 46 inhibitor in Japanese patients Cancer Sci 2016 Jun107(6)755-63 doi 101111cas12932 Epub 2016 May 11
Pfizer
Ibrancereg (palbociclib)
CDK 46 Inhibitor
HR+ HER2- MBC
Heavily pretreated Relapsed Metastatic Cancer
2004-2008
41 (5 BC)
chemo naiumlve (17) 1-2 (51)3 (29) 3+ (2)
Palbociclib 25-150 mg dose ranging
0
20 Gr34 Neutropenia23 Gr34 Leucopenia
$933M in 1Q2018 $31B in 2017
Flaherty KT Lorusso PM Demichele A Abramson VG Courtney R Randolph SS Shaik MN Wilner KD ODwyer PJ Schwartz GK Phase I dose-escalation trial of the oral cyclin-dependent kinase 46 inhibitor PD 0332991 administered using a 21-day schedule in patients with advanced cancer Clin Cancer Res 2012 Jan 1518(2)568-76 doi 1011581078-0432CCR-11-0509 Epub 2011 Nov 16
Novartis
Kisqalireg (ribociclib)
CDK 46 Inhibitors
Premenopausal HR+ HER2- MBC
Heavily pretreated Relapsed Metastatic Cancer
2016
132 (20 BC)
0-1 (25) 2-3 (42) 4+ (32)
Ribociclib 50 mg ranging up to 1200 mg dose escalation
23 PRndashincluded 1 in BC (5 of BC pts)
27 Gr34 Neutropenia17 Gr34 Leucopenia
Peak sales projected at $25B
Infante JR Cassier PA Gerecitano JF Witteveen PO Chugh R Ribrag V Chakraborty A Matano A Dobson JR Crystal AS Parasuraman S Shapiro GI A Phase I Study of the Cyclin-Dependent Kinase 46 Inhibitor Ribociclib (LEE011) in Patients with Advanced Solid Tumors and Lymphomas Clin Cancer Res 2016 Dec 122(23)5696-5705 Epub 2016 Aug 19
Eli Lilly
Verzenioreg (abemaciclib)
CDK 46 Inhibitors
HR+HER2minusMBC
Heavily pretreated Relapsed Metastatic Cancer
2016
12 (1 BC)
1 (312) 2 (212) 3+ (7)
Abemaciclib 100 mg ranging up to 200 mg dose escalation
17 PR (included 1 in BC)
17 Gr34 Neutropenia33 Gr34 Leucopenia
Peak sales projected at $2B
Fujiwara Y Tamura K Kondo S Tanabe Y Iwasa S Shimomura A Kitano S Ogasawara K Turner PK Mori J Asou H Chan EM Yamamoto N Phase 1 study of abemaciclib an inhibitor of CDK 4 and 6 as a single agent for Japanese patients with advanced cancer Cancer Chemother Pharmacol 2016 Aug78(2)281-8 doi 101007s00280-016-3085-8 Epub 2016 Jun 16
Mukai H Saeki T Shimada K Naito Y Matsubara N Nakanishi T Obaishi H Namiki M Sasaki Y Phase 1 combination study of eribulin mesylate with trastuzumab for advanced or recurrent human epidermal growth factor receptor 2 positive breast cancer Invest New Drugs 2015 Feb33(1)119-27
AstraZeneca
Lynparza (Olaparib)+ Cediranib
PARP inhibitor+ inhibitor of VEGF RTK
HR+ HER2- MBC
BC amp OC
13
28 (8 BC)
3 for BC
Olaparib (a poly (ADP-ribose) polymerase (PARP) inhibitor) amp Cediranib (Vascular endothelial growth factor receptor (VEGFR) 1 2 and 3 tyrosine kinase inhibitor)3 at dose level (DL) 0 (cediranib 20mg olaparib 100mg) 3 at DL1 (cediranib 20mg olaparib 200mg) 7 at DL2 (cediranib 30mg olaparib 200mg) 6 at DL3 (cediranib 30mg olaparib 400mg)
Liu JF Tolaney SM Birrer M Fleming GF Buss MK Dahlberg SE Lee H Whalen C Tyburski K Winer E Ivy P Matulonis UA A Phase 1 trial of the poly(ADP-ribose) polymerase inhibitor olaparib (AZD2281) in combination with the anti-angiogenic cediranib (AZD2171) in recurrent epithelial ovarian or triple-negative breast cancer Eur J Cancer 2013 Sep49(14)2972-8
ReyonPharma
VM206RY
Heterologous prime-boost with a truncated HER2 sequence
HER2+ Stg IIIampIV BC
15
9
2 chemo
Plasmid DNA (pHM-GM-CSF expressing truncated HER2 amp GM-CSF) amp adenoviral vector (Ad-HM containing modified HER2) (2 4 and 8 mgpatientvisit) of pHM-GM-CSF 3x IM weeks 0 2 and 4 Ad-HM 3 times 109 virus particles at week 6
11 PR
4 pts 7 minor AEs
Unclear
Kim SB Ahn JH Kim J Jung KH A phase 1 study of a heterologous prime-boost vaccination involving a truncated HER2 sequence in patients with HER2-expressing breast cancer Mol Ther Methods Clin Dev 2015 Sep 30215031 doi 101038mtm201531 eCollection 2015
Rodon J Peacuterez-Fidalgo A Krop IE Burris H Guerrero-Zotano A Britten CD Becerra C Schellens J Richards DA Schuler M Abu-Khalaf M Johnson FM Ranson M Edenfield J Silva AP Hackl W Quadt C Demanse D Duval V Baselga J Phase 11b dose escalation and expansion study of BEZ235 a dual PI3KmTOR inhibitor in patients with advanced solid tumors including patients with advanced breast cancer Cancer Chemother Pharmacol 2018 Jun 7 doi 101007s00280-018-3610-z [Epub ahead of print]
Celgene(Abraxane)
Gemcitabine + Abraxane (nab-paclitaxel)
Chemo+ Chemo
OC BC NSCLC PC + LC OC BC KS
MBC
16
9
Adjuv chemo (100)chemo post-adjuv (33)
Gem (nucleoside metabolic inhibitor 1250 mgm2) on days 1 and 8 nab-Pac (microtubule inhibitor) starting dose of 180 mgm2 (cohort 1) 220 mgm2 (cohort 2) and 260 mgm2 (cohort 3) on day 1 of the 21-day cycle using a 3 + 3 design
0
MTD not reached29 Gr3 Neutropenia59 Gr1 Peripheralneuropathy
Yoshitomi S Taira N Doihara H Mizoo T Nogami T Iwamoto T Motoki T Shien T Ogasawara Y Matsuoka J Tsuji H Mitsuhashi T A phase 1 dose-finding and pharmacokinetic study of gemcitabine with nab-paclitaxel in patients with metastatic breast cancer Cancer Chemother Pharmacol 2016 Aug78(2)289-94
Eli Lilly
Erbituxreg (cetuximab) + Taxane
EGFR inhibitor antineoplastic agent + Chemo
Head amp NeckColorectal
TNBC
07-10
18
1 chemo
Cetuximab (epidermal growth factor receptor (EGFR) antagonist ) an initial loading dose of cetuximab 400 mgm2 followed by a weekly dose of 250 mgm2Paclitaxel (microtubule inhibitor) 80 mgm2 or Docetaxel at an initial dose of 30 mgm2 was administered weekly
56 CR 22 PR
83 Dermatologic toxicity11 Grade3+
Nechushtan H Vainer G Stainberg H Salmon AY Hamburger T Peretz T A phase 12 of a combination of cetuximab and taxane for triple negative breast cancer patients Breast 2014 Aug23(4)435-8
Polyphor
Balixafortide (POL6326) + eribulin
CXCR4 antagonist + tubulin-based antimitotic
Heavily pretreatedRelapsed MBC
14-16
56
3rd line 3 chemo
3+3 dose escalation The highest dose was established as eribulin 14 mgmsup2 on days 2 and 9 and balixafortide 55 mgkg on days 1minus3 and 8minus10 of the 21-day cycle
30 PR
41 Gr34 Neutropenia11 Gr34 Leucopenia11 Gr34 Febrileneutropenia2 Related mortalities
42018 Fast Track (HER2-MBC failed 2 prior regimens)
Pernas S Martin M Kaufman PA Gil-Martin M Gomez Pardo P Lopez-Tarruella S Manso L Ciruelos E Perez-Fidalgo JA Hernando C Ademuyiwa FO Weilbaecher K Mayer I Pluard TJ Martinez Garcia M Vahdat L Perez-Garcia J Wach A Barker D Fung S Romagnoli B Cortes J Balixafortide plus eribulin in HER2-negative metastatic breast cancer a phase 1 single-arm dose-escalation trial Lancet Oncol 2018 Jun19(6)812-824
1 PRndashbut only + letrozoleNo Resp on monotherapy
61 Gr34 Neutropenia39 Gr34 Leucopenia
$933M (1Q18)$31B (2017)
Tamura K Mukai H Naito Y Yonemori K Kodaira M Tanabe Y Yamamoto N Osera S Sasaki M Mori Y Hashigaki S Nagasawa T Umeyama Y Yoshino T Phase I study of palbociclib a cyclin-dependent kinase 46 inhibitor in Japanese patients Cancer Sci 2016 Jun107(6)755-63 doi 101111cas12932 Epub 2016 May 11
Pfizer
Ibrancereg (palbociclib)
CDK 46 Inhibitor
HR+ HER2- MBC
Heavily pretreatedRelapsed Met Cancer
04-08
41 (5 BC)
chemo naiumlve (17)1-2(51) 3(29) 3+(2)
Palbociclib 25-150 mg dose ranging
0
20 Gr34 Neutropenia23 Gr34 Leucopenia
$933M (1Q18)$31B (2017)
Flaherty KT Lorusso PM Demichele A Abramson VG Courtney R Randolph SS Shaik MN Wilner KD ODwyer PJ Schwartz GK Phase I dose-escalation trial of the oral cyclin-dependent kinase 46 inhibitor PD 0332991 administered using a 21-day schedule in patients with advanced cancer Clin Cancer Res 2012 Jan 1518(2)568-76 doi 1011581078-0432CCR-11-0509 Epub 2011 Nov 16
Novartis
Kisqalireg (ribociclib)
CDK 46 Inhibitor
Premenopausal HR+ HER2- MBC
Heavily pretreatedRelapsed Met Cancer
16
132 (20 BC)
0-1 (25) 2-3 (42)4+ (32)
Ribociclib 50 mg ranging up to 1200 mg dose escalation
23 PR-included 1 BC (5 of BC pts)
27 Gr34 Neutropenia17 Gr34 Leucopenia
Peak sales est at $25B
Infante JR Cassier PA Gerecitano JF Witteveen PO Chugh R Ribrag V Chakraborty A Matano A Dobson JR Crystal AS Parasuraman S Shapiro GI A Phase I Study of the Cyclin-Dependent Kinase 46 Inhibitor Ribociclib (LEE011) in Patients with Advanced Solid Tumors and Lymphomas Clin Cancer Res 2016 Dec 122(23)5696-5705 Epub 2016 Aug 19
Eli Lilly
Verzenioreg (abemaciclib)
CDK 46 Inhibitor
HR+HER2minusMBC
Heavily pretreatedRelapsed Met Cancer
16
12 (1 BC)
1 (312) 2 (212) 3+(7)
Abemaciclib 100 mg ranging up to 200 mg dose escalation
17 PR (included 1 BC)
17 Gr34 Neutropenia33 Gr34 Leucopenia
Peak sales est at $2B
Fujiwara Y Tamura K Kondo S Tanabe Y Iwasa S Shimomura A Kitano S Ogasawara K Turner PK Mori J Asou H Chan EM Yamamoto N Phase 1 study of abemaciclib an inhibitor of CDK 4 and 6 as a single agent for Japanese patients with advanced cancer Cancer Chemother Pharmacol 2016 Aug78(2)281-8 doi 101007s00280-016-3085-8 Epub 2016 Jun 16
Bria-IMTtrade - First Product CandidateHuman Proof-of-Concept Trials in Advanced Breast Cancer
Bria-IMTtrade Non-Personalized Immunotherapy
First Proof-of-Concept Phase I (1999-2003) Used unmodified cell line + GM-CSF + cyclophosphamide N = 14 late stage treatment-refractory breast cancer patients Well tolerated no severe drug related AEs Median Overall Survival = 121 months
Second Proof-of-Concept Phase I (2005) Used GM-CSF-engineered cell line + cyclophosphamide + interferon-α N = 4 late stage treatment-refractory (3 breast cancer and 1 ovarian cancer) patients Well tolerated no life-threatening drug related adverse events One patient with transient urticaria reported as grade 3 responded to antihistamines Median Overall Survival = 35 months One robust responder with gt90 regression during treatment subsequent relapse (upon halting
treatment) responded to re-treatment
6
Bria-IMTtrade amp Bria-OTStradePotential Mechanisms of Action in Advanced Breast Cancer
Bria-IMTTM directly stimulates cancerfighting CD4+ and CD8+ T cells(further boosts the response)
Bria-IMTTM produces breastcancer antigens which aretaken up by dendritic cellsand ldquopresentedrdquo to CD4+and CD8+ T cells implicatedin tumor destruction
Bria-IMTTM secretes GM-CSF which further promotes dendritic cell-based antigen presentation (boosts the response) 7
Bria-IMTtradeHuman Proof-of-Concept Trials in Breast Cancer (Patient A002) Bria-IMTtrade Non-Personalized Immunotherapy ndash Given as Monotherapy
Second Proof-of-Concept Phase I (2005) 1 out of 4 patients responded with substantial tumor regression Patient A002 was the only patient with key HLA matches with Bria-IMTtrade
8
Bria-IMTtradeHuman Proof-of-Concept Trials in Breast Cancer (Patient A002) Approximately 3 months (106 days) after last inoculation Patient A002rsquos breast cancer returned and
spread to brain lung and other sites
Patient A002 was then re-treated with 10 inoculations of Bria-IMTtrade over 4 months
Repeat imaging studies showed normal findings on MRI and PET consistent with a completeremission of the previous multiple central nervous system metastases as shown in the brain scansbelow
Bria-IMTtrade and Bria-OTStrade shouldsynergize with existing approvedimmunotherapies as well as those stillunder development
This includes immune checkpointinhibitors such as antibodies to PD-1CTLA-4 GITR and CD73 inhibitors whicheliminate tumor immunosuppression Checkpoint Inhibitors were the
subject of the 2018 Nobel Prize inMedicine
In addition immunostimulatoryantibodies to molecules such as OX40should enhance responses to Bria-IMTtradeand Bria-OTStrade
13
Q3 2018 Data on first 20 Patients on Bria-IMTtrade Q3 2018 Initiate Combination Study of Bria-IMTtrade with Keytruda or Yervoy
Q4 2018 Switch to a novel frozen Bria-IMTtrade formulation Q4 2018 Safety Data (6 patients) of the Bria-IMTtrade - Keytrudareg Combination Study (SABC meeting) Q4 2018 Ongoing Corporate PartnershipCollaboration Discussions
Q1 2019 Efficacy Data (6 patients) of the Bria-IMTtrade - Keytrudareg Combination Study Q2 2019 Initiation of Bria-OTStrade GMP manufacturing (KBI BioPharma) Q2 2019 Additional Safety amp Efficacy data Monotherapy and Combination Studies (AACR meeting) Q2 2019 Final data for Monotherapy and Additional Data for the Combination Study (ASCO meeting) H1 2019 Candidate Selection for a PKCδ Inhibitor H1 2019 Initiate additional immunotherapy program H2 2019 Bria-OTStrade Authorization from FDA clearance for dosing H2 2019 Bria-OTStrade First Patient Dosed
Upcoming Milestones amp Catalysts
14
Involved in over 10 drugs brought to the market
Experienced Management Team
Management
William V Williams MD FACP President amp CEO VP Exploratory Development Incyte Corporation VP Experimental Medicine GlaxoSmithKline Head Rheumatology Research University of Pennsylvania Facilitated entry of over 20 compounds into the clinic including ruxolitinib (Jakafi)
baricitinib amp epacadostat NDAs including Jakafi Boniva Bexxar Author of over 120 peer-reviewed publications amp over 20 patents
Gadi Levin CA MBA CFO CFO of Labstyle Innovations Ltd VP of Finance for two Israeli investment houses in the fields of private equity
hedge funds and real estate Financial Consultant various firms Accountant Arthur Andersen
Markus Lacher PhD Senior Director RampD Founder T cell Therapeutics Inc an immuno-oncology company Sr Clinical Scientist Cesca Therapeutics Inc a clinical-stage autologous cell
therapy company Scientist at BioTime Inc and OncoCyte Corporation Editorial advisory board Recent Patents on Anti-Cancer Drug Discovery
Farrah Dean MSc MBA Manager Corp Development Investor relations CytRx Corporation amp CCG Investor Relations Senior Associate Equity Analyst Oppenheimer amp Co Rodman amp Renshaw amp
Brian Metcalf PhD Recently retired as CSO from Global Blood Therapeutics Former Head of Research amp Development Incyte Corporation Former Head of Medicinal Chemistry SmithKline Beecham
Douglas Faller MD PhD Professor of Medicine Pediatrics Biochemistry Microbiology Pathology and
Laboratory Medicine HematologistOncologist former Director of the Cancer Center Boston University School of Medicine
Founder of several successful biotechnology companies
Robert Williams PhD University Distinguished Professor of Chemistry Colorado State University Founder of several successful biotechnology companies including Microcide Xcyte
Therapies HemaQuest Arch Therapeutics and Cetya Therapeutics
Thomas Kieber-Emmons PhD Deputy Director University of Arkansas Cancer Center Expert in targeted cancer immunotherapies structural biology and computational
chemistry
Maria Trojanowska PhD Professor of Medicine Boston University School of Medicine Director The Arthritis Center
16
Veteran Board of Directors
Board of Directors
Saeid Babaei PhD MBA Chairman Entrepreneur 20 yrs of biotech leadership roles Current CEO AbCelex VP Bus Develop Lorus Therap Dir of Corp Develop Northern Therapeutics
Rahoul Sharan CA Director Chairman Potash Ridge Director of the Board Ansell Capital Corp Parallel Resources amp Galaxy Capital
Corporation
Martin Schmieg CPA Director CFO Sirna Therapeutics Inc amp Isolagen Inc CEO Freedom-2 Inc (now PharmaCyte Inc) Advisor Caladrius Biosciences Inc Beckman Coulter Genomics Calimmune
Charles Wiseman MD Co-Founder amp Director Director Immunotherapy Lab St Vincent Medical Center Chief Breast Cancer Basic Research Lab Univ of Texas MD Anderson Hospital amp
Tumour Institute Assist Prof Dept of Molecular Carcinogenesis amp Virology MD Anderson Acting Chief Div of Oncology White Memorial Medical Center LA
William V Williams MD FACP President amp CEO VP Exploratory Development Incyte Corporation VP Experimental Medicine GlaxoSmithKline Head Rheumatology Research University of Pennsylvania
Prior Affiliations
17
Drug Approvals by BriaCell Management Team
Bexxarreg (tositumomab and Iodine I131 tositumomab) Treatment of CD20 antigen-expressing relapsed or refractory low grade follicular or transformed non-Hodgkins lymphoma
Myleranreg (busulfan) for chronic myelogenous leukemia Defense of formulation change sNDA
Hycamtinreg (topotecan) for ovarian cancer Pediatric use sNDA
Navelbinereg (vinorelbine tartrate) for non-small cell lung cancer Pediatric use sNDA
Bonivareg (ibandronate) monthly oral treatment of osteoporosis
Bonivareg (ibandronate) quarterly intraveous treatment of osteoporosis
Zofranreg (ondansetron) for prevention of nausea and vomiting Pediatric use sNDA
Jakafireg (ruxolitinib) for myelofibrosis Jakafireg (ruxolitinib) for polycythemia vera
Olumiantreg (baricitinib) for rheumatoid arthritis Approved in USA Japan and Europe
18
Share Metrics
BCTV BCTXF 19
Data as of 1092018
Ticker TSX BCTV
US Ticker OTCQBBCTXF
Share Price (CAD) as of Oct 9 2018 $012
52-Week Range (CAD) $009-019
Shares Outstanding as of Oct 9 2018 1611M
Market Cap as of Oct 9 2018 (CAD) $193M
Cash and Short Term Investments as of July 31 2018 (CAD) $23M
Total Shareholders Equity as of July 31 2018 (CAD) $12M
Number of Warrants $014-$035 (CAD) as of Oct 9 2018 601M
Number of Compensation Warrants $014-$030 (CAD) as of Oct 9 2018 45M
Number of Options $014- $026 (CAD$) as of Oct 9 2018 93M
Developing Bria-OTStrade the First Off-the-Shelf Personalized Immunotherapy
Targeting Adv Breast Cancer Unmet medical need (42000 death in the US in 2017 ) $1 Bil- $5 Bil market opportunity depending on patient treatment stage
Impressive results in 2 proof-of-concept clinical trials Rapid Response Rate Repeated following re-treatment Excellent Safety Profile
Completed enrollment in Phase IIIa clinical trial of Bria-IMTtrade with outstanding safety amp efficacy data Initiated Phase IIa Combination Study of Bria-IMTtrade with Keytrudareg (Merck amp Co Inc)
Developing Bria-OTStrade along with BriaDXtrade its companion diagnostic test Ability to match and treat ~90 of patient population with Off-the-Shelf personalized immunotherapy
Experienced Management has been involved in over 10 drug approvals
Patient B001 Breast 70 No 1101 - 3501 4001 Negative -
Bria-IMTtradeHuman Proof-of-Concept Trials in Breast Cancer (Patient A002)
24
Proof-of-Concept Results Resulted in BriaCellrsquos Immunotherapy Strategy Use BriaDXtrade diagnostic to select only those patients matching Bria-IMTtrade Use BriaDXtrade diagnostic test to select Bria-OTStrade alleles matching ~90 of all patients
Bria-IMTtradeCurrent Phase IIIa Data Supports HLA Matching Hypothesis Six patients treated in 2017 Bria-IMTtrade was safe and well tolerated
Patient 01-002 73-year-old woman with breast cancer diagnosed in 1995 Developed liver metastases in2010 and lung metastases in 2017 Previously treated with 7 rounds of chemotherapy with 8 differentchemotherapy agents Received 5 cycles of Bria-IMTtrade over 3 months then monthly cycles (6 months total)Evaluated after 3 months and 6 months After 3 months despite the extensive prior therapy her scans notedthat ldquothere has been a clear response in the multiple bilateral pulmonary nodulesrdquo The response wasmaintained after 6 months of Bria-IMTtrade treatment She matches Bria-IMTtrade at 2 HLA alleles
The liver tumors were stable to slightly increased at 3 months and then progressed after 6 months
This supports our hypothesis of heightened anti-tumor activity in patients with a matched HLA types Clear path to develop BriaDXtrade to select the patients using HLA testing
1 RLL 29 Not Detectable Not Detectable2 LUL apical pleural based 34 tiny nodule lt 1mm scar tiny nodule lt 1mm scar3 xxx 39 Not Detectable Not Detectable4 40 Not Detectable Not Detectable5 RLL 45 Not Detectable Not Detectable6 LLL 49 Not Detectable Not Detectable7 xxx 52 Not Detectable Not Detectable8 RLL 52 Not Detectable Not Detectable9 RLL 56 Not Detectable Not Detectable
10 RLL costophrenic recess 56 Not Detectable Not Detectable11 XXX 58 Not Detectable Not Detectable12 LUL 60 Not Detectable Not Detectable13 XXX 67 15 1514 RUL 72 15 1515 LLL 76 Not Detectable Not Detectable16 RUL Noncalcified Nodule 77 Not Detectable Not Detectable17 RLL costophrenic recess 79 10 1018 RUL 82 Not Detectable Not Detectable19 RLL 90 Not Detectable Not Detectable20 RLL 91 lt 01 lt 0121 xxx xxx Not Detectable Not Detectable
27
Clinical Development Update ndash Summary 2018 September 26
Completed enrollment of Adv Breast cancer patients in the Phase IIIa ldquomonotherapyrdquo study of Bria-IMTtrade
We have confirmed our mechanism of action and achieved proof of concept
Initial safety data appears superior to that of the other advanced or approved drugs for breast cancer when they were at a similar clinical stage of development
Initial efficacy data is similar or superior to those of other advanced or approved drugs for breast cancer when they were at a similar clinical stage of development
Initiated Combination Study of Bria-IMTtrade with Keytrudareg or Yervoyreg in Adv breast cancer patients expecting even better response rates than those in the ldquomonotherapyrdquo study Initial safety data is expected in 4Q2018 Initial efficacy data is expected in 1Q2019
Bria-OTStrade the first off-the-shelf personalized treatment for advanced breast cancer is expected to enter the clinic in 2019
28
Bria-IMTtrade Excellent Safety Data - To Date
To date Bria-IMTtrade has been dosed in 24 patients (4 in 2004-2005 20 in 2017-2018)
Interim Data (20 patients)-Ongoing Phase IIIa Study (2017-2018)
Bria-IMTtrade has been very well tolerated (ge60 doses given to date) The majority of adverse events (AEs) were limited to expected minor local irritation at the
injection sites No related grade gt3 or unexpected AEs No related serious AEs No serious unexpected related AEs Most patients who have dropped out did so due to worsening of their underlying disease
Based on the current study Bria-IMTtrade has an excellent safety profile
29
Bria-IMTtrade - Efficacy as Predicted
Interim Data (19 patients)-Ongoing Phase IIIa Study (2017-2018) amp Original Study (2004-2005)
PD-L1 expression on circulating cancer cells amp cancer-associated cells in 100 of patients (to date) Strong rationale for combination with checkpoint inhibitors like Keytruda
30
Bria-IMTtrade appears to be most effective in patients who match with Bria-IMT trade at 2 HLA loci (types) further supporting our ldquoHLA Matching Hypothesisrdquo and the development of Bria-OTS trade to cover 90 of the patient population
Combination with immune checkpoint inhibitors may induce a more potent anti-cancer response leading to our strategy of combination studies of Bria-IMT trade with Keytruda or Yervoy
Patients (n) HLA Match
Tumor Shrinkage
Biological Response
4 ge2 50 7515 ge1 27 334 0 0 0
Biological response includes tumor shrinkage or lower circulating cancer associated cells
The confirmatory Bria-IMTtrade monotherapy Phase IIa trial has completed enrollment Additional Support for the HLA-matching hypothesis has been obtained
Bria-IMTtrade Combination Therapy study with immune checkpoint inhibitors Keytrudareg if PD-L12 positive (ge1) Yervoyreg if PD-L12 negative (lt1) Accepting patients from the monotherapy study who develop progressive disease Also enrolling patients directly into this study to enhance experience with the combination In discussion with other pharmaceutical companies to evaluate additional combinations with other
immunotherapies
Bria-OTStrade Off-the-Shelf Personalized Targeted Immunotherapy Developing Bria-OTStrade to co-express GM-CSF and interferon-α Pre-manufacture additional HLA alleles ndash Total of 15 alleles (8 Class I and 7 Class II) Co-development of BriaDXtrade companion diagnostic for HLA typing Combination therapy clinical trial with immune checkpoint inhibitors for non-responders using
information from the Bria-IMTtrade Combination Therapy Study
33
Development Timeline ndash Breast Cancer
20192018 2020 2021
Phase IIIaBria-IMTtrade
Monotherapy
Currently Enrolling Phase IIaBria-IMTtrade + Checkpoint
Currently in discussions with potential partnersPhase II Bria-IMTtrade plus Additional Combinations (1Q19 4Q22)(eg PD-1 Inhibitor PD-L1 inhibitor anti-CTLA4 anti-GITR anti-OX40)
1Q 2Q 3Q 4Q
2023
Bria-OTStrade Off-The-Shelf Personalized ImmunotherapyMonotherapy and Potential Partnered Combo Therapy
(2H19 Ongoing)
Bria-OTStradeOff-the-Shelf Cell Line cGMP Manufacturing
and BriaDXtrade(1Q18 1Q19)
Registration Studies (1Q20 2H22)Bria-IMTtrade with Checkpoint InhibitorsBria-OTStrade +- Checkpoint Inhibitors
34
Immuno-oncology Deals
Recent deals of small biotechs with big pharma in immuno-oncology
35
Date PartnershipDevelopment stage at the time of the deal Deal size
07122018 Immatics-Genmab Preclinical Up to $28B
04042018 OSE Immunotherapeutics-Boehringer Ingelheim Preclinical Up to euro113B ($139B)
02092018 Pieris Pharmaceuticals-Seattle Genetics Preclinical Up to $123B
2142018 Nektar-BMS Ph III Up to $36B
01222018 Juno-Celgene Ph II $9B (Acquisition)
11142017 Loxo-Bayer Larotrectinib (Ph II) LOXO-195 (Ph III) Up to $155B
1032017 CytomX-Amgen Preclinical Up to $15B
03202017 CytomX--BMS Ph III Up to $36B
6282016 Xencor-Novartis Preclinical Up to $24B
Early Stage Clinical Studies (Comparison)
We compared the interim data of Ph IIIa study of Bria-IMTtrade in advanced breast cancer with thedata in the early stage clinical studies of recently approved breast cancer drugs and one fasttracked product candidate
Apples to apples comparison Early Stage Clinical Studies in oncology are typically done in patientswith no other therapeutic options Thus the patients have very advanced disease and response ratesare typically quite low
The patients in our Ph IIIa study have been heavily pre-treated (median 45 prior regimens)Some recent studies of relevance in breast cancer are noted in the following slides
36
Breast Cancer Market Opportunity
Drug Technology Approved for Market (US)Ibrance (palbociclib) CDK 46 Inhibitor HR+HER2- MBC in combination with
fluvestrant or aromatase inhibitor$933M in 1Q2018 $3126M in 2017
Kisqali (ribociclib) CDK 46 Inhibitor 2017 HR+HER2- MBC in combination with fluvestrant or aromatase inhibitor
Peak sales projected at $25B
Verzenio (abemaciclib) CDK 46 Inhibitor 2017 HR+HER2- MBC in combination with fluvestrant or aromatase inhibitor
balixafortide CXCR4 antagonist Fast track designation in 2018 for HER2- MBC who have failed 2 prior regimens
The market for breast cancer drugs is a multibillion dollar market with new drugs being approvedon an ongoing basis indicating the shortage of safe and effective treatments for this deadly disease
37
Competitors- Phase III Clinical Data Bria-IMTtrade shows superior safety and similar to superior efficacy data compared with those of the multi-billion dollar drugs when they were at a similar early stage of clinical development
Injection site reactions No related SAEs or SUSARs
Tumor vol darr ampor darr circul tumor cellsAll Comers 21(419) 26(519)One or More HLA matches 27(415) 33(515)Two or More HLA matches 50 (24) 75 (34)
Sheet1 (3)
Comp -Slides
Data
HLA (2)
HLA
Data (Ph1-2+4Pt)
Competitors (2018)-Slide
Competitors (2018)
In the Pipeline Protein Kinase C delta (PKCδ) Inhibitors
30 of all human malignancies display activating RAS mutations Another 60 showing over-activity of Ras-signaling pathways
Ras has been termed ldquoundruggablerdquo (no one has been able to make a Ras inhibitor drug)
BriaCellrsquos novel proprietary PKCδ inhibitors have shown activity against multiple RAS transformed tumors Lung cancer Melanoma Breast cancer Neuroendocrine cancer Pancreatic cancer Colorectal cancer
This target has an attractive safety profile based on in vivo studies and knock out mouse studies
PKCδ inhibitors should qualify for an accelerated clinical development plan and regulatory pathway
Could be in clinic within 24 months
Cost-Effective Additional Shot-on-Goal and additional partnership opportunities
Early-Stage Preclinical Program
39
Protein Kinase C delta (PKCδ) Inhibitors
Activated PKCδ inhibits RAS degradation which in turn stimulates tumor growth
Koo et al Oncotarget 621328 2016
30 of all human malignancies display activating RASmutations with another 60 showing over-activity of Ras-signaling pathways
BriaCellrsquos novel proprietary PKCδ inhibitors have shownactivity against multiple RAS transformed tumors
This target has an attractive safety profile based on in vivostudies and knock out mouse studies
PKCδ also has potential activity as an immunotherapeuticby blocking TGFβ signaling
PKCδ inhibitors are applicable to specific niche tumor typeswhich provide an accelerated clinical development plan
Structural aspects of first generation inhibitor rottlerin and staurosporine (pan-PKC activator) were combined to create second generation inhibitor KAM1
Third generation inhibitors such as BJE6-106 have improved potency and selectivity Fourth generation inhibitors under development to optimize drug-like characteristics PKCδ inhibitors lack endothelial cell cytotoxicity amp PKCδ deficient mice develop normally and are fertile Potentially no marked intrinsic toxicity by inhibiting PKCδ
Mukai H Saeki T Shimada K Naito Y Matsubara N Nakanishi T Obaishi H Namiki M Sasaki Y Phase 1 combination study of eribulin mesylate with trastuzumab for advanced or recurrent human epidermal growth factor receptor 2 positive breast cancer Invest New Drugs 2015 Feb33(1)119-27
AstraZeneca
Lynparza (Olaparib) + Cediranib
PARP inhibitor + inhibitor of VEGF receptor tyrosine kinases
HR+ HER2- MBC
BC amp OC
2013
28 (8 BC)
3 for BC
Olaparib (a poly (ADP-ribose) polymerase (PARP) inhibitor) amp Cediranib (Vascular endothelial growth factor receptor (VEGFR) 1 2 and 3 tyrosine kinase inhibitor)3 at dose level (DL) 0 (cediranib 20mg olaparib 100mg) 3 at DL1 (cediranib 20mg olaparib 200mg) 7 at DL2 (cediranib 30mg olaparib 200mg) 6 at DL3 (cediranib 30mg olaparib 400mg)
Liu JF Tolaney SM Birrer M Fleming GF Buss MK Dahlberg SE Lee H Whalen C Tyburski K Winer E Ivy P Matulonis UA A Phase 1 trial of the poly(ADP-ribose) polymerase inhibitor olaparib (AZD2281) in combination with the anti-angiogenic cediranib (AZD2171) in recurrent epithelial ovarian or triple-negative breast cancer Eur J Cancer 2013 Sep49(14)2972-8
Reyon Pharmaceutical
VM206RY
Heterologous prime-boost with a truncated HER2 sequence
HER2+ Stage IIIampIV BC
2015
9
2 chemo
Plasmid DNA (pHM-GM-CSF expressing truncated HER2 amp GM-CSF) amp adenoviral vector (Ad-HM containing modified HER2) (2 4 and 8 mgpatientvisit) of pHM-GM-CSF 3x IM weeks 0 2 and 4 Ad-HM 3 times 109 virus particles at week 6
11 PR
4 pts showed 7 minor AEs
Unclear
Kim SB Ahn JH Kim J Jung KH A phase 1 study of a heterologous prime-boost vaccination involving a truncated HER2 sequence in patients with HER2-expressing breast cancer Mol Ther Methods Clin Dev 2015 Sep 30215031 doi 101038mtm201531 eCollection 2015
Rodon J Peacuterez-Fidalgo A Krop IE Burris H Guerrero-Zotano A Britten CD Becerra C Schellens J Richards DA Schuler M Abu-Khalaf M Johnson FM Ranson M Edenfield J Silva AP Hackl W Quadt C Demanse D Duval V Baselga J Phase 11b dose escalation and expansion study of BEZ235 a dual PI3KmTOR inhibitor in patients with advanced solid tumors including patients with advanced breast cancer Cancer Chemother Pharmacol 2018 Jun 7 doi 101007s00280-018-3610-z [Epub ahead of print]
Celgene (Abraxane)
Gemcitabine + Abraxane (nab-paclitaxel)
Chemo + Chemo
OC BC NSCLC amp Panc cancer + Lung OC BC Kaposi sarcoma
MBC
2016
9
Adjuvant chemo (100)chemo post-adjuvant (33)
Gem (nucleoside metabolic inhibitor 1250 mgm2) on days 1 and 8 nab-Pac (microtubule inhibitor) starting dose of 180 mgm2 (cohort 1) 220 mgm2 (cohort 2) and 260 mgm2 (cohort 3) on day 1 of the 21-day cycle using a 3 + 3 design
0
MTD not reached29 Gr3 Neutropenia59 Gr1 Peripheralneuropathy
Yoshitomi S Taira N Doihara H Mizoo T Nogami T Iwamoto T Motoki T Shien T Ogasawara Y Matsuoka J Tsuji H Mitsuhashi T A phase 1 dose-finding and pharmacokinetic study of gemcitabine with nab-paclitaxel in patients with metastatic breast cancer Cancer Chemother Pharmacol 2016 Aug78(2)289-94
Eli Lilly
Erbituxreg (cetuximab) + Taxane
EGFR inhibitor antineoplastic agent + Chemo
Headamp Neck Colorectal Cancer
TNBC
2007-2010
18
1 chemo
Cetuximab (epidermal growth factor receptor (EGFR) antagonist ) an initial loading dose of cetuximab 400 mgm2 followed by a weekly dose of 250 mgm2Paclitaxel (microtubule inhibitor) 80 mgm2 or Docetaxel at an initial dose of 30 mgm2 was administered weekly
56 CR 22 PR
83 Dermatologic toxicity11 Grade3+
Nechushtan H Vainer G Stainberg H Salmon AY Hamburger T Peretz T A phase 12 of a combination of cetuximab and taxane for triple negative breast cancer patients Breast 2014 Aug23(4)435-8
Polyphor
Balixafortide (POL6326) + eribulin
CXCR4 antagonist + tubulin-based antimitotic
Heavily pretreated Relapsed MBC
2014-2016
56
3rd line 3 chemo
3+3 dose escalation The highest dose was established as eribulin 14 mgmsup2 on days 2 and 9 and balixafortide 55 mgkg on days 1minus3 and 8minus10 of the 21-day cycle
30 PR
41 Gr34 Neutropenia11 Gr34 Leucopenia11 Gr34 Febrileneutropenia2 Related mortalities
Apr 2018 Fast Track for HER2-MBC who have failed 2prior regimens
Pernas S Martin M Kaufman PA Gil-Martin M Gomez Pardo P Lopez-Tarruella S Manso L Ciruelos E Perez-Fidalgo JA Hernando C Ademuyiwa FO Weilbaecher K Mayer I Pluard TJ Martinez Garcia M Vahdat L Perez-Garcia J Wach A Barker D Fung S Romagnoli B Cortes J Balixafortide plus eribulin in HER2-negative metastatic breast cancer a phase 1 single-arm dose-escalation trial Lancet Oncol 2018 Jun19(6)812-824
11 PRndashbut only + letrozole (No Resp on monotherapy)
61 Gr34 Neutropenia39 Gr34 Leucopenia
$933M in 1Q2018 $31B in 2017
Tamura K Mukai H Naito Y Yonemori K Kodaira M Tanabe Y Yamamoto N Osera S Sasaki M Mori Y Hashigaki S Nagasawa T Umeyama Y Yoshino T Phase I study of palbociclib a cyclin-dependent kinase 46 inhibitor in Japanese patients Cancer Sci 2016 Jun107(6)755-63 doi 101111cas12932 Epub 2016 May 11
Pfizer
Ibrancereg (palbociclib)
CDK 46 Inhibitor
HR+ HER2- MBC
Heavily pretreated Relapsed Metastatic Cancer
2004-2008
41 (5 BC)
chemo naiumlve (17) 1-2 (51)3 (29) 3+ (2)
Palbociclib 25-150 mg dose ranging
0
20 Gr34 Neutropenia23 Gr34 Leucopenia
$933M in 1Q2018 $31B in 2017
Flaherty KT Lorusso PM Demichele A Abramson VG Courtney R Randolph SS Shaik MN Wilner KD ODwyer PJ Schwartz GK Phase I dose-escalation trial of the oral cyclin-dependent kinase 46 inhibitor PD 0332991 administered using a 21-day schedule in patients with advanced cancer Clin Cancer Res 2012 Jan 1518(2)568-76 doi 1011581078-0432CCR-11-0509 Epub 2011 Nov 16
Novartis
Kisqalireg (ribociclib)
CDK 46 Inhibitors
Premenopausal HR+ HER2- MBC
Heavily pretreated Relapsed Metastatic Cancer
2016
132 (20 BC)
0-1 (25) 2-3 (42) 4+ (32)
Ribociclib 50 mg ranging up to 1200 mg dose escalation
23 PRndashincluded 1 in BC (5 of BC pts)
27 Gr34 Neutropenia17 Gr34 Leucopenia
Peak sales projected at $25B
Infante JR Cassier PA Gerecitano JF Witteveen PO Chugh R Ribrag V Chakraborty A Matano A Dobson JR Crystal AS Parasuraman S Shapiro GI A Phase I Study of the Cyclin-Dependent Kinase 46 Inhibitor Ribociclib (LEE011) in Patients with Advanced Solid Tumors and Lymphomas Clin Cancer Res 2016 Dec 122(23)5696-5705 Epub 2016 Aug 19
Eli Lilly
Verzenioreg (abemaciclib)
CDK 46 Inhibitors
HR+HER2minusMBC
Heavily pretreated Relapsed Metastatic Cancer
2016
12 (1 BC)
1 (312) 2 (212) 3+ (7)
Abemaciclib 100 mg ranging up to 200 mg dose escalation
17 PR (included 1 in BC)
17 Gr34 Neutropenia33 Gr34 Leucopenia
Peak sales projected at $2B
Fujiwara Y Tamura K Kondo S Tanabe Y Iwasa S Shimomura A Kitano S Ogasawara K Turner PK Mori J Asou H Chan EM Yamamoto N Phase 1 study of abemaciclib an inhibitor of CDK 4 and 6 as a single agent for Japanese patients with advanced cancer Cancer Chemother Pharmacol 2016 Aug78(2)281-8 doi 101007s00280-016-3085-8 Epub 2016 Jun 16
Mukai H Saeki T Shimada K Naito Y Matsubara N Nakanishi T Obaishi H Namiki M Sasaki Y Phase 1 combination study of eribulin mesylate with trastuzumab for advanced or recurrent human epidermal growth factor receptor 2 positive breast cancer Invest New Drugs 2015 Feb33(1)119-27
AstraZeneca
Lynparza (Olaparib)+ Cediranib
PARP inhibitor+ inhibitor of VEGF RTK
HR+ HER2- MBC
BC amp OC
13
28 (8 BC)
3 for BC
Olaparib (a poly (ADP-ribose) polymerase (PARP) inhibitor) amp Cediranib (Vascular endothelial growth factor receptor (VEGFR) 1 2 and 3 tyrosine kinase inhibitor)3 at dose level (DL) 0 (cediranib 20mg olaparib 100mg) 3 at DL1 (cediranib 20mg olaparib 200mg) 7 at DL2 (cediranib 30mg olaparib 200mg) 6 at DL3 (cediranib 30mg olaparib 400mg)
Liu JF Tolaney SM Birrer M Fleming GF Buss MK Dahlberg SE Lee H Whalen C Tyburski K Winer E Ivy P Matulonis UA A Phase 1 trial of the poly(ADP-ribose) polymerase inhibitor olaparib (AZD2281) in combination with the anti-angiogenic cediranib (AZD2171) in recurrent epithelial ovarian or triple-negative breast cancer Eur J Cancer 2013 Sep49(14)2972-8
ReyonPharma
VM206RY
Heterologous prime-boost with a truncated HER2 sequence
HER2+ Stg IIIampIV BC
15
9
2 chemo
Plasmid DNA (pHM-GM-CSF expressing truncated HER2 amp GM-CSF) amp adenoviral vector (Ad-HM containing modified HER2) (2 4 and 8 mgpatientvisit) of pHM-GM-CSF 3x IM weeks 0 2 and 4 Ad-HM 3 times 109 virus particles at week 6
11 PR
4 pts 7 minor AEs
Unclear
Kim SB Ahn JH Kim J Jung KH A phase 1 study of a heterologous prime-boost vaccination involving a truncated HER2 sequence in patients with HER2-expressing breast cancer Mol Ther Methods Clin Dev 2015 Sep 30215031 doi 101038mtm201531 eCollection 2015
Rodon J Peacuterez-Fidalgo A Krop IE Burris H Guerrero-Zotano A Britten CD Becerra C Schellens J Richards DA Schuler M Abu-Khalaf M Johnson FM Ranson M Edenfield J Silva AP Hackl W Quadt C Demanse D Duval V Baselga J Phase 11b dose escalation and expansion study of BEZ235 a dual PI3KmTOR inhibitor in patients with advanced solid tumors including patients with advanced breast cancer Cancer Chemother Pharmacol 2018 Jun 7 doi 101007s00280-018-3610-z [Epub ahead of print]
Celgene(Abraxane)
Gemcitabine + Abraxane (nab-paclitaxel)
Chemo+ Chemo
OC BC NSCLC PC + LC OC BC KS
MBC
16
9
Adjuv chemo (100)chemo post-adjuv (33)
Gem (nucleoside metabolic inhibitor 1250 mgm2) on days 1 and 8 nab-Pac (microtubule inhibitor) starting dose of 180 mgm2 (cohort 1) 220 mgm2 (cohort 2) and 260 mgm2 (cohort 3) on day 1 of the 21-day cycle using a 3 + 3 design
0
MTD not reached29 Gr3 Neutropenia59 Gr1 Peripheralneuropathy
Yoshitomi S Taira N Doihara H Mizoo T Nogami T Iwamoto T Motoki T Shien T Ogasawara Y Matsuoka J Tsuji H Mitsuhashi T A phase 1 dose-finding and pharmacokinetic study of gemcitabine with nab-paclitaxel in patients with metastatic breast cancer Cancer Chemother Pharmacol 2016 Aug78(2)289-94
Eli Lilly
Erbituxreg (cetuximab) + Taxane
EGFR inhibitor antineoplastic agent + Chemo
Head amp NeckColorectal
TNBC
07-10
18
1 chemo
Cetuximab (epidermal growth factor receptor (EGFR) antagonist ) an initial loading dose of cetuximab 400 mgm2 followed by a weekly dose of 250 mgm2Paclitaxel (microtubule inhibitor) 80 mgm2 or Docetaxel at an initial dose of 30 mgm2 was administered weekly
56 CR 22 PR
83 Dermatologic toxicity11 Grade3+
Nechushtan H Vainer G Stainberg H Salmon AY Hamburger T Peretz T A phase 12 of a combination of cetuximab and taxane for triple negative breast cancer patients Breast 2014 Aug23(4)435-8
Polyphor
Balixafortide (POL6326) + eribulin
CXCR4 antagonist + tubulin-based antimitotic
Heavily pretreatedRelapsed MBC
14-16
56
3rd line 3 chemo
3+3 dose escalation The highest dose was established as eribulin 14 mgmsup2 on days 2 and 9 and balixafortide 55 mgkg on days 1minus3 and 8minus10 of the 21-day cycle
30 PR
41 Gr34 Neutropenia11 Gr34 Leucopenia11 Gr34 Febrileneutropenia2 Related mortalities
42018 Fast Track (HER2-MBC failed 2 prior regimens)
Pernas S Martin M Kaufman PA Gil-Martin M Gomez Pardo P Lopez-Tarruella S Manso L Ciruelos E Perez-Fidalgo JA Hernando C Ademuyiwa FO Weilbaecher K Mayer I Pluard TJ Martinez Garcia M Vahdat L Perez-Garcia J Wach A Barker D Fung S Romagnoli B Cortes J Balixafortide plus eribulin in HER2-negative metastatic breast cancer a phase 1 single-arm dose-escalation trial Lancet Oncol 2018 Jun19(6)812-824
1 PRndashbut only + letrozoleNo Resp on monotherapy
61 Gr34 Neutropenia39 Gr34 Leucopenia
$933M (1Q18)$31B (2017)
Tamura K Mukai H Naito Y Yonemori K Kodaira M Tanabe Y Yamamoto N Osera S Sasaki M Mori Y Hashigaki S Nagasawa T Umeyama Y Yoshino T Phase I study of palbociclib a cyclin-dependent kinase 46 inhibitor in Japanese patients Cancer Sci 2016 Jun107(6)755-63 doi 101111cas12932 Epub 2016 May 11
Pfizer
Ibrancereg (palbociclib)
CDK 46 Inhibitor
HR+ HER2- MBC
Heavily pretreatedRelapsed Met Cancer
04-08
41 (5 BC)
chemo naiumlve (17)1-2(51) 3(29) 3+(2)
Palbociclib 25-150 mg dose ranging
0
20 Gr34 Neutropenia23 Gr34 Leucopenia
$933M (1Q18)$31B (2017)
Flaherty KT Lorusso PM Demichele A Abramson VG Courtney R Randolph SS Shaik MN Wilner KD ODwyer PJ Schwartz GK Phase I dose-escalation trial of the oral cyclin-dependent kinase 46 inhibitor PD 0332991 administered using a 21-day schedule in patients with advanced cancer Clin Cancer Res 2012 Jan 1518(2)568-76 doi 1011581078-0432CCR-11-0509 Epub 2011 Nov 16
Novartis
Kisqalireg (ribociclib)
CDK 46 Inhibitor
Premenopausal HR+ HER2- MBC
Heavily pretreatedRelapsed Met Cancer
16
132 (20 BC)
0-1 (25) 2-3 (42)4+ (32)
Ribociclib 50 mg ranging up to 1200 mg dose escalation
23 PR-included 1 BC (5 of BC pts)
27 Gr34 Neutropenia17 Gr34 Leucopenia
Peak sales est at $25B
Infante JR Cassier PA Gerecitano JF Witteveen PO Chugh R Ribrag V Chakraborty A Matano A Dobson JR Crystal AS Parasuraman S Shapiro GI A Phase I Study of the Cyclin-Dependent Kinase 46 Inhibitor Ribociclib (LEE011) in Patients with Advanced Solid Tumors and Lymphomas Clin Cancer Res 2016 Dec 122(23)5696-5705 Epub 2016 Aug 19
Eli Lilly
Verzenioreg (abemaciclib)
CDK 46 Inhibitor
HR+HER2minusMBC
Heavily pretreatedRelapsed Met Cancer
16
12 (1 BC)
1 (312) 2 (212) 3+(7)
Abemaciclib 100 mg ranging up to 200 mg dose escalation
17 PR (included 1 BC)
17 Gr34 Neutropenia33 Gr34 Leucopenia
Peak sales est at $2B
Fujiwara Y Tamura K Kondo S Tanabe Y Iwasa S Shimomura A Kitano S Ogasawara K Turner PK Mori J Asou H Chan EM Yamamoto N Phase 1 study of abemaciclib an inhibitor of CDK 4 and 6 as a single agent for Japanese patients with advanced cancer Cancer Chemother Pharmacol 2016 Aug78(2)281-8 doi 101007s00280-016-3085-8 Epub 2016 Jun 16
Mukai H Saeki T Shimada K Naito Y Matsubara N Nakanishi T Obaishi H Namiki M Sasaki Y Phase 1 combination study of eribulin mesylate with trastuzumab for advanced or recurrent human epidermal growth factor receptor 2 positive breast cancer Invest New Drugs 2015 Feb33(1)119-27
AstraZeneca
Lynparza (Olaparib) + Cediranib
PARP inhibitor + inhibitor of VEGF receptor tyrosine kinases
HR+ HER2- MBC
BC amp OC
2013
28 (8 BC)
3 for BC
Olaparib (a poly (ADP-ribose) polymerase (PARP) inhibitor) amp Cediranib (Vascular endothelial growth factor receptor (VEGFR) 1 2 and 3 tyrosine kinase inhibitor)3 at dose level (DL) 0 (cediranib 20mg olaparib 100mg) 3 at DL1 (cediranib 20mg olaparib 200mg) 7 at DL2 (cediranib 30mg olaparib 200mg) 6 at DL3 (cediranib 30mg olaparib 400mg)
Liu JF Tolaney SM Birrer M Fleming GF Buss MK Dahlberg SE Lee H Whalen C Tyburski K Winer E Ivy P Matulonis UA A Phase 1 trial of the poly(ADP-ribose) polymerase inhibitor olaparib (AZD2281) in combination with the anti-angiogenic cediranib (AZD2171) in recurrent epithelial ovarian or triple-negative breast cancer Eur J Cancer 2013 Sep49(14)2972-8
Reyon Pharmaceutical
VM206RY
Heterologous prime-boost with a truncated HER2 sequence
HER2+ Stage IIIampIV BC
2015
9
2 chemo
Plasmid DNA (pHM-GM-CSF expressing truncated HER2 amp GM-CSF) amp adenoviral vector (Ad-HM containing modified HER2) (2 4 and 8 mgpatientvisit) of pHM-GM-CSF 3x IM weeks 0 2 and 4 Ad-HM 3 times 109 virus particles at week 6
11 PR
4 pts showed 7 minor AEs
Unclear
Kim SB Ahn JH Kim J Jung KH A phase 1 study of a heterologous prime-boost vaccination involving a truncated HER2 sequence in patients with HER2-expressing breast cancer Mol Ther Methods Clin Dev 2015 Sep 30215031 doi 101038mtm201531 eCollection 2015
Rodon J Peacuterez-Fidalgo A Krop IE Burris H Guerrero-Zotano A Britten CD Becerra C Schellens J Richards DA Schuler M Abu-Khalaf M Johnson FM Ranson M Edenfield J Silva AP Hackl W Quadt C Demanse D Duval V Baselga J Phase 11b dose escalation and expansion study of BEZ235 a dual PI3KmTOR inhibitor in patients with advanced solid tumors including patients with advanced breast cancer Cancer Chemother Pharmacol 2018 Jun 7 doi 101007s00280-018-3610-z [Epub ahead of print]
Celgene (Abraxane)
Gemcitabine + Abraxane (nab-paclitaxel)
Chemo + Chemo
OC BC NSCLC amp Panc cancer + Lung OC BC Kaposi sarcoma
MBC
2016
9
Adjuvant chemo (100)chemo post-adjuvant (33)
Gem (nucleoside metabolic inhibitor 1250 mgm2) on days 1 and 8 nab-Pac (microtubule inhibitor) starting dose of 180 mgm2 (cohort 1) 220 mgm2 (cohort 2) and 260 mgm2 (cohort 3) on day 1 of the 21-day cycle using a 3 + 3 design
0
MTD not reached29 Gr3 Neutropenia59 Gr1 Peripheralneuropathy
Yoshitomi S Taira N Doihara H Mizoo T Nogami T Iwamoto T Motoki T Shien T Ogasawara Y Matsuoka J Tsuji H Mitsuhashi T A phase 1 dose-finding and pharmacokinetic study of gemcitabine with nab-paclitaxel in patients with metastatic breast cancer Cancer Chemother Pharmacol 2016 Aug78(2)289-94
Eli Lilly
Erbituxreg (cetuximab) + Taxane
EGFR inhibitor antineoplastic agent + Chemo
Headamp Neck Colorectal Cancer
TNBC
2007-2010
18
1 chemo
Cetuximab (epidermal growth factor receptor (EGFR) antagonist ) an initial loading dose of cetuximab 400 mgm2 followed by a weekly dose of 250 mgm2Paclitaxel (microtubule inhibitor) 80 mgm2 or Docetaxel at an initial dose of 30 mgm2 was administered weekly
56 CR 22 PR
83 Dermatologic toxicity11 Grade3+
Nechushtan H Vainer G Stainberg H Salmon AY Hamburger T Peretz T A phase 12 of a combination of cetuximab and taxane for triple negative breast cancer patients Breast 2014 Aug23(4)435-8
Polyphor
Balixafortide (POL6326) + eribulin
CXCR4 antagonist + tubulin-based antimitotic
Heavily pretreated Relapsed MBC
2014-2016
56
3rd line 3 chemo
3+3 dose escalation The highest dose was established as eribulin 14 mgmsup2 on days 2 and 9 and balixafortide 55 mgkg on days 1minus3 and 8minus10 of the 21-day cycle
30 PR
41 Gr34 Neutropenia11 Gr34 Leucopenia11 Gr34 Febrileneutropenia2 Related mortalities
Apr 2018 Fast Track for HER2-MBC who have failed 2prior regimens
Pernas S Martin M Kaufman PA Gil-Martin M Gomez Pardo P Lopez-Tarruella S Manso L Ciruelos E Perez-Fidalgo JA Hernando C Ademuyiwa FO Weilbaecher K Mayer I Pluard TJ Martinez Garcia M Vahdat L Perez-Garcia J Wach A Barker D Fung S Romagnoli B Cortes J Balixafortide plus eribulin in HER2-negative metastatic breast cancer a phase 1 single-arm dose-escalation trial Lancet Oncol 2018 Jun19(6)812-824
11 PRndashbut only + letrozole (No Resp on monotherapy)
61 Gr34 Neutropenia39 Gr34 Leucopenia
$933M in 1Q2018 $31B in 2017
Tamura K Mukai H Naito Y Yonemori K Kodaira M Tanabe Y Yamamoto N Osera S Sasaki M Mori Y Hashigaki S Nagasawa T Umeyama Y Yoshino T Phase I study of palbociclib a cyclin-dependent kinase 46 inhibitor in Japanese patients Cancer Sci 2016 Jun107(6)755-63 doi 101111cas12932 Epub 2016 May 11
Pfizer
Ibrancereg (palbociclib)
CDK 46 Inhibitor
HR+ HER2- MBC
Heavily pretreated Relapsed Metastatic Cancer
2004-2008
41 (5 BC)
chemo naiumlve (17) 1-2 (51)3 (29) 3+ (2)
Palbociclib 25-150 mg dose ranging
0
20 Gr34 Neutropenia23 Gr34 Leucopenia
$933M in 1Q2018 $31B in 2017
Flaherty KT Lorusso PM Demichele A Abramson VG Courtney R Randolph SS Shaik MN Wilner KD ODwyer PJ Schwartz GK Phase I dose-escalation trial of the oral cyclin-dependent kinase 46 inhibitor PD 0332991 administered using a 21-day schedule in patients with advanced cancer Clin Cancer Res 2012 Jan 1518(2)568-76 doi 1011581078-0432CCR-11-0509 Epub 2011 Nov 16
Novartis
Kisqalireg (ribociclib)
CDK 46 Inhibitors
Premenopausal HR+ HER2- MBC
Heavily pretreated Relapsed Metastatic Cancer
2016
132 (20 BC)
0-1 (25) 2-3 (42) 4+ (32)
Ribociclib 50 mg ranging up to 1200 mg dose escalation
23 PRndashincluded 1 in BC (5 of BC pts)
27 Gr34 Neutropenia17 Gr34 Leucopenia
Peak sales projected at $25B
Infante JR Cassier PA Gerecitano JF Witteveen PO Chugh R Ribrag V Chakraborty A Matano A Dobson JR Crystal AS Parasuraman S Shapiro GI A Phase I Study of the Cyclin-Dependent Kinase 46 Inhibitor Ribociclib (LEE011) in Patients with Advanced Solid Tumors and Lymphomas Clin Cancer Res 2016 Dec 122(23)5696-5705 Epub 2016 Aug 19
Eli Lilly
Verzenioreg (abemaciclib)
CDK 46 Inhibitors
HR+HER2minusMBC
Heavily pretreated Relapsed Metastatic Cancer
2016
12 (1 BC)
1 (312) 2 (212) 3+ (7)
Abemaciclib 100 mg ranging up to 200 mg dose escalation
17 PR (included 1 in BC)
17 Gr34 Neutropenia33 Gr34 Leucopenia
Peak sales projected at $2B
Fujiwara Y Tamura K Kondo S Tanabe Y Iwasa S Shimomura A Kitano S Ogasawara K Turner PK Mori J Asou H Chan EM Yamamoto N Phase 1 study of abemaciclib an inhibitor of CDK 4 and 6 as a single agent for Japanese patients with advanced cancer Cancer Chemother Pharmacol 2016 Aug78(2)281-8 doi 101007s00280-016-3085-8 Epub 2016 Jun 16
Mukai H Saeki T Shimada K Naito Y Matsubara N Nakanishi T Obaishi H Namiki M Sasaki Y Phase 1 combination study of eribulin mesylate with trastuzumab for advanced or recurrent human epidermal growth factor receptor 2 positive breast cancer Invest New Drugs 2015 Feb33(1)119-27
AstraZeneca
Lynparza (Olaparib)+ Cediranib
PARP inhibitor+ inhibitor of VEGF RTK
HR+ HER2- MBC
BC amp OC
13
28 (8 BC)
3 for BC
Olaparib (a poly (ADP-ribose) polymerase (PARP) inhibitor) amp Cediranib (Vascular endothelial growth factor receptor (VEGFR) 1 2 and 3 tyrosine kinase inhibitor)3 at dose level (DL) 0 (cediranib 20mg olaparib 100mg) 3 at DL1 (cediranib 20mg olaparib 200mg) 7 at DL2 (cediranib 30mg olaparib 200mg) 6 at DL3 (cediranib 30mg olaparib 400mg)
Liu JF Tolaney SM Birrer M Fleming GF Buss MK Dahlberg SE Lee H Whalen C Tyburski K Winer E Ivy P Matulonis UA A Phase 1 trial of the poly(ADP-ribose) polymerase inhibitor olaparib (AZD2281) in combination with the anti-angiogenic cediranib (AZD2171) in recurrent epithelial ovarian or triple-negative breast cancer Eur J Cancer 2013 Sep49(14)2972-8
ReyonPharma
VM206RY
Heterologous prime-boost with a truncated HER2 sequence
HER2+ Stg IIIampIV BC
15
9
2 chemo
Plasmid DNA (pHM-GM-CSF expressing truncated HER2 amp GM-CSF) amp adenoviral vector (Ad-HM containing modified HER2) (2 4 and 8 mgpatientvisit) of pHM-GM-CSF 3x IM weeks 0 2 and 4 Ad-HM 3 times 109 virus particles at week 6
11 PR
4 pts 7 minor AEs
Unclear
Kim SB Ahn JH Kim J Jung KH A phase 1 study of a heterologous prime-boost vaccination involving a truncated HER2 sequence in patients with HER2-expressing breast cancer Mol Ther Methods Clin Dev 2015 Sep 30215031 doi 101038mtm201531 eCollection 2015
Rodon J Peacuterez-Fidalgo A Krop IE Burris H Guerrero-Zotano A Britten CD Becerra C Schellens J Richards DA Schuler M Abu-Khalaf M Johnson FM Ranson M Edenfield J Silva AP Hackl W Quadt C Demanse D Duval V Baselga J Phase 11b dose escalation and expansion study of BEZ235 a dual PI3KmTOR inhibitor in patients with advanced solid tumors including patients with advanced breast cancer Cancer Chemother Pharmacol 2018 Jun 7 doi 101007s00280-018-3610-z [Epub ahead of print]
Celgene(Abraxane)
Gemcitabine + Abraxane (nab-paclitaxel)
Chemo+ Chemo
OC BC NSCLC PC + LC OC BC KS
MBC
16
9
Adjuv chemo (100)chemo post-adjuv (33)
Gem (nucleoside metabolic inhibitor 1250 mgm2) on days 1 and 8 nab-Pac (microtubule inhibitor) starting dose of 180 mgm2 (cohort 1) 220 mgm2 (cohort 2) and 260 mgm2 (cohort 3) on day 1 of the 21-day cycle using a 3 + 3 design
0
MTD not reached29 Gr3 Neutropenia59 Gr1 Peripheralneuropathy
Yoshitomi S Taira N Doihara H Mizoo T Nogami T Iwamoto T Motoki T Shien T Ogasawara Y Matsuoka J Tsuji H Mitsuhashi T A phase 1 dose-finding and pharmacokinetic study of gemcitabine with nab-paclitaxel in patients with metastatic breast cancer Cancer Chemother Pharmacol 2016 Aug78(2)289-94
Eli Lilly
Erbituxreg (cetuximab) + Taxane
EGFR inhibitor antineoplastic agent + Chemo
Head amp NeckColorectal
TNBC
07-10
18
1 chemo
Cetuximab (epidermal growth factor receptor (EGFR) antagonist ) an initial loading dose of cetuximab 400 mgm2 followed by a weekly dose of 250 mgm2Paclitaxel (microtubule inhibitor) 80 mgm2 or Docetaxel at an initial dose of 30 mgm2 was administered weekly
56 CR 22 PR
83 Dermatologic toxicity11 Grade3+
Nechushtan H Vainer G Stainberg H Salmon AY Hamburger T Peretz T A phase 12 of a combination of cetuximab and taxane for triple negative breast cancer patients Breast 2014 Aug23(4)435-8
Polyphor
Balixafortide (POL6326) + eribulin
CXCR4 antagonist + tubulin-based antimitotic
Heavily pretreatedRelapsed MBC
14-16
56
3rd line 3 chemo
3+3 dose escalation The highest dose was established as eribulin 14 mgmsup2 on days 2 and 9 and balixafortide 55 mgkg on days 1minus3 and 8minus10 of the 21-day cycle
30 PR
41 Gr34 Neutropenia11 Gr34 Leucopenia11 Gr34 Febrileneutropenia2 Related mortalities
42018 Fast Track (HER2-MBC failed 2 prior regimens)
Pernas S Martin M Kaufman PA Gil-Martin M Gomez Pardo P Lopez-Tarruella S Manso L Ciruelos E Perez-Fidalgo JA Hernando C Ademuyiwa FO Weilbaecher K Mayer I Pluard TJ Martinez Garcia M Vahdat L Perez-Garcia J Wach A Barker D Fung S Romagnoli B Cortes J Balixafortide plus eribulin in HER2-negative metastatic breast cancer a phase 1 single-arm dose-escalation trial Lancet Oncol 2018 Jun19(6)812-824
1 PRndashbut only + letrozoleNo Resp on monotherapy
61 Gr34 Neutropenia39 Gr34 Leucopenia
$933M (1Q18)$31B (2017)
Tamura K Mukai H Naito Y Yonemori K Kodaira M Tanabe Y Yamamoto N Osera S Sasaki M Mori Y Hashigaki S Nagasawa T Umeyama Y Yoshino T Phase I study of palbociclib a cyclin-dependent kinase 46 inhibitor in Japanese patients Cancer Sci 2016 Jun107(6)755-63 doi 101111cas12932 Epub 2016 May 11
Pfizer
Ibrancereg (palbociclib)
CDK 46 Inhibitor
HR+ HER2- MBC
Heavily pretreatedRelapsed Met Cancer
04-08
41 (5 BC)
chemo naiumlve (17)1-2(51) 3(29) 3+(2)
Palbociclib 25-150 mg dose ranging
0
20 Gr34 Neutropenia23 Gr34 Leucopenia
$933M (1Q18)$31B (2017)
Flaherty KT Lorusso PM Demichele A Abramson VG Courtney R Randolph SS Shaik MN Wilner KD ODwyer PJ Schwartz GK Phase I dose-escalation trial of the oral cyclin-dependent kinase 46 inhibitor PD 0332991 administered using a 21-day schedule in patients with advanced cancer Clin Cancer Res 2012 Jan 1518(2)568-76 doi 1011581078-0432CCR-11-0509 Epub 2011 Nov 16
Novartis
Kisqalireg (ribociclib)
CDK 46 Inhibitor
Premenopausal HR+ HER2- MBC
Heavily pretreatedRelapsed Met Cancer
16
132 (20 BC)
0-1 (25) 2-3 (42)4+ (32)
Ribociclib 50 mg ranging up to 1200 mg dose escalation
23 PR-included 1 BC (5 of BC pts)
27 Gr34 Neutropenia17 Gr34 Leucopenia
Peak sales est at $25B
Infante JR Cassier PA Gerecitano JF Witteveen PO Chugh R Ribrag V Chakraborty A Matano A Dobson JR Crystal AS Parasuraman S Shapiro GI A Phase I Study of the Cyclin-Dependent Kinase 46 Inhibitor Ribociclib (LEE011) in Patients with Advanced Solid Tumors and Lymphomas Clin Cancer Res 2016 Dec 122(23)5696-5705 Epub 2016 Aug 19
Eli Lilly
Verzenioreg (abemaciclib)
CDK 46 Inhibitor
HR+HER2minusMBC
Heavily pretreatedRelapsed Met Cancer
16
12 (1 BC)
1 (312) 2 (212) 3+(7)
Abemaciclib 100 mg ranging up to 200 mg dose escalation
17 PR (included 1 BC)
17 Gr34 Neutropenia33 Gr34 Leucopenia
Peak sales est at $2B
Fujiwara Y Tamura K Kondo S Tanabe Y Iwasa S Shimomura A Kitano S Ogasawara K Turner PK Mori J Asou H Chan EM Yamamoto N Phase 1 study of abemaciclib an inhibitor of CDK 4 and 6 as a single agent for Japanese patients with advanced cancer Cancer Chemother Pharmacol 2016 Aug78(2)281-8 doi 101007s00280-016-3085-8 Epub 2016 Jun 16
Bria-IMTtrade - First Product CandidateHuman Proof-of-Concept Trials in Advanced Breast Cancer
Bria-IMTtrade Non-Personalized Immunotherapy
First Proof-of-Concept Phase I (1999-2003) Used unmodified cell line + GM-CSF + cyclophosphamide N = 14 late stage treatment-refractory breast cancer patients Well tolerated no severe drug related AEs Median Overall Survival = 121 months
Second Proof-of-Concept Phase I (2005) Used GM-CSF-engineered cell line + cyclophosphamide + interferon-α N = 4 late stage treatment-refractory (3 breast cancer and 1 ovarian cancer) patients Well tolerated no life-threatening drug related adverse events One patient with transient urticaria reported as grade 3 responded to antihistamines Median Overall Survival = 35 months One robust responder with gt90 regression during treatment subsequent relapse (upon halting
treatment) responded to re-treatment
6
Bria-IMTtrade amp Bria-OTStradePotential Mechanisms of Action in Advanced Breast Cancer
Bria-IMTTM directly stimulates cancerfighting CD4+ and CD8+ T cells(further boosts the response)
Bria-IMTTM produces breastcancer antigens which aretaken up by dendritic cellsand ldquopresentedrdquo to CD4+and CD8+ T cells implicatedin tumor destruction
Bria-IMTTM secretes GM-CSF which further promotes dendritic cell-based antigen presentation (boosts the response) 7
Bria-IMTtradeHuman Proof-of-Concept Trials in Breast Cancer (Patient A002) Bria-IMTtrade Non-Personalized Immunotherapy ndash Given as Monotherapy
Second Proof-of-Concept Phase I (2005) 1 out of 4 patients responded with substantial tumor regression Patient A002 was the only patient with key HLA matches with Bria-IMTtrade
8
Bria-IMTtradeHuman Proof-of-Concept Trials in Breast Cancer (Patient A002) Approximately 3 months (106 days) after last inoculation Patient A002rsquos breast cancer returned and
spread to brain lung and other sites
Patient A002 was then re-treated with 10 inoculations of Bria-IMTtrade over 4 months
Repeat imaging studies showed normal findings on MRI and PET consistent with a completeremission of the previous multiple central nervous system metastases as shown in the brain scansbelow
Bria-IMTtrade and Bria-OTStrade shouldsynergize with existing approvedimmunotherapies as well as those stillunder development
This includes immune checkpointinhibitors such as antibodies to PD-1CTLA-4 GITR and CD73 inhibitors whicheliminate tumor immunosuppression Checkpoint Inhibitors were the
subject of the 2018 Nobel Prize inMedicine
In addition immunostimulatoryantibodies to molecules such as OX40should enhance responses to Bria-IMTtradeand Bria-OTStrade
13
Q3 2018 Data on first 20 Patients on Bria-IMTtrade Q3 2018 Initiate Combination Study of Bria-IMTtrade with Keytruda or Yervoy
Q4 2018 Switch to a novel frozen Bria-IMTtrade formulation Q4 2018 Safety Data (6 patients) of the Bria-IMTtrade - Keytrudareg Combination Study (SABC meeting) Q4 2018 Ongoing Corporate PartnershipCollaboration Discussions
Q1 2019 Efficacy Data (6 patients) of the Bria-IMTtrade - Keytrudareg Combination Study Q2 2019 Initiation of Bria-OTStrade GMP manufacturing (KBI BioPharma) Q2 2019 Additional Safety amp Efficacy data Monotherapy and Combination Studies (AACR meeting) Q2 2019 Final data for Monotherapy and Additional Data for the Combination Study (ASCO meeting) H1 2019 Candidate Selection for a PKCδ Inhibitor H1 2019 Initiate additional immunotherapy program H2 2019 Bria-OTStrade Authorization from FDA clearance for dosing H2 2019 Bria-OTStrade First Patient Dosed
Upcoming Milestones amp Catalysts
14
Involved in over 10 drugs brought to the market
Experienced Management Team
Management
William V Williams MD FACP President amp CEO VP Exploratory Development Incyte Corporation VP Experimental Medicine GlaxoSmithKline Head Rheumatology Research University of Pennsylvania Facilitated entry of over 20 compounds into the clinic including ruxolitinib (Jakafi)
baricitinib amp epacadostat NDAs including Jakafi Boniva Bexxar Author of over 120 peer-reviewed publications amp over 20 patents
Gadi Levin CA MBA CFO CFO of Labstyle Innovations Ltd VP of Finance for two Israeli investment houses in the fields of private equity
hedge funds and real estate Financial Consultant various firms Accountant Arthur Andersen
Markus Lacher PhD Senior Director RampD Founder T cell Therapeutics Inc an immuno-oncology company Sr Clinical Scientist Cesca Therapeutics Inc a clinical-stage autologous cell
therapy company Scientist at BioTime Inc and OncoCyte Corporation Editorial advisory board Recent Patents on Anti-Cancer Drug Discovery
Farrah Dean MSc MBA Manager Corp Development Investor relations CytRx Corporation amp CCG Investor Relations Senior Associate Equity Analyst Oppenheimer amp Co Rodman amp Renshaw amp
Brian Metcalf PhD Recently retired as CSO from Global Blood Therapeutics Former Head of Research amp Development Incyte Corporation Former Head of Medicinal Chemistry SmithKline Beecham
Douglas Faller MD PhD Professor of Medicine Pediatrics Biochemistry Microbiology Pathology and
Laboratory Medicine HematologistOncologist former Director of the Cancer Center Boston University School of Medicine
Founder of several successful biotechnology companies
Robert Williams PhD University Distinguished Professor of Chemistry Colorado State University Founder of several successful biotechnology companies including Microcide Xcyte
Therapies HemaQuest Arch Therapeutics and Cetya Therapeutics
Thomas Kieber-Emmons PhD Deputy Director University of Arkansas Cancer Center Expert in targeted cancer immunotherapies structural biology and computational
chemistry
Maria Trojanowska PhD Professor of Medicine Boston University School of Medicine Director The Arthritis Center
16
Veteran Board of Directors
Board of Directors
Saeid Babaei PhD MBA Chairman Entrepreneur 20 yrs of biotech leadership roles Current CEO AbCelex VP Bus Develop Lorus Therap Dir of Corp Develop Northern Therapeutics
Rahoul Sharan CA Director Chairman Potash Ridge Director of the Board Ansell Capital Corp Parallel Resources amp Galaxy Capital
Corporation
Martin Schmieg CPA Director CFO Sirna Therapeutics Inc amp Isolagen Inc CEO Freedom-2 Inc (now PharmaCyte Inc) Advisor Caladrius Biosciences Inc Beckman Coulter Genomics Calimmune
Charles Wiseman MD Co-Founder amp Director Director Immunotherapy Lab St Vincent Medical Center Chief Breast Cancer Basic Research Lab Univ of Texas MD Anderson Hospital amp
Tumour Institute Assist Prof Dept of Molecular Carcinogenesis amp Virology MD Anderson Acting Chief Div of Oncology White Memorial Medical Center LA
William V Williams MD FACP President amp CEO VP Exploratory Development Incyte Corporation VP Experimental Medicine GlaxoSmithKline Head Rheumatology Research University of Pennsylvania
Prior Affiliations
17
Drug Approvals by BriaCell Management Team
Bexxarreg (tositumomab and Iodine I131 tositumomab) Treatment of CD20 antigen-expressing relapsed or refractory low grade follicular or transformed non-Hodgkins lymphoma
Myleranreg (busulfan) for chronic myelogenous leukemia Defense of formulation change sNDA
Hycamtinreg (topotecan) for ovarian cancer Pediatric use sNDA
Navelbinereg (vinorelbine tartrate) for non-small cell lung cancer Pediatric use sNDA
Bonivareg (ibandronate) monthly oral treatment of osteoporosis
Bonivareg (ibandronate) quarterly intraveous treatment of osteoporosis
Zofranreg (ondansetron) for prevention of nausea and vomiting Pediatric use sNDA
Jakafireg (ruxolitinib) for myelofibrosis Jakafireg (ruxolitinib) for polycythemia vera
Olumiantreg (baricitinib) for rheumatoid arthritis Approved in USA Japan and Europe
18
Share Metrics
BCTV BCTXF 19
Data as of 1092018
Ticker TSX BCTV
US Ticker OTCQBBCTXF
Share Price (CAD) as of Oct 9 2018 $012
52-Week Range (CAD) $009-019
Shares Outstanding as of Oct 9 2018 1611M
Market Cap as of Oct 9 2018 (CAD) $193M
Cash and Short Term Investments as of July 31 2018 (CAD) $23M
Total Shareholders Equity as of July 31 2018 (CAD) $12M
Number of Warrants $014-$035 (CAD) as of Oct 9 2018 601M
Number of Compensation Warrants $014-$030 (CAD) as of Oct 9 2018 45M
Number of Options $014- $026 (CAD$) as of Oct 9 2018 93M
Developing Bria-OTStrade the First Off-the-Shelf Personalized Immunotherapy
Targeting Adv Breast Cancer Unmet medical need (42000 death in the US in 2017 ) $1 Bil- $5 Bil market opportunity depending on patient treatment stage
Impressive results in 2 proof-of-concept clinical trials Rapid Response Rate Repeated following re-treatment Excellent Safety Profile
Completed enrollment in Phase IIIa clinical trial of Bria-IMTtrade with outstanding safety amp efficacy data Initiated Phase IIa Combination Study of Bria-IMTtrade with Keytrudareg (Merck amp Co Inc)
Developing Bria-OTStrade along with BriaDXtrade its companion diagnostic test Ability to match and treat ~90 of patient population with Off-the-Shelf personalized immunotherapy
Experienced Management has been involved in over 10 drug approvals
Patient B001 Breast 70 No 1101 - 3501 4001 Negative -
Bria-IMTtradeHuman Proof-of-Concept Trials in Breast Cancer (Patient A002)
24
Proof-of-Concept Results Resulted in BriaCellrsquos Immunotherapy Strategy Use BriaDXtrade diagnostic to select only those patients matching Bria-IMTtrade Use BriaDXtrade diagnostic test to select Bria-OTStrade alleles matching ~90 of all patients
Bria-IMTtradeCurrent Phase IIIa Data Supports HLA Matching Hypothesis Six patients treated in 2017 Bria-IMTtrade was safe and well tolerated
Patient 01-002 73-year-old woman with breast cancer diagnosed in 1995 Developed liver metastases in2010 and lung metastases in 2017 Previously treated with 7 rounds of chemotherapy with 8 differentchemotherapy agents Received 5 cycles of Bria-IMTtrade over 3 months then monthly cycles (6 months total)Evaluated after 3 months and 6 months After 3 months despite the extensive prior therapy her scans notedthat ldquothere has been a clear response in the multiple bilateral pulmonary nodulesrdquo The response wasmaintained after 6 months of Bria-IMTtrade treatment She matches Bria-IMTtrade at 2 HLA alleles
The liver tumors were stable to slightly increased at 3 months and then progressed after 6 months
This supports our hypothesis of heightened anti-tumor activity in patients with a matched HLA types Clear path to develop BriaDXtrade to select the patients using HLA testing
1 RLL 29 Not Detectable Not Detectable2 LUL apical pleural based 34 tiny nodule lt 1mm scar tiny nodule lt 1mm scar3 xxx 39 Not Detectable Not Detectable4 40 Not Detectable Not Detectable5 RLL 45 Not Detectable Not Detectable6 LLL 49 Not Detectable Not Detectable7 xxx 52 Not Detectable Not Detectable8 RLL 52 Not Detectable Not Detectable9 RLL 56 Not Detectable Not Detectable
10 RLL costophrenic recess 56 Not Detectable Not Detectable11 XXX 58 Not Detectable Not Detectable12 LUL 60 Not Detectable Not Detectable13 XXX 67 15 1514 RUL 72 15 1515 LLL 76 Not Detectable Not Detectable16 RUL Noncalcified Nodule 77 Not Detectable Not Detectable17 RLL costophrenic recess 79 10 1018 RUL 82 Not Detectable Not Detectable19 RLL 90 Not Detectable Not Detectable20 RLL 91 lt 01 lt 0121 xxx xxx Not Detectable Not Detectable
27
Clinical Development Update ndash Summary 2018 September 26
Completed enrollment of Adv Breast cancer patients in the Phase IIIa ldquomonotherapyrdquo study of Bria-IMTtrade
We have confirmed our mechanism of action and achieved proof of concept
Initial safety data appears superior to that of the other advanced or approved drugs for breast cancer when they were at a similar clinical stage of development
Initial efficacy data is similar or superior to those of other advanced or approved drugs for breast cancer when they were at a similar clinical stage of development
Initiated Combination Study of Bria-IMTtrade with Keytrudareg or Yervoyreg in Adv breast cancer patients expecting even better response rates than those in the ldquomonotherapyrdquo study Initial safety data is expected in 4Q2018 Initial efficacy data is expected in 1Q2019
Bria-OTStrade the first off-the-shelf personalized treatment for advanced breast cancer is expected to enter the clinic in 2019
28
Bria-IMTtrade Excellent Safety Data - To Date
To date Bria-IMTtrade has been dosed in 24 patients (4 in 2004-2005 20 in 2017-2018)
Interim Data (20 patients)-Ongoing Phase IIIa Study (2017-2018)
Bria-IMTtrade has been very well tolerated (ge60 doses given to date) The majority of adverse events (AEs) were limited to expected minor local irritation at the
injection sites No related grade gt3 or unexpected AEs No related serious AEs No serious unexpected related AEs Most patients who have dropped out did so due to worsening of their underlying disease
Based on the current study Bria-IMTtrade has an excellent safety profile
29
Bria-IMTtrade - Efficacy as Predicted
Interim Data (19 patients)-Ongoing Phase IIIa Study (2017-2018) amp Original Study (2004-2005)
PD-L1 expression on circulating cancer cells amp cancer-associated cells in 100 of patients (to date) Strong rationale for combination with checkpoint inhibitors like Keytruda
30
Bria-IMTtrade appears to be most effective in patients who match with Bria-IMT trade at 2 HLA loci (types) further supporting our ldquoHLA Matching Hypothesisrdquo and the development of Bria-OTS trade to cover 90 of the patient population
Combination with immune checkpoint inhibitors may induce a more potent anti-cancer response leading to our strategy of combination studies of Bria-IMT trade with Keytruda or Yervoy
Patients (n) HLA Match
Tumor Shrinkage
Biological Response
4 ge2 50 7515 ge1 27 334 0 0 0
Biological response includes tumor shrinkage or lower circulating cancer associated cells
The confirmatory Bria-IMTtrade monotherapy Phase IIa trial has completed enrollment Additional Support for the HLA-matching hypothesis has been obtained
Bria-IMTtrade Combination Therapy study with immune checkpoint inhibitors Keytrudareg if PD-L12 positive (ge1) Yervoyreg if PD-L12 negative (lt1) Accepting patients from the monotherapy study who develop progressive disease Also enrolling patients directly into this study to enhance experience with the combination In discussion with other pharmaceutical companies to evaluate additional combinations with other
immunotherapies
Bria-OTStrade Off-the-Shelf Personalized Targeted Immunotherapy Developing Bria-OTStrade to co-express GM-CSF and interferon-α Pre-manufacture additional HLA alleles ndash Total of 15 alleles (8 Class I and 7 Class II) Co-development of BriaDXtrade companion diagnostic for HLA typing Combination therapy clinical trial with immune checkpoint inhibitors for non-responders using
information from the Bria-IMTtrade Combination Therapy Study
33
Development Timeline ndash Breast Cancer
20192018 2020 2021
Phase IIIaBria-IMTtrade
Monotherapy
Currently Enrolling Phase IIaBria-IMTtrade + Checkpoint
Currently in discussions with potential partnersPhase II Bria-IMTtrade plus Additional Combinations (1Q19 4Q22)(eg PD-1 Inhibitor PD-L1 inhibitor anti-CTLA4 anti-GITR anti-OX40)
1Q 2Q 3Q 4Q
2023
Bria-OTStrade Off-The-Shelf Personalized ImmunotherapyMonotherapy and Potential Partnered Combo Therapy
(2H19 Ongoing)
Bria-OTStradeOff-the-Shelf Cell Line cGMP Manufacturing
and BriaDXtrade(1Q18 1Q19)
Registration Studies (1Q20 2H22)Bria-IMTtrade with Checkpoint InhibitorsBria-OTStrade +- Checkpoint Inhibitors
34
Immuno-oncology Deals
Recent deals of small biotechs with big pharma in immuno-oncology
35
Date PartnershipDevelopment stage at the time of the deal Deal size
07122018 Immatics-Genmab Preclinical Up to $28B
04042018 OSE Immunotherapeutics-Boehringer Ingelheim Preclinical Up to euro113B ($139B)
02092018 Pieris Pharmaceuticals-Seattle Genetics Preclinical Up to $123B
2142018 Nektar-BMS Ph III Up to $36B
01222018 Juno-Celgene Ph II $9B (Acquisition)
11142017 Loxo-Bayer Larotrectinib (Ph II) LOXO-195 (Ph III) Up to $155B
1032017 CytomX-Amgen Preclinical Up to $15B
03202017 CytomX--BMS Ph III Up to $36B
6282016 Xencor-Novartis Preclinical Up to $24B
Early Stage Clinical Studies (Comparison)
We compared the interim data of Ph IIIa study of Bria-IMTtrade in advanced breast cancer with thedata in the early stage clinical studies of recently approved breast cancer drugs and one fasttracked product candidate
Apples to apples comparison Early Stage Clinical Studies in oncology are typically done in patientswith no other therapeutic options Thus the patients have very advanced disease and response ratesare typically quite low
The patients in our Ph IIIa study have been heavily pre-treated (median 45 prior regimens)Some recent studies of relevance in breast cancer are noted in the following slides
36
Breast Cancer Market Opportunity
Drug Technology Approved for Market (US)Ibrance (palbociclib) CDK 46 Inhibitor HR+HER2- MBC in combination with
fluvestrant or aromatase inhibitor$933M in 1Q2018 $3126M in 2017
Kisqali (ribociclib) CDK 46 Inhibitor 2017 HR+HER2- MBC in combination with fluvestrant or aromatase inhibitor
Peak sales projected at $25B
Verzenio (abemaciclib) CDK 46 Inhibitor 2017 HR+HER2- MBC in combination with fluvestrant or aromatase inhibitor
balixafortide CXCR4 antagonist Fast track designation in 2018 for HER2- MBC who have failed 2 prior regimens
The market for breast cancer drugs is a multibillion dollar market with new drugs being approvedon an ongoing basis indicating the shortage of safe and effective treatments for this deadly disease
37
Competitors- Phase III Clinical Data Bria-IMTtrade shows superior safety and similar to superior efficacy data compared with those of the multi-billion dollar drugs when they were at a similar early stage of clinical development
Injection site reactions No related SAEs or SUSARs
Tumor vol darr ampor darr circul tumor cellsAll Comers 21(419) 26(519)One or More HLA matches 27(415) 33(515)Two or More HLA matches 50 (24) 75 (34)
Sheet1 (3)
Comp -Slides
Data
HLA (2)
HLA
Data (Ph1-2+4Pt)
Competitors (2018)-Slide
Competitors (2018)
In the Pipeline Protein Kinase C delta (PKCδ) Inhibitors
30 of all human malignancies display activating RAS mutations Another 60 showing over-activity of Ras-signaling pathways
Ras has been termed ldquoundruggablerdquo (no one has been able to make a Ras inhibitor drug)
BriaCellrsquos novel proprietary PKCδ inhibitors have shown activity against multiple RAS transformed tumors Lung cancer Melanoma Breast cancer Neuroendocrine cancer Pancreatic cancer Colorectal cancer
This target has an attractive safety profile based on in vivo studies and knock out mouse studies
PKCδ inhibitors should qualify for an accelerated clinical development plan and regulatory pathway
Could be in clinic within 24 months
Cost-Effective Additional Shot-on-Goal and additional partnership opportunities
Early-Stage Preclinical Program
39
Protein Kinase C delta (PKCδ) Inhibitors
Activated PKCδ inhibits RAS degradation which in turn stimulates tumor growth
Koo et al Oncotarget 621328 2016
30 of all human malignancies display activating RASmutations with another 60 showing over-activity of Ras-signaling pathways
BriaCellrsquos novel proprietary PKCδ inhibitors have shownactivity against multiple RAS transformed tumors
This target has an attractive safety profile based on in vivostudies and knock out mouse studies
PKCδ also has potential activity as an immunotherapeuticby blocking TGFβ signaling
PKCδ inhibitors are applicable to specific niche tumor typeswhich provide an accelerated clinical development plan
Structural aspects of first generation inhibitor rottlerin and staurosporine (pan-PKC activator) were combined to create second generation inhibitor KAM1
Third generation inhibitors such as BJE6-106 have improved potency and selectivity Fourth generation inhibitors under development to optimize drug-like characteristics PKCδ inhibitors lack endothelial cell cytotoxicity amp PKCδ deficient mice develop normally and are fertile Potentially no marked intrinsic toxicity by inhibiting PKCδ
Mukai H Saeki T Shimada K Naito Y Matsubara N Nakanishi T Obaishi H Namiki M Sasaki Y Phase 1 combination study of eribulin mesylate with trastuzumab for advanced or recurrent human epidermal growth factor receptor 2 positive breast cancer Invest New Drugs 2015 Feb33(1)119-27
AstraZeneca
Lynparza (Olaparib) + Cediranib
PARP inhibitor + inhibitor of VEGF receptor tyrosine kinases
HR+ HER2- MBC
BC amp OC
2013
28 (8 BC)
3 for BC
Olaparib (a poly (ADP-ribose) polymerase (PARP) inhibitor) amp Cediranib (Vascular endothelial growth factor receptor (VEGFR) 1 2 and 3 tyrosine kinase inhibitor)3 at dose level (DL) 0 (cediranib 20mg olaparib 100mg) 3 at DL1 (cediranib 20mg olaparib 200mg) 7 at DL2 (cediranib 30mg olaparib 200mg) 6 at DL3 (cediranib 30mg olaparib 400mg)
Liu JF Tolaney SM Birrer M Fleming GF Buss MK Dahlberg SE Lee H Whalen C Tyburski K Winer E Ivy P Matulonis UA A Phase 1 trial of the poly(ADP-ribose) polymerase inhibitor olaparib (AZD2281) in combination with the anti-angiogenic cediranib (AZD2171) in recurrent epithelial ovarian or triple-negative breast cancer Eur J Cancer 2013 Sep49(14)2972-8
Reyon Pharmaceutical
VM206RY
Heterologous prime-boost with a truncated HER2 sequence
HER2+ Stage IIIampIV BC
2015
9
2 chemo
Plasmid DNA (pHM-GM-CSF expressing truncated HER2 amp GM-CSF) amp adenoviral vector (Ad-HM containing modified HER2) (2 4 and 8 mgpatientvisit) of pHM-GM-CSF 3x IM weeks 0 2 and 4 Ad-HM 3 times 109 virus particles at week 6
11 PR
4 pts showed 7 minor AEs
Unclear
Kim SB Ahn JH Kim J Jung KH A phase 1 study of a heterologous prime-boost vaccination involving a truncated HER2 sequence in patients with HER2-expressing breast cancer Mol Ther Methods Clin Dev 2015 Sep 30215031 doi 101038mtm201531 eCollection 2015
Rodon J Peacuterez-Fidalgo A Krop IE Burris H Guerrero-Zotano A Britten CD Becerra C Schellens J Richards DA Schuler M Abu-Khalaf M Johnson FM Ranson M Edenfield J Silva AP Hackl W Quadt C Demanse D Duval V Baselga J Phase 11b dose escalation and expansion study of BEZ235 a dual PI3KmTOR inhibitor in patients with advanced solid tumors including patients with advanced breast cancer Cancer Chemother Pharmacol 2018 Jun 7 doi 101007s00280-018-3610-z [Epub ahead of print]
Celgene (Abraxane)
Gemcitabine + Abraxane (nab-paclitaxel)
Chemo + Chemo
OC BC NSCLC amp Panc cancer + Lung OC BC Kaposi sarcoma
MBC
2016
9
Adjuvant chemo (100)chemo post-adjuvant (33)
Gem (nucleoside metabolic inhibitor 1250 mgm2) on days 1 and 8 nab-Pac (microtubule inhibitor) starting dose of 180 mgm2 (cohort 1) 220 mgm2 (cohort 2) and 260 mgm2 (cohort 3) on day 1 of the 21-day cycle using a 3 + 3 design
0
MTD not reached29 Gr3 Neutropenia59 Gr1 Peripheralneuropathy
Yoshitomi S Taira N Doihara H Mizoo T Nogami T Iwamoto T Motoki T Shien T Ogasawara Y Matsuoka J Tsuji H Mitsuhashi T A phase 1 dose-finding and pharmacokinetic study of gemcitabine with nab-paclitaxel in patients with metastatic breast cancer Cancer Chemother Pharmacol 2016 Aug78(2)289-94
Eli Lilly
Erbituxreg (cetuximab) + Taxane
EGFR inhibitor antineoplastic agent + Chemo
Headamp Neck Colorectal Cancer
TNBC
2007-2010
18
1 chemo
Cetuximab (epidermal growth factor receptor (EGFR) antagonist ) an initial loading dose of cetuximab 400 mgm2 followed by a weekly dose of 250 mgm2Paclitaxel (microtubule inhibitor) 80 mgm2 or Docetaxel at an initial dose of 30 mgm2 was administered weekly
56 CR 22 PR
83 Dermatologic toxicity11 Grade3+
Nechushtan H Vainer G Stainberg H Salmon AY Hamburger T Peretz T A phase 12 of a combination of cetuximab and taxane for triple negative breast cancer patients Breast 2014 Aug23(4)435-8
Polyphor
Balixafortide (POL6326) + eribulin
CXCR4 antagonist + tubulin-based antimitotic
Heavily pretreated Relapsed MBC
2014-2016
56
3rd line 3 chemo
3+3 dose escalation The highest dose was established as eribulin 14 mgmsup2 on days 2 and 9 and balixafortide 55 mgkg on days 1minus3 and 8minus10 of the 21-day cycle
30 PR
41 Gr34 Neutropenia11 Gr34 Leucopenia11 Gr34 Febrileneutropenia2 Related mortalities
Apr 2018 Fast Track for HER2-MBC who have failed 2prior regimens
Pernas S Martin M Kaufman PA Gil-Martin M Gomez Pardo P Lopez-Tarruella S Manso L Ciruelos E Perez-Fidalgo JA Hernando C Ademuyiwa FO Weilbaecher K Mayer I Pluard TJ Martinez Garcia M Vahdat L Perez-Garcia J Wach A Barker D Fung S Romagnoli B Cortes J Balixafortide plus eribulin in HER2-negative metastatic breast cancer a phase 1 single-arm dose-escalation trial Lancet Oncol 2018 Jun19(6)812-824
11 PRndashbut only + letrozole (No Resp on monotherapy)
61 Gr34 Neutropenia39 Gr34 Leucopenia
$933M in 1Q2018 $31B in 2017
Tamura K Mukai H Naito Y Yonemori K Kodaira M Tanabe Y Yamamoto N Osera S Sasaki M Mori Y Hashigaki S Nagasawa T Umeyama Y Yoshino T Phase I study of palbociclib a cyclin-dependent kinase 46 inhibitor in Japanese patients Cancer Sci 2016 Jun107(6)755-63 doi 101111cas12932 Epub 2016 May 11
Pfizer
Ibrancereg (palbociclib)
CDK 46 Inhibitor
HR+ HER2- MBC
Heavily pretreated Relapsed Metastatic Cancer
2004-2008
41 (5 BC)
chemo naiumlve (17) 1-2 (51)3 (29) 3+ (2)
Palbociclib 25-150 mg dose ranging
0
20 Gr34 Neutropenia23 Gr34 Leucopenia
$933M in 1Q2018 $31B in 2017
Flaherty KT Lorusso PM Demichele A Abramson VG Courtney R Randolph SS Shaik MN Wilner KD ODwyer PJ Schwartz GK Phase I dose-escalation trial of the oral cyclin-dependent kinase 46 inhibitor PD 0332991 administered using a 21-day schedule in patients with advanced cancer Clin Cancer Res 2012 Jan 1518(2)568-76 doi 1011581078-0432CCR-11-0509 Epub 2011 Nov 16
Novartis
Kisqalireg (ribociclib)
CDK 46 Inhibitors
Premenopausal HR+ HER2- MBC
Heavily pretreated Relapsed Metastatic Cancer
2016
132 (20 BC)
0-1 (25) 2-3 (42) 4+ (32)
Ribociclib 50 mg ranging up to 1200 mg dose escalation
23 PRndashincluded 1 in BC (5 of BC pts)
27 Gr34 Neutropenia17 Gr34 Leucopenia
Peak sales projected at $25B
Infante JR Cassier PA Gerecitano JF Witteveen PO Chugh R Ribrag V Chakraborty A Matano A Dobson JR Crystal AS Parasuraman S Shapiro GI A Phase I Study of the Cyclin-Dependent Kinase 46 Inhibitor Ribociclib (LEE011) in Patients with Advanced Solid Tumors and Lymphomas Clin Cancer Res 2016 Dec 122(23)5696-5705 Epub 2016 Aug 19
Eli Lilly
Verzenioreg (abemaciclib)
CDK 46 Inhibitors
HR+HER2minusMBC
Heavily pretreated Relapsed Metastatic Cancer
2016
12 (1 BC)
1 (312) 2 (212) 3+ (7)
Abemaciclib 100 mg ranging up to 200 mg dose escalation
17 PR (included 1 in BC)
17 Gr34 Neutropenia33 Gr34 Leucopenia
Peak sales projected at $2B
Fujiwara Y Tamura K Kondo S Tanabe Y Iwasa S Shimomura A Kitano S Ogasawara K Turner PK Mori J Asou H Chan EM Yamamoto N Phase 1 study of abemaciclib an inhibitor of CDK 4 and 6 as a single agent for Japanese patients with advanced cancer Cancer Chemother Pharmacol 2016 Aug78(2)281-8 doi 101007s00280-016-3085-8 Epub 2016 Jun 16
Mukai H Saeki T Shimada K Naito Y Matsubara N Nakanishi T Obaishi H Namiki M Sasaki Y Phase 1 combination study of eribulin mesylate with trastuzumab for advanced or recurrent human epidermal growth factor receptor 2 positive breast cancer Invest New Drugs 2015 Feb33(1)119-27
AstraZeneca
Lynparza (Olaparib)+ Cediranib
PARP inhibitor+ inhibitor of VEGF RTK
HR+ HER2- MBC
BC amp OC
13
28 (8 BC)
3 for BC
Olaparib (a poly (ADP-ribose) polymerase (PARP) inhibitor) amp Cediranib (Vascular endothelial growth factor receptor (VEGFR) 1 2 and 3 tyrosine kinase inhibitor)3 at dose level (DL) 0 (cediranib 20mg olaparib 100mg) 3 at DL1 (cediranib 20mg olaparib 200mg) 7 at DL2 (cediranib 30mg olaparib 200mg) 6 at DL3 (cediranib 30mg olaparib 400mg)
Liu JF Tolaney SM Birrer M Fleming GF Buss MK Dahlberg SE Lee H Whalen C Tyburski K Winer E Ivy P Matulonis UA A Phase 1 trial of the poly(ADP-ribose) polymerase inhibitor olaparib (AZD2281) in combination with the anti-angiogenic cediranib (AZD2171) in recurrent epithelial ovarian or triple-negative breast cancer Eur J Cancer 2013 Sep49(14)2972-8
ReyonPharma
VM206RY
Heterologous prime-boost with a truncated HER2 sequence
HER2+ Stg IIIampIV BC
15
9
2 chemo
Plasmid DNA (pHM-GM-CSF expressing truncated HER2 amp GM-CSF) amp adenoviral vector (Ad-HM containing modified HER2) (2 4 and 8 mgpatientvisit) of pHM-GM-CSF 3x IM weeks 0 2 and 4 Ad-HM 3 times 109 virus particles at week 6
11 PR
4 pts 7 minor AEs
Unclear
Kim SB Ahn JH Kim J Jung KH A phase 1 study of a heterologous prime-boost vaccination involving a truncated HER2 sequence in patients with HER2-expressing breast cancer Mol Ther Methods Clin Dev 2015 Sep 30215031 doi 101038mtm201531 eCollection 2015
Rodon J Peacuterez-Fidalgo A Krop IE Burris H Guerrero-Zotano A Britten CD Becerra C Schellens J Richards DA Schuler M Abu-Khalaf M Johnson FM Ranson M Edenfield J Silva AP Hackl W Quadt C Demanse D Duval V Baselga J Phase 11b dose escalation and expansion study of BEZ235 a dual PI3KmTOR inhibitor in patients with advanced solid tumors including patients with advanced breast cancer Cancer Chemother Pharmacol 2018 Jun 7 doi 101007s00280-018-3610-z [Epub ahead of print]
Celgene(Abraxane)
Gemcitabine + Abraxane (nab-paclitaxel)
Chemo+ Chemo
OC BC NSCLC PC + LC OC BC KS
MBC
16
9
Adjuv chemo (100)chemo post-adjuv (33)
Gem (nucleoside metabolic inhibitor 1250 mgm2) on days 1 and 8 nab-Pac (microtubule inhibitor) starting dose of 180 mgm2 (cohort 1) 220 mgm2 (cohort 2) and 260 mgm2 (cohort 3) on day 1 of the 21-day cycle using a 3 + 3 design
0
MTD not reached29 Gr3 Neutropenia59 Gr1 Peripheralneuropathy
Yoshitomi S Taira N Doihara H Mizoo T Nogami T Iwamoto T Motoki T Shien T Ogasawara Y Matsuoka J Tsuji H Mitsuhashi T A phase 1 dose-finding and pharmacokinetic study of gemcitabine with nab-paclitaxel in patients with metastatic breast cancer Cancer Chemother Pharmacol 2016 Aug78(2)289-94
Eli Lilly
Erbituxreg (cetuximab) + Taxane
EGFR inhibitor antineoplastic agent + Chemo
Head amp NeckColorectal
TNBC
07-10
18
1 chemo
Cetuximab (epidermal growth factor receptor (EGFR) antagonist ) an initial loading dose of cetuximab 400 mgm2 followed by a weekly dose of 250 mgm2Paclitaxel (microtubule inhibitor) 80 mgm2 or Docetaxel at an initial dose of 30 mgm2 was administered weekly
56 CR 22 PR
83 Dermatologic toxicity11 Grade3+
Nechushtan H Vainer G Stainberg H Salmon AY Hamburger T Peretz T A phase 12 of a combination of cetuximab and taxane for triple negative breast cancer patients Breast 2014 Aug23(4)435-8
Polyphor
Balixafortide (POL6326) + eribulin
CXCR4 antagonist + tubulin-based antimitotic
Heavily pretreatedRelapsed MBC
14-16
56
3rd line 3 chemo
3+3 dose escalation The highest dose was established as eribulin 14 mgmsup2 on days 2 and 9 and balixafortide 55 mgkg on days 1minus3 and 8minus10 of the 21-day cycle
30 PR
41 Gr34 Neutropenia11 Gr34 Leucopenia11 Gr34 Febrileneutropenia2 Related mortalities
42018 Fast Track (HER2-MBC failed 2 prior regimens)
Pernas S Martin M Kaufman PA Gil-Martin M Gomez Pardo P Lopez-Tarruella S Manso L Ciruelos E Perez-Fidalgo JA Hernando C Ademuyiwa FO Weilbaecher K Mayer I Pluard TJ Martinez Garcia M Vahdat L Perez-Garcia J Wach A Barker D Fung S Romagnoli B Cortes J Balixafortide plus eribulin in HER2-negative metastatic breast cancer a phase 1 single-arm dose-escalation trial Lancet Oncol 2018 Jun19(6)812-824
1 PRndashbut only + letrozoleNo Resp on monotherapy
61 Gr34 Neutropenia39 Gr34 Leucopenia
$933M (1Q18)$31B (2017)
Tamura K Mukai H Naito Y Yonemori K Kodaira M Tanabe Y Yamamoto N Osera S Sasaki M Mori Y Hashigaki S Nagasawa T Umeyama Y Yoshino T Phase I study of palbociclib a cyclin-dependent kinase 46 inhibitor in Japanese patients Cancer Sci 2016 Jun107(6)755-63 doi 101111cas12932 Epub 2016 May 11
Pfizer
Ibrancereg (palbociclib)
CDK 46 Inhibitor
HR+ HER2- MBC
Heavily pretreatedRelapsed Met Cancer
04-08
41 (5 BC)
chemo naiumlve (17)1-2(51) 3(29) 3+(2)
Palbociclib 25-150 mg dose ranging
0
20 Gr34 Neutropenia23 Gr34 Leucopenia
$933M (1Q18)$31B (2017)
Flaherty KT Lorusso PM Demichele A Abramson VG Courtney R Randolph SS Shaik MN Wilner KD ODwyer PJ Schwartz GK Phase I dose-escalation trial of the oral cyclin-dependent kinase 46 inhibitor PD 0332991 administered using a 21-day schedule in patients with advanced cancer Clin Cancer Res 2012 Jan 1518(2)568-76 doi 1011581078-0432CCR-11-0509 Epub 2011 Nov 16
Novartis
Kisqalireg (ribociclib)
CDK 46 Inhibitor
Premenopausal HR+ HER2- MBC
Heavily pretreatedRelapsed Met Cancer
16
132 (20 BC)
0-1 (25) 2-3 (42)4+ (32)
Ribociclib 50 mg ranging up to 1200 mg dose escalation
23 PR-included 1 BC (5 of BC pts)
27 Gr34 Neutropenia17 Gr34 Leucopenia
Peak sales est at $25B
Infante JR Cassier PA Gerecitano JF Witteveen PO Chugh R Ribrag V Chakraborty A Matano A Dobson JR Crystal AS Parasuraman S Shapiro GI A Phase I Study of the Cyclin-Dependent Kinase 46 Inhibitor Ribociclib (LEE011) in Patients with Advanced Solid Tumors and Lymphomas Clin Cancer Res 2016 Dec 122(23)5696-5705 Epub 2016 Aug 19
Eli Lilly
Verzenioreg (abemaciclib)
CDK 46 Inhibitor
HR+HER2minusMBC
Heavily pretreatedRelapsed Met Cancer
16
12 (1 BC)
1 (312) 2 (212) 3+(7)
Abemaciclib 100 mg ranging up to 200 mg dose escalation
17 PR (included 1 BC)
17 Gr34 Neutropenia33 Gr34 Leucopenia
Peak sales est at $2B
Fujiwara Y Tamura K Kondo S Tanabe Y Iwasa S Shimomura A Kitano S Ogasawara K Turner PK Mori J Asou H Chan EM Yamamoto N Phase 1 study of abemaciclib an inhibitor of CDK 4 and 6 as a single agent for Japanese patients with advanced cancer Cancer Chemother Pharmacol 2016 Aug78(2)281-8 doi 101007s00280-016-3085-8 Epub 2016 Jun 16
Mukai H Saeki T Shimada K Naito Y Matsubara N Nakanishi T Obaishi H Namiki M Sasaki Y Phase 1 combination study of eribulin mesylate with trastuzumab for advanced or recurrent human epidermal growth factor receptor 2 positive breast cancer Invest New Drugs 2015 Feb33(1)119-27
AstraZeneca
Lynparza (Olaparib) + Cediranib
PARP inhibitor + inhibitor of VEGF receptor tyrosine kinases
HR+ HER2- MBC
BC amp OC
2013
28 (8 BC)
3 for BC
Olaparib (a poly (ADP-ribose) polymerase (PARP) inhibitor) amp Cediranib (Vascular endothelial growth factor receptor (VEGFR) 1 2 and 3 tyrosine kinase inhibitor)3 at dose level (DL) 0 (cediranib 20mg olaparib 100mg) 3 at DL1 (cediranib 20mg olaparib 200mg) 7 at DL2 (cediranib 30mg olaparib 200mg) 6 at DL3 (cediranib 30mg olaparib 400mg)
Liu JF Tolaney SM Birrer M Fleming GF Buss MK Dahlberg SE Lee H Whalen C Tyburski K Winer E Ivy P Matulonis UA A Phase 1 trial of the poly(ADP-ribose) polymerase inhibitor olaparib (AZD2281) in combination with the anti-angiogenic cediranib (AZD2171) in recurrent epithelial ovarian or triple-negative breast cancer Eur J Cancer 2013 Sep49(14)2972-8
Reyon Pharmaceutical
VM206RY
Heterologous prime-boost with a truncated HER2 sequence
HER2+ Stage IIIampIV BC
2015
9
2 chemo
Plasmid DNA (pHM-GM-CSF expressing truncated HER2 amp GM-CSF) amp adenoviral vector (Ad-HM containing modified HER2) (2 4 and 8 mgpatientvisit) of pHM-GM-CSF 3x IM weeks 0 2 and 4 Ad-HM 3 times 109 virus particles at week 6
11 PR
4 pts showed 7 minor AEs
Unclear
Kim SB Ahn JH Kim J Jung KH A phase 1 study of a heterologous prime-boost vaccination involving a truncated HER2 sequence in patients with HER2-expressing breast cancer Mol Ther Methods Clin Dev 2015 Sep 30215031 doi 101038mtm201531 eCollection 2015
Rodon J Peacuterez-Fidalgo A Krop IE Burris H Guerrero-Zotano A Britten CD Becerra C Schellens J Richards DA Schuler M Abu-Khalaf M Johnson FM Ranson M Edenfield J Silva AP Hackl W Quadt C Demanse D Duval V Baselga J Phase 11b dose escalation and expansion study of BEZ235 a dual PI3KmTOR inhibitor in patients with advanced solid tumors including patients with advanced breast cancer Cancer Chemother Pharmacol 2018 Jun 7 doi 101007s00280-018-3610-z [Epub ahead of print]
Celgene (Abraxane)
Gemcitabine + Abraxane (nab-paclitaxel)
Chemo + Chemo
OC BC NSCLC amp Panc cancer + Lung OC BC Kaposi sarcoma
MBC
2016
9
Adjuvant chemo (100)chemo post-adjuvant (33)
Gem (nucleoside metabolic inhibitor 1250 mgm2) on days 1 and 8 nab-Pac (microtubule inhibitor) starting dose of 180 mgm2 (cohort 1) 220 mgm2 (cohort 2) and 260 mgm2 (cohort 3) on day 1 of the 21-day cycle using a 3 + 3 design
0
MTD not reached29 Gr3 Neutropenia59 Gr1 Peripheralneuropathy
Yoshitomi S Taira N Doihara H Mizoo T Nogami T Iwamoto T Motoki T Shien T Ogasawara Y Matsuoka J Tsuji H Mitsuhashi T A phase 1 dose-finding and pharmacokinetic study of gemcitabine with nab-paclitaxel in patients with metastatic breast cancer Cancer Chemother Pharmacol 2016 Aug78(2)289-94
Eli Lilly
Erbituxreg (cetuximab) + Taxane
EGFR inhibitor antineoplastic agent + Chemo
Headamp Neck Colorectal Cancer
TNBC
2007-2010
18
1 chemo
Cetuximab (epidermal growth factor receptor (EGFR) antagonist ) an initial loading dose of cetuximab 400 mgm2 followed by a weekly dose of 250 mgm2Paclitaxel (microtubule inhibitor) 80 mgm2 or Docetaxel at an initial dose of 30 mgm2 was administered weekly
56 CR 22 PR
83 Dermatologic toxicity11 Grade3+
Nechushtan H Vainer G Stainberg H Salmon AY Hamburger T Peretz T A phase 12 of a combination of cetuximab and taxane for triple negative breast cancer patients Breast 2014 Aug23(4)435-8
Polyphor
Balixafortide (POL6326) + eribulin
CXCR4 antagonist + tubulin-based antimitotic
Heavily pretreated Relapsed MBC
2014-2016
56
3rd line 3 chemo
3+3 dose escalation The highest dose was established as eribulin 14 mgmsup2 on days 2 and 9 and balixafortide 55 mgkg on days 1minus3 and 8minus10 of the 21-day cycle
30 PR
41 Gr34 Neutropenia11 Gr34 Leucopenia11 Gr34 Febrileneutropenia2 Related mortalities
Apr 2018 Fast Track for HER2-MBC who have failed 2prior regimens
Pernas S Martin M Kaufman PA Gil-Martin M Gomez Pardo P Lopez-Tarruella S Manso L Ciruelos E Perez-Fidalgo JA Hernando C Ademuyiwa FO Weilbaecher K Mayer I Pluard TJ Martinez Garcia M Vahdat L Perez-Garcia J Wach A Barker D Fung S Romagnoli B Cortes J Balixafortide plus eribulin in HER2-negative metastatic breast cancer a phase 1 single-arm dose-escalation trial Lancet Oncol 2018 Jun19(6)812-824
11 PRndashbut only + letrozole (No Resp on monotherapy)
61 Gr34 Neutropenia39 Gr34 Leucopenia
$933M in 1Q2018 $31B in 2017
Tamura K Mukai H Naito Y Yonemori K Kodaira M Tanabe Y Yamamoto N Osera S Sasaki M Mori Y Hashigaki S Nagasawa T Umeyama Y Yoshino T Phase I study of palbociclib a cyclin-dependent kinase 46 inhibitor in Japanese patients Cancer Sci 2016 Jun107(6)755-63 doi 101111cas12932 Epub 2016 May 11
Pfizer
Ibrancereg (palbociclib)
CDK 46 Inhibitor
HR+ HER2- MBC
Heavily pretreated Relapsed Metastatic Cancer
2004-2008
41 (5 BC)
chemo naiumlve (17) 1-2 (51)3 (29) 3+ (2)
Palbociclib 25-150 mg dose ranging
0
20 Gr34 Neutropenia23 Gr34 Leucopenia
$933M in 1Q2018 $31B in 2017
Flaherty KT Lorusso PM Demichele A Abramson VG Courtney R Randolph SS Shaik MN Wilner KD ODwyer PJ Schwartz GK Phase I dose-escalation trial of the oral cyclin-dependent kinase 46 inhibitor PD 0332991 administered using a 21-day schedule in patients with advanced cancer Clin Cancer Res 2012 Jan 1518(2)568-76 doi 1011581078-0432CCR-11-0509 Epub 2011 Nov 16
Novartis
Kisqalireg (ribociclib)
CDK 46 Inhibitors
Premenopausal HR+ HER2- MBC
Heavily pretreated Relapsed Metastatic Cancer
2016
132 (20 BC)
0-1 (25) 2-3 (42) 4+ (32)
Ribociclib 50 mg ranging up to 1200 mg dose escalation
23 PRndashincluded 1 in BC (5 of BC pts)
27 Gr34 Neutropenia17 Gr34 Leucopenia
Peak sales projected at $25B
Infante JR Cassier PA Gerecitano JF Witteveen PO Chugh R Ribrag V Chakraborty A Matano A Dobson JR Crystal AS Parasuraman S Shapiro GI A Phase I Study of the Cyclin-Dependent Kinase 46 Inhibitor Ribociclib (LEE011) in Patients with Advanced Solid Tumors and Lymphomas Clin Cancer Res 2016 Dec 122(23)5696-5705 Epub 2016 Aug 19
Eli Lilly
Verzenioreg (abemaciclib)
CDK 46 Inhibitors
HR+HER2minusMBC
Heavily pretreated Relapsed Metastatic Cancer
2016
12 (1 BC)
1 (312) 2 (212) 3+ (7)
Abemaciclib 100 mg ranging up to 200 mg dose escalation
17 PR (included 1 in BC)
17 Gr34 Neutropenia33 Gr34 Leucopenia
Peak sales projected at $2B
Fujiwara Y Tamura K Kondo S Tanabe Y Iwasa S Shimomura A Kitano S Ogasawara K Turner PK Mori J Asou H Chan EM Yamamoto N Phase 1 study of abemaciclib an inhibitor of CDK 4 and 6 as a single agent for Japanese patients with advanced cancer Cancer Chemother Pharmacol 2016 Aug78(2)281-8 doi 101007s00280-016-3085-8 Epub 2016 Jun 16
Mukai H Saeki T Shimada K Naito Y Matsubara N Nakanishi T Obaishi H Namiki M Sasaki Y Phase 1 combination study of eribulin mesylate with trastuzumab for advanced or recurrent human epidermal growth factor receptor 2 positive breast cancer Invest New Drugs 2015 Feb33(1)119-27
AstraZeneca
Lynparza (Olaparib)+ Cediranib
PARP inhibitor+ inhibitor of VEGF RTK
HR+ HER2- MBC
BC amp OC
13
28 (8 BC)
3 for BC
Olaparib (a poly (ADP-ribose) polymerase (PARP) inhibitor) amp Cediranib (Vascular endothelial growth factor receptor (VEGFR) 1 2 and 3 tyrosine kinase inhibitor)3 at dose level (DL) 0 (cediranib 20mg olaparib 100mg) 3 at DL1 (cediranib 20mg olaparib 200mg) 7 at DL2 (cediranib 30mg olaparib 200mg) 6 at DL3 (cediranib 30mg olaparib 400mg)
Liu JF Tolaney SM Birrer M Fleming GF Buss MK Dahlberg SE Lee H Whalen C Tyburski K Winer E Ivy P Matulonis UA A Phase 1 trial of the poly(ADP-ribose) polymerase inhibitor olaparib (AZD2281) in combination with the anti-angiogenic cediranib (AZD2171) in recurrent epithelial ovarian or triple-negative breast cancer Eur J Cancer 2013 Sep49(14)2972-8
ReyonPharma
VM206RY
Heterologous prime-boost with a truncated HER2 sequence
HER2+ Stg IIIampIV BC
15
9
2 chemo
Plasmid DNA (pHM-GM-CSF expressing truncated HER2 amp GM-CSF) amp adenoviral vector (Ad-HM containing modified HER2) (2 4 and 8 mgpatientvisit) of pHM-GM-CSF 3x IM weeks 0 2 and 4 Ad-HM 3 times 109 virus particles at week 6
11 PR
4 pts 7 minor AEs
Unclear
Kim SB Ahn JH Kim J Jung KH A phase 1 study of a heterologous prime-boost vaccination involving a truncated HER2 sequence in patients with HER2-expressing breast cancer Mol Ther Methods Clin Dev 2015 Sep 30215031 doi 101038mtm201531 eCollection 2015
Rodon J Peacuterez-Fidalgo A Krop IE Burris H Guerrero-Zotano A Britten CD Becerra C Schellens J Richards DA Schuler M Abu-Khalaf M Johnson FM Ranson M Edenfield J Silva AP Hackl W Quadt C Demanse D Duval V Baselga J Phase 11b dose escalation and expansion study of BEZ235 a dual PI3KmTOR inhibitor in patients with advanced solid tumors including patients with advanced breast cancer Cancer Chemother Pharmacol 2018 Jun 7 doi 101007s00280-018-3610-z [Epub ahead of print]
Celgene(Abraxane)
Gemcitabine + Abraxane (nab-paclitaxel)
Chemo+ Chemo
OC BC NSCLC PC + LC OC BC KS
MBC
16
9
Adjuv chemo (100)chemo post-adjuv (33)
Gem (nucleoside metabolic inhibitor 1250 mgm2) on days 1 and 8 nab-Pac (microtubule inhibitor) starting dose of 180 mgm2 (cohort 1) 220 mgm2 (cohort 2) and 260 mgm2 (cohort 3) on day 1 of the 21-day cycle using a 3 + 3 design
0
MTD not reached29 Gr3 Neutropenia59 Gr1 Peripheralneuropathy
Yoshitomi S Taira N Doihara H Mizoo T Nogami T Iwamoto T Motoki T Shien T Ogasawara Y Matsuoka J Tsuji H Mitsuhashi T A phase 1 dose-finding and pharmacokinetic study of gemcitabine with nab-paclitaxel in patients with metastatic breast cancer Cancer Chemother Pharmacol 2016 Aug78(2)289-94
Eli Lilly
Erbituxreg (cetuximab) + Taxane
EGFR inhibitor antineoplastic agent + Chemo
Head amp NeckColorectal
TNBC
07-10
18
1 chemo
Cetuximab (epidermal growth factor receptor (EGFR) antagonist ) an initial loading dose of cetuximab 400 mgm2 followed by a weekly dose of 250 mgm2Paclitaxel (microtubule inhibitor) 80 mgm2 or Docetaxel at an initial dose of 30 mgm2 was administered weekly
56 CR 22 PR
83 Dermatologic toxicity11 Grade3+
Nechushtan H Vainer G Stainberg H Salmon AY Hamburger T Peretz T A phase 12 of a combination of cetuximab and taxane for triple negative breast cancer patients Breast 2014 Aug23(4)435-8
Polyphor
Balixafortide (POL6326) + eribulin
CXCR4 antagonist + tubulin-based antimitotic
Heavily pretreatedRelapsed MBC
14-16
56
3rd line 3 chemo
3+3 dose escalation The highest dose was established as eribulin 14 mgmsup2 on days 2 and 9 and balixafortide 55 mgkg on days 1minus3 and 8minus10 of the 21-day cycle
30 PR
41 Gr34 Neutropenia11 Gr34 Leucopenia11 Gr34 Febrileneutropenia2 Related mortalities
42018 Fast Track (HER2-MBC failed 2 prior regimens)
Pernas S Martin M Kaufman PA Gil-Martin M Gomez Pardo P Lopez-Tarruella S Manso L Ciruelos E Perez-Fidalgo JA Hernando C Ademuyiwa FO Weilbaecher K Mayer I Pluard TJ Martinez Garcia M Vahdat L Perez-Garcia J Wach A Barker D Fung S Romagnoli B Cortes J Balixafortide plus eribulin in HER2-negative metastatic breast cancer a phase 1 single-arm dose-escalation trial Lancet Oncol 2018 Jun19(6)812-824
1 PRndashbut only + letrozoleNo Resp on monotherapy
61 Gr34 Neutropenia39 Gr34 Leucopenia
$933M (1Q18)$31B (2017)
Tamura K Mukai H Naito Y Yonemori K Kodaira M Tanabe Y Yamamoto N Osera S Sasaki M Mori Y Hashigaki S Nagasawa T Umeyama Y Yoshino T Phase I study of palbociclib a cyclin-dependent kinase 46 inhibitor in Japanese patients Cancer Sci 2016 Jun107(6)755-63 doi 101111cas12932 Epub 2016 May 11
Pfizer
Ibrancereg (palbociclib)
CDK 46 Inhibitor
HR+ HER2- MBC
Heavily pretreatedRelapsed Met Cancer
04-08
41 (5 BC)
chemo naiumlve (17)1-2(51) 3(29) 3+(2)
Palbociclib 25-150 mg dose ranging
0
20 Gr34 Neutropenia23 Gr34 Leucopenia
$933M (1Q18)$31B (2017)
Flaherty KT Lorusso PM Demichele A Abramson VG Courtney R Randolph SS Shaik MN Wilner KD ODwyer PJ Schwartz GK Phase I dose-escalation trial of the oral cyclin-dependent kinase 46 inhibitor PD 0332991 administered using a 21-day schedule in patients with advanced cancer Clin Cancer Res 2012 Jan 1518(2)568-76 doi 1011581078-0432CCR-11-0509 Epub 2011 Nov 16
Novartis
Kisqalireg (ribociclib)
CDK 46 Inhibitor
Premenopausal HR+ HER2- MBC
Heavily pretreatedRelapsed Met Cancer
16
132 (20 BC)
0-1 (25) 2-3 (42)4+ (32)
Ribociclib 50 mg ranging up to 1200 mg dose escalation
23 PR-included 1 BC (5 of BC pts)
27 Gr34 Neutropenia17 Gr34 Leucopenia
Peak sales est at $25B
Infante JR Cassier PA Gerecitano JF Witteveen PO Chugh R Ribrag V Chakraborty A Matano A Dobson JR Crystal AS Parasuraman S Shapiro GI A Phase I Study of the Cyclin-Dependent Kinase 46 Inhibitor Ribociclib (LEE011) in Patients with Advanced Solid Tumors and Lymphomas Clin Cancer Res 2016 Dec 122(23)5696-5705 Epub 2016 Aug 19
Eli Lilly
Verzenioreg (abemaciclib)
CDK 46 Inhibitor
HR+HER2minusMBC
Heavily pretreatedRelapsed Met Cancer
16
12 (1 BC)
1 (312) 2 (212) 3+(7)
Abemaciclib 100 mg ranging up to 200 mg dose escalation
17 PR (included 1 BC)
17 Gr34 Neutropenia33 Gr34 Leucopenia
Peak sales est at $2B
Fujiwara Y Tamura K Kondo S Tanabe Y Iwasa S Shimomura A Kitano S Ogasawara K Turner PK Mori J Asou H Chan EM Yamamoto N Phase 1 study of abemaciclib an inhibitor of CDK 4 and 6 as a single agent for Japanese patients with advanced cancer Cancer Chemother Pharmacol 2016 Aug78(2)281-8 doi 101007s00280-016-3085-8 Epub 2016 Jun 16
41 Gr34 Neutropenia11 Gr34 Leucopenia11 Gr34 Febrileneutropenia2 Related mortalities
30 PRs in combination with Halaven
Bria-IMTTM
20
Injection site reactions No related SAEs or SUSARs
Tumor vol darr ampor darr circul tumor cells)All Comers 21(419) 26(519)One or More HLA matches 27(415) 33(515)Two or More HLA matches 50 (24) 75 (34))
Drug
Technology
Approved for
Market (US)
Ibrance (palbociclib)
CDK 46 Inhibitor
HR+HER2- MBC in combination with fluvestrant or aromatase inhibitor
$933M in 1Q2018 $3126M in 2017
Kisqali (ribociclib)
CDK 46 Inhibitor
2017 HR+HER2- MBC in combination with fluvestrant or aromatase inhibitor
Peak sales projected at $25B
Verzenio (abemaciclib)
CDK 46 Inhibitor
2017 HR+HER2- MBC in combination with fluvestrant or aromatase inhibitor
Peak sales projected at $2B
Lynparza (olaparib)
Poly (ADP-ribose) polymerase (PARP) inhibitor
2017 ovarian amp breast cancer
$997M in 2017
Halaven (eribulin mesylate)
Tubulin-based antimitotic
2H2017 3rd line MBC amp liposarcoma
$181M in 2017
balixafortide
CXCR4 antagonist
Fast track designation in 2018 for HER2- MBC who have failed 2 prior regimens
Bria-IMTtrade - First Product CandidateHuman Proof-of-Concept Trials in Advanced Breast Cancer
Bria-IMTtrade Non-Personalized Immunotherapy
First Proof-of-Concept Phase I (1999-2003) Used unmodified cell line + GM-CSF + cyclophosphamide N = 14 late stage treatment-refractory breast cancer patients Well tolerated no severe drug related AEs Median Overall Survival = 121 months
Second Proof-of-Concept Phase I (2005) Used GM-CSF-engineered cell line + cyclophosphamide + interferon-α N = 4 late stage treatment-refractory (3 breast cancer and 1 ovarian cancer) patients Well tolerated no life-threatening drug related adverse events One patient with transient urticaria reported as grade 3 responded to antihistamines Median Overall Survival = 35 months One robust responder with gt90 regression during treatment subsequent relapse (upon halting
treatment) responded to re-treatment
6
Bria-IMTtrade amp Bria-OTStradePotential Mechanisms of Action in Advanced Breast Cancer
Bria-IMTTM directly stimulates cancerfighting CD4+ and CD8+ T cells(further boosts the response)
Bria-IMTTM produces breastcancer antigens which aretaken up by dendritic cellsand ldquopresentedrdquo to CD4+and CD8+ T cells implicatedin tumor destruction
Bria-IMTTM secretes GM-CSF which further promotes dendritic cell-based antigen presentation (boosts the response) 7
Bria-IMTtradeHuman Proof-of-Concept Trials in Breast Cancer (Patient A002) Bria-IMTtrade Non-Personalized Immunotherapy ndash Given as Monotherapy
Second Proof-of-Concept Phase I (2005) 1 out of 4 patients responded with substantial tumor regression Patient A002 was the only patient with key HLA matches with Bria-IMTtrade
8
Bria-IMTtradeHuman Proof-of-Concept Trials in Breast Cancer (Patient A002) Approximately 3 months (106 days) after last inoculation Patient A002rsquos breast cancer returned and
spread to brain lung and other sites
Patient A002 was then re-treated with 10 inoculations of Bria-IMTtrade over 4 months
Repeat imaging studies showed normal findings on MRI and PET consistent with a completeremission of the previous multiple central nervous system metastases as shown in the brain scansbelow
Bria-IMTtrade and Bria-OTStrade shouldsynergize with existing approvedimmunotherapies as well as those stillunder development
This includes immune checkpointinhibitors such as antibodies to PD-1CTLA-4 GITR and CD73 inhibitors whicheliminate tumor immunosuppression Checkpoint Inhibitors were the
subject of the 2018 Nobel Prize inMedicine
In addition immunostimulatoryantibodies to molecules such as OX40should enhance responses to Bria-IMTtradeand Bria-OTStrade
13
Q3 2018 Data on first 20 Patients on Bria-IMTtrade Q3 2018 Initiate Combination Study of Bria-IMTtrade with Keytruda or Yervoy
Q4 2018 Switch to a novel frozen Bria-IMTtrade formulation Q4 2018 Safety Data (6 patients) of the Bria-IMTtrade - Keytrudareg Combination Study (SABC meeting) Q4 2018 Ongoing Corporate PartnershipCollaboration Discussions
Q1 2019 Efficacy Data (6 patients) of the Bria-IMTtrade - Keytrudareg Combination Study Q2 2019 Initiation of Bria-OTStrade GMP manufacturing (KBI BioPharma) Q2 2019 Additional Safety amp Efficacy data Monotherapy and Combination Studies (AACR meeting) Q2 2019 Final data for Monotherapy and Additional Data for the Combination Study (ASCO meeting) H1 2019 Candidate Selection for a PKCδ Inhibitor H1 2019 Initiate additional immunotherapy program H2 2019 Bria-OTStrade Authorization from FDA clearance for dosing H2 2019 Bria-OTStrade First Patient Dosed
Upcoming Milestones amp Catalysts
14
Involved in over 10 drugs brought to the market
Experienced Management Team
Management
William V Williams MD FACP President amp CEO VP Exploratory Development Incyte Corporation VP Experimental Medicine GlaxoSmithKline Head Rheumatology Research University of Pennsylvania Facilitated entry of over 20 compounds into the clinic including ruxolitinib (Jakafi)
baricitinib amp epacadostat NDAs including Jakafi Boniva Bexxar Author of over 120 peer-reviewed publications amp over 20 patents
Gadi Levin CA MBA CFO CFO of Labstyle Innovations Ltd VP of Finance for two Israeli investment houses in the fields of private equity
hedge funds and real estate Financial Consultant various firms Accountant Arthur Andersen
Markus Lacher PhD Senior Director RampD Founder T cell Therapeutics Inc an immuno-oncology company Sr Clinical Scientist Cesca Therapeutics Inc a clinical-stage autologous cell
therapy company Scientist at BioTime Inc and OncoCyte Corporation Editorial advisory board Recent Patents on Anti-Cancer Drug Discovery
Farrah Dean MSc MBA Manager Corp Development Investor relations CytRx Corporation amp CCG Investor Relations Senior Associate Equity Analyst Oppenheimer amp Co Rodman amp Renshaw amp
Brian Metcalf PhD Recently retired as CSO from Global Blood Therapeutics Former Head of Research amp Development Incyte Corporation Former Head of Medicinal Chemistry SmithKline Beecham
Douglas Faller MD PhD Professor of Medicine Pediatrics Biochemistry Microbiology Pathology and
Laboratory Medicine HematologistOncologist former Director of the Cancer Center Boston University School of Medicine
Founder of several successful biotechnology companies
Robert Williams PhD University Distinguished Professor of Chemistry Colorado State University Founder of several successful biotechnology companies including Microcide Xcyte
Therapies HemaQuest Arch Therapeutics and Cetya Therapeutics
Thomas Kieber-Emmons PhD Deputy Director University of Arkansas Cancer Center Expert in targeted cancer immunotherapies structural biology and computational
chemistry
Maria Trojanowska PhD Professor of Medicine Boston University School of Medicine Director The Arthritis Center
16
Veteran Board of Directors
Board of Directors
Saeid Babaei PhD MBA Chairman Entrepreneur 20 yrs of biotech leadership roles Current CEO AbCelex VP Bus Develop Lorus Therap Dir of Corp Develop Northern Therapeutics
Rahoul Sharan CA Director Chairman Potash Ridge Director of the Board Ansell Capital Corp Parallel Resources amp Galaxy Capital
Corporation
Martin Schmieg CPA Director CFO Sirna Therapeutics Inc amp Isolagen Inc CEO Freedom-2 Inc (now PharmaCyte Inc) Advisor Caladrius Biosciences Inc Beckman Coulter Genomics Calimmune
Charles Wiseman MD Co-Founder amp Director Director Immunotherapy Lab St Vincent Medical Center Chief Breast Cancer Basic Research Lab Univ of Texas MD Anderson Hospital amp
Tumour Institute Assist Prof Dept of Molecular Carcinogenesis amp Virology MD Anderson Acting Chief Div of Oncology White Memorial Medical Center LA
William V Williams MD FACP President amp CEO VP Exploratory Development Incyte Corporation VP Experimental Medicine GlaxoSmithKline Head Rheumatology Research University of Pennsylvania
Prior Affiliations
17
Drug Approvals by BriaCell Management Team
Bexxarreg (tositumomab and Iodine I131 tositumomab) Treatment of CD20 antigen-expressing relapsed or refractory low grade follicular or transformed non-Hodgkins lymphoma
Myleranreg (busulfan) for chronic myelogenous leukemia Defense of formulation change sNDA
Hycamtinreg (topotecan) for ovarian cancer Pediatric use sNDA
Navelbinereg (vinorelbine tartrate) for non-small cell lung cancer Pediatric use sNDA
Bonivareg (ibandronate) monthly oral treatment of osteoporosis
Bonivareg (ibandronate) quarterly intraveous treatment of osteoporosis
Zofranreg (ondansetron) for prevention of nausea and vomiting Pediatric use sNDA
Jakafireg (ruxolitinib) for myelofibrosis Jakafireg (ruxolitinib) for polycythemia vera
Olumiantreg (baricitinib) for rheumatoid arthritis Approved in USA Japan and Europe
18
Share Metrics
BCTV BCTXF 19
Data as of 1092018
Ticker TSX BCTV
US Ticker OTCQBBCTXF
Share Price (CAD) as of Oct 9 2018 $012
52-Week Range (CAD) $009-019
Shares Outstanding as of Oct 9 2018 1611M
Market Cap as of Oct 9 2018 (CAD) $193M
Cash and Short Term Investments as of July 31 2018 (CAD) $23M
Total Shareholders Equity as of July 31 2018 (CAD) $12M
Number of Warrants $014-$035 (CAD) as of Oct 9 2018 601M
Number of Compensation Warrants $014-$030 (CAD) as of Oct 9 2018 45M
Number of Options $014- $026 (CAD$) as of Oct 9 2018 93M
Developing Bria-OTStrade the First Off-the-Shelf Personalized Immunotherapy
Targeting Adv Breast Cancer Unmet medical need (42000 death in the US in 2017 ) $1 Bil- $5 Bil market opportunity depending on patient treatment stage
Impressive results in 2 proof-of-concept clinical trials Rapid Response Rate Repeated following re-treatment Excellent Safety Profile
Completed enrollment in Phase IIIa clinical trial of Bria-IMTtrade with outstanding safety amp efficacy data Initiated Phase IIa Combination Study of Bria-IMTtrade with Keytrudareg (Merck amp Co Inc)
Developing Bria-OTStrade along with BriaDXtrade its companion diagnostic test Ability to match and treat ~90 of patient population with Off-the-Shelf personalized immunotherapy
Experienced Management has been involved in over 10 drug approvals
Patient B001 Breast 70 No 1101 - 3501 4001 Negative -
Bria-IMTtradeHuman Proof-of-Concept Trials in Breast Cancer (Patient A002)
24
Proof-of-Concept Results Resulted in BriaCellrsquos Immunotherapy Strategy Use BriaDXtrade diagnostic to select only those patients matching Bria-IMTtrade Use BriaDXtrade diagnostic test to select Bria-OTStrade alleles matching ~90 of all patients
Bria-IMTtradeCurrent Phase IIIa Data Supports HLA Matching Hypothesis Six patients treated in 2017 Bria-IMTtrade was safe and well tolerated
Patient 01-002 73-year-old woman with breast cancer diagnosed in 1995 Developed liver metastases in2010 and lung metastases in 2017 Previously treated with 7 rounds of chemotherapy with 8 differentchemotherapy agents Received 5 cycles of Bria-IMTtrade over 3 months then monthly cycles (6 months total)Evaluated after 3 months and 6 months After 3 months despite the extensive prior therapy her scans notedthat ldquothere has been a clear response in the multiple bilateral pulmonary nodulesrdquo The response wasmaintained after 6 months of Bria-IMTtrade treatment She matches Bria-IMTtrade at 2 HLA alleles
The liver tumors were stable to slightly increased at 3 months and then progressed after 6 months
This supports our hypothesis of heightened anti-tumor activity in patients with a matched HLA types Clear path to develop BriaDXtrade to select the patients using HLA testing
1 RLL 29 Not Detectable Not Detectable2 LUL apical pleural based 34 tiny nodule lt 1mm scar tiny nodule lt 1mm scar3 xxx 39 Not Detectable Not Detectable4 40 Not Detectable Not Detectable5 RLL 45 Not Detectable Not Detectable6 LLL 49 Not Detectable Not Detectable7 xxx 52 Not Detectable Not Detectable8 RLL 52 Not Detectable Not Detectable9 RLL 56 Not Detectable Not Detectable
10 RLL costophrenic recess 56 Not Detectable Not Detectable11 XXX 58 Not Detectable Not Detectable12 LUL 60 Not Detectable Not Detectable13 XXX 67 15 1514 RUL 72 15 1515 LLL 76 Not Detectable Not Detectable16 RUL Noncalcified Nodule 77 Not Detectable Not Detectable17 RLL costophrenic recess 79 10 1018 RUL 82 Not Detectable Not Detectable19 RLL 90 Not Detectable Not Detectable20 RLL 91 lt 01 lt 0121 xxx xxx Not Detectable Not Detectable
27
Clinical Development Update ndash Summary 2018 September 26
Completed enrollment of Adv Breast cancer patients in the Phase IIIa ldquomonotherapyrdquo study of Bria-IMTtrade
We have confirmed our mechanism of action and achieved proof of concept
Initial safety data appears superior to that of the other advanced or approved drugs for breast cancer when they were at a similar clinical stage of development
Initial efficacy data is similar or superior to those of other advanced or approved drugs for breast cancer when they were at a similar clinical stage of development
Initiated Combination Study of Bria-IMTtrade with Keytrudareg or Yervoyreg in Adv breast cancer patients expecting even better response rates than those in the ldquomonotherapyrdquo study Initial safety data is expected in 4Q2018 Initial efficacy data is expected in 1Q2019
Bria-OTStrade the first off-the-shelf personalized treatment for advanced breast cancer is expected to enter the clinic in 2019
28
Bria-IMTtrade Excellent Safety Data - To Date
To date Bria-IMTtrade has been dosed in 24 patients (4 in 2004-2005 20 in 2017-2018)
Interim Data (20 patients)-Ongoing Phase IIIa Study (2017-2018)
Bria-IMTtrade has been very well tolerated (ge60 doses given to date) The majority of adverse events (AEs) were limited to expected minor local irritation at the
injection sites No related grade gt3 or unexpected AEs No related serious AEs No serious unexpected related AEs Most patients who have dropped out did so due to worsening of their underlying disease
Based on the current study Bria-IMTtrade has an excellent safety profile
29
Bria-IMTtrade - Efficacy as Predicted
Interim Data (19 patients)-Ongoing Phase IIIa Study (2017-2018) amp Original Study (2004-2005)
PD-L1 expression on circulating cancer cells amp cancer-associated cells in 100 of patients (to date) Strong rationale for combination with checkpoint inhibitors like Keytruda
30
Bria-IMTtrade appears to be most effective in patients who match with Bria-IMT trade at 2 HLA loci (types) further supporting our ldquoHLA Matching Hypothesisrdquo and the development of Bria-OTS trade to cover 90 of the patient population
Combination with immune checkpoint inhibitors may induce a more potent anti-cancer response leading to our strategy of combination studies of Bria-IMT trade with Keytruda or Yervoy
Patients (n) HLA Match
Tumor Shrinkage
Biological Response
4 ge2 50 7515 ge1 27 334 0 0 0
Biological response includes tumor shrinkage or lower circulating cancer associated cells
The confirmatory Bria-IMTtrade monotherapy Phase IIa trial has completed enrollment Additional Support for the HLA-matching hypothesis has been obtained
Bria-IMTtrade Combination Therapy study with immune checkpoint inhibitors Keytrudareg if PD-L12 positive (ge1) Yervoyreg if PD-L12 negative (lt1) Accepting patients from the monotherapy study who develop progressive disease Also enrolling patients directly into this study to enhance experience with the combination In discussion with other pharmaceutical companies to evaluate additional combinations with other
immunotherapies
Bria-OTStrade Off-the-Shelf Personalized Targeted Immunotherapy Developing Bria-OTStrade to co-express GM-CSF and interferon-α Pre-manufacture additional HLA alleles ndash Total of 15 alleles (8 Class I and 7 Class II) Co-development of BriaDXtrade companion diagnostic for HLA typing Combination therapy clinical trial with immune checkpoint inhibitors for non-responders using
information from the Bria-IMTtrade Combination Therapy Study
33
Development Timeline ndash Breast Cancer
20192018 2020 2021
Phase IIIaBria-IMTtrade
Monotherapy
Currently Enrolling Phase IIaBria-IMTtrade + Checkpoint
Currently in discussions with potential partnersPhase II Bria-IMTtrade plus Additional Combinations (1Q19 4Q22)(eg PD-1 Inhibitor PD-L1 inhibitor anti-CTLA4 anti-GITR anti-OX40)
1Q 2Q 3Q 4Q
2023
Bria-OTStrade Off-The-Shelf Personalized ImmunotherapyMonotherapy and Potential Partnered Combo Therapy
(2H19 Ongoing)
Bria-OTStradeOff-the-Shelf Cell Line cGMP Manufacturing
and BriaDXtrade(1Q18 1Q19)
Registration Studies (1Q20 2H22)Bria-IMTtrade with Checkpoint InhibitorsBria-OTStrade +- Checkpoint Inhibitors
34
Immuno-oncology Deals
Recent deals of small biotechs with big pharma in immuno-oncology
35
Date PartnershipDevelopment stage at the time of the deal Deal size
07122018 Immatics-Genmab Preclinical Up to $28B
04042018 OSE Immunotherapeutics-Boehringer Ingelheim Preclinical Up to euro113B ($139B)
02092018 Pieris Pharmaceuticals-Seattle Genetics Preclinical Up to $123B
2142018 Nektar-BMS Ph III Up to $36B
01222018 Juno-Celgene Ph II $9B (Acquisition)
11142017 Loxo-Bayer Larotrectinib (Ph II) LOXO-195 (Ph III) Up to $155B
1032017 CytomX-Amgen Preclinical Up to $15B
03202017 CytomX--BMS Ph III Up to $36B
6282016 Xencor-Novartis Preclinical Up to $24B
Early Stage Clinical Studies (Comparison)
We compared the interim data of Ph IIIa study of Bria-IMTtrade in advanced breast cancer with thedata in the early stage clinical studies of recently approved breast cancer drugs and one fasttracked product candidate
Apples to apples comparison Early Stage Clinical Studies in oncology are typically done in patientswith no other therapeutic options Thus the patients have very advanced disease and response ratesare typically quite low
The patients in our Ph IIIa study have been heavily pre-treated (median 45 prior regimens)Some recent studies of relevance in breast cancer are noted in the following slides
36
Breast Cancer Market Opportunity
Drug Technology Approved for Market (US)Ibrance (palbociclib) CDK 46 Inhibitor HR+HER2- MBC in combination with
fluvestrant or aromatase inhibitor$933M in 1Q2018 $3126M in 2017
Kisqali (ribociclib) CDK 46 Inhibitor 2017 HR+HER2- MBC in combination with fluvestrant or aromatase inhibitor
Peak sales projected at $25B
Verzenio (abemaciclib) CDK 46 Inhibitor 2017 HR+HER2- MBC in combination with fluvestrant or aromatase inhibitor
balixafortide CXCR4 antagonist Fast track designation in 2018 for HER2- MBC who have failed 2 prior regimens
The market for breast cancer drugs is a multibillion dollar market with new drugs being approvedon an ongoing basis indicating the shortage of safe and effective treatments for this deadly disease
37
Competitors- Phase III Clinical Data Bria-IMTtrade shows superior safety and similar to superior efficacy data compared with those of the multi-billion dollar drugs when they were at a similar early stage of clinical development
Injection site reactions No related SAEs or SUSARs
Tumor vol darr ampor darr circul tumor cellsAll Comers 21(419) 26(519)One or More HLA matches 27(415) 33(515)Two or More HLA matches 50 (24) 75 (34)
Sheet1 (3)
Comp -Slides
Data
HLA (2)
HLA
Data (Ph1-2+4Pt)
Competitors (2018)-Slide
Competitors (2018)
In the Pipeline Protein Kinase C delta (PKCδ) Inhibitors
30 of all human malignancies display activating RAS mutations Another 60 showing over-activity of Ras-signaling pathways
Ras has been termed ldquoundruggablerdquo (no one has been able to make a Ras inhibitor drug)
BriaCellrsquos novel proprietary PKCδ inhibitors have shown activity against multiple RAS transformed tumors Lung cancer Melanoma Breast cancer Neuroendocrine cancer Pancreatic cancer Colorectal cancer
This target has an attractive safety profile based on in vivo studies and knock out mouse studies
PKCδ inhibitors should qualify for an accelerated clinical development plan and regulatory pathway
Could be in clinic within 24 months
Cost-Effective Additional Shot-on-Goal and additional partnership opportunities
Early-Stage Preclinical Program
39
Protein Kinase C delta (PKCδ) Inhibitors
Activated PKCδ inhibits RAS degradation which in turn stimulates tumor growth
Koo et al Oncotarget 621328 2016
30 of all human malignancies display activating RASmutations with another 60 showing over-activity of Ras-signaling pathways
BriaCellrsquos novel proprietary PKCδ inhibitors have shownactivity against multiple RAS transformed tumors
This target has an attractive safety profile based on in vivostudies and knock out mouse studies
PKCδ also has potential activity as an immunotherapeuticby blocking TGFβ signaling
PKCδ inhibitors are applicable to specific niche tumor typeswhich provide an accelerated clinical development plan
Structural aspects of first generation inhibitor rottlerin and staurosporine (pan-PKC activator) were combined to create second generation inhibitor KAM1
Third generation inhibitors such as BJE6-106 have improved potency and selectivity Fourth generation inhibitors under development to optimize drug-like characteristics PKCδ inhibitors lack endothelial cell cytotoxicity amp PKCδ deficient mice develop normally and are fertile Potentially no marked intrinsic toxicity by inhibiting PKCδ
Mukai H Saeki T Shimada K Naito Y Matsubara N Nakanishi T Obaishi H Namiki M Sasaki Y Phase 1 combination study of eribulin mesylate with trastuzumab for advanced or recurrent human epidermal growth factor receptor 2 positive breast cancer Invest New Drugs 2015 Feb33(1)119-27
AstraZeneca
Lynparza (Olaparib) + Cediranib
PARP inhibitor + inhibitor of VEGF receptor tyrosine kinases
HR+ HER2- MBC
BC amp OC
2013
28 (8 BC)
3 for BC
Olaparib (a poly (ADP-ribose) polymerase (PARP) inhibitor) amp Cediranib (Vascular endothelial growth factor receptor (VEGFR) 1 2 and 3 tyrosine kinase inhibitor)3 at dose level (DL) 0 (cediranib 20mg olaparib 100mg) 3 at DL1 (cediranib 20mg olaparib 200mg) 7 at DL2 (cediranib 30mg olaparib 200mg) 6 at DL3 (cediranib 30mg olaparib 400mg)
Liu JF Tolaney SM Birrer M Fleming GF Buss MK Dahlberg SE Lee H Whalen C Tyburski K Winer E Ivy P Matulonis UA A Phase 1 trial of the poly(ADP-ribose) polymerase inhibitor olaparib (AZD2281) in combination with the anti-angiogenic cediranib (AZD2171) in recurrent epithelial ovarian or triple-negative breast cancer Eur J Cancer 2013 Sep49(14)2972-8
Reyon Pharmaceutical
VM206RY
Heterologous prime-boost with a truncated HER2 sequence
HER2+ Stage IIIampIV BC
2015
9
2 chemo
Plasmid DNA (pHM-GM-CSF expressing truncated HER2 amp GM-CSF) amp adenoviral vector (Ad-HM containing modified HER2) (2 4 and 8 mgpatientvisit) of pHM-GM-CSF 3x IM weeks 0 2 and 4 Ad-HM 3 times 109 virus particles at week 6
11 PR
4 pts showed 7 minor AEs
Unclear
Kim SB Ahn JH Kim J Jung KH A phase 1 study of a heterologous prime-boost vaccination involving a truncated HER2 sequence in patients with HER2-expressing breast cancer Mol Ther Methods Clin Dev 2015 Sep 30215031 doi 101038mtm201531 eCollection 2015
Rodon J Peacuterez-Fidalgo A Krop IE Burris H Guerrero-Zotano A Britten CD Becerra C Schellens J Richards DA Schuler M Abu-Khalaf M Johnson FM Ranson M Edenfield J Silva AP Hackl W Quadt C Demanse D Duval V Baselga J Phase 11b dose escalation and expansion study of BEZ235 a dual PI3KmTOR inhibitor in patients with advanced solid tumors including patients with advanced breast cancer Cancer Chemother Pharmacol 2018 Jun 7 doi 101007s00280-018-3610-z [Epub ahead of print]
Celgene (Abraxane)
Gemcitabine + Abraxane (nab-paclitaxel)
Chemo + Chemo
OC BC NSCLC amp Panc cancer + Lung OC BC Kaposi sarcoma
MBC
2016
9
Adjuvant chemo (100)chemo post-adjuvant (33)
Gem (nucleoside metabolic inhibitor 1250 mgm2) on days 1 and 8 nab-Pac (microtubule inhibitor) starting dose of 180 mgm2 (cohort 1) 220 mgm2 (cohort 2) and 260 mgm2 (cohort 3) on day 1 of the 21-day cycle using a 3 + 3 design
0
MTD not reached29 Gr3 Neutropenia59 Gr1 Peripheralneuropathy
Yoshitomi S Taira N Doihara H Mizoo T Nogami T Iwamoto T Motoki T Shien T Ogasawara Y Matsuoka J Tsuji H Mitsuhashi T A phase 1 dose-finding and pharmacokinetic study of gemcitabine with nab-paclitaxel in patients with metastatic breast cancer Cancer Chemother Pharmacol 2016 Aug78(2)289-94
Eli Lilly
Erbituxreg (cetuximab) + Taxane
EGFR inhibitor antineoplastic agent + Chemo
Headamp Neck Colorectal Cancer
TNBC
2007-2010
18
1 chemo
Cetuximab (epidermal growth factor receptor (EGFR) antagonist ) an initial loading dose of cetuximab 400 mgm2 followed by a weekly dose of 250 mgm2Paclitaxel (microtubule inhibitor) 80 mgm2 or Docetaxel at an initial dose of 30 mgm2 was administered weekly
56 CR 22 PR
83 Dermatologic toxicity11 Grade3+
Nechushtan H Vainer G Stainberg H Salmon AY Hamburger T Peretz T A phase 12 of a combination of cetuximab and taxane for triple negative breast cancer patients Breast 2014 Aug23(4)435-8
Polyphor
Balixafortide (POL6326) + eribulin
CXCR4 antagonist + tubulin-based antimitotic
Heavily pretreated Relapsed MBC
2014-2016
56
3rd line 3 chemo
3+3 dose escalation The highest dose was established as eribulin 14 mgmsup2 on days 2 and 9 and balixafortide 55 mgkg on days 1minus3 and 8minus10 of the 21-day cycle
30 PR
41 Gr34 Neutropenia11 Gr34 Leucopenia11 Gr34 Febrileneutropenia2 Related mortalities
Apr 2018 Fast Track for HER2-MBC who have failed 2prior regimens
Pernas S Martin M Kaufman PA Gil-Martin M Gomez Pardo P Lopez-Tarruella S Manso L Ciruelos E Perez-Fidalgo JA Hernando C Ademuyiwa FO Weilbaecher K Mayer I Pluard TJ Martinez Garcia M Vahdat L Perez-Garcia J Wach A Barker D Fung S Romagnoli B Cortes J Balixafortide plus eribulin in HER2-negative metastatic breast cancer a phase 1 single-arm dose-escalation trial Lancet Oncol 2018 Jun19(6)812-824
11 PRndashbut only + letrozole (No Resp on monotherapy)
61 Gr34 Neutropenia39 Gr34 Leucopenia
$933M in 1Q2018 $31B in 2017
Tamura K Mukai H Naito Y Yonemori K Kodaira M Tanabe Y Yamamoto N Osera S Sasaki M Mori Y Hashigaki S Nagasawa T Umeyama Y Yoshino T Phase I study of palbociclib a cyclin-dependent kinase 46 inhibitor in Japanese patients Cancer Sci 2016 Jun107(6)755-63 doi 101111cas12932 Epub 2016 May 11
Pfizer
Ibrancereg (palbociclib)
CDK 46 Inhibitor
HR+ HER2- MBC
Heavily pretreated Relapsed Metastatic Cancer
2004-2008
41 (5 BC)
chemo naiumlve (17) 1-2 (51)3 (29) 3+ (2)
Palbociclib 25-150 mg dose ranging
0
20 Gr34 Neutropenia23 Gr34 Leucopenia
$933M in 1Q2018 $31B in 2017
Flaherty KT Lorusso PM Demichele A Abramson VG Courtney R Randolph SS Shaik MN Wilner KD ODwyer PJ Schwartz GK Phase I dose-escalation trial of the oral cyclin-dependent kinase 46 inhibitor PD 0332991 administered using a 21-day schedule in patients with advanced cancer Clin Cancer Res 2012 Jan 1518(2)568-76 doi 1011581078-0432CCR-11-0509 Epub 2011 Nov 16
Novartis
Kisqalireg (ribociclib)
CDK 46 Inhibitors
Premenopausal HR+ HER2- MBC
Heavily pretreated Relapsed Metastatic Cancer
2016
132 (20 BC)
0-1 (25) 2-3 (42) 4+ (32)
Ribociclib 50 mg ranging up to 1200 mg dose escalation
23 PRndashincluded 1 in BC (5 of BC pts)
27 Gr34 Neutropenia17 Gr34 Leucopenia
Peak sales projected at $25B
Infante JR Cassier PA Gerecitano JF Witteveen PO Chugh R Ribrag V Chakraborty A Matano A Dobson JR Crystal AS Parasuraman S Shapiro GI A Phase I Study of the Cyclin-Dependent Kinase 46 Inhibitor Ribociclib (LEE011) in Patients with Advanced Solid Tumors and Lymphomas Clin Cancer Res 2016 Dec 122(23)5696-5705 Epub 2016 Aug 19
Eli Lilly
Verzenioreg (abemaciclib)
CDK 46 Inhibitors
HR+HER2minusMBC
Heavily pretreated Relapsed Metastatic Cancer
2016
12 (1 BC)
1 (312) 2 (212) 3+ (7)
Abemaciclib 100 mg ranging up to 200 mg dose escalation
17 PR (included 1 in BC)
17 Gr34 Neutropenia33 Gr34 Leucopenia
Peak sales projected at $2B
Fujiwara Y Tamura K Kondo S Tanabe Y Iwasa S Shimomura A Kitano S Ogasawara K Turner PK Mori J Asou H Chan EM Yamamoto N Phase 1 study of abemaciclib an inhibitor of CDK 4 and 6 as a single agent for Japanese patients with advanced cancer Cancer Chemother Pharmacol 2016 Aug78(2)281-8 doi 101007s00280-016-3085-8 Epub 2016 Jun 16
Mukai H Saeki T Shimada K Naito Y Matsubara N Nakanishi T Obaishi H Namiki M Sasaki Y Phase 1 combination study of eribulin mesylate with trastuzumab for advanced or recurrent human epidermal growth factor receptor 2 positive breast cancer Invest New Drugs 2015 Feb33(1)119-27
AstraZeneca
Lynparza (Olaparib)+ Cediranib
PARP inhibitor+ inhibitor of VEGF RTK
HR+ HER2- MBC
BC amp OC
13
28 (8 BC)
3 for BC
Olaparib (a poly (ADP-ribose) polymerase (PARP) inhibitor) amp Cediranib (Vascular endothelial growth factor receptor (VEGFR) 1 2 and 3 tyrosine kinase inhibitor)3 at dose level (DL) 0 (cediranib 20mg olaparib 100mg) 3 at DL1 (cediranib 20mg olaparib 200mg) 7 at DL2 (cediranib 30mg olaparib 200mg) 6 at DL3 (cediranib 30mg olaparib 400mg)
Liu JF Tolaney SM Birrer M Fleming GF Buss MK Dahlberg SE Lee H Whalen C Tyburski K Winer E Ivy P Matulonis UA A Phase 1 trial of the poly(ADP-ribose) polymerase inhibitor olaparib (AZD2281) in combination with the anti-angiogenic cediranib (AZD2171) in recurrent epithelial ovarian or triple-negative breast cancer Eur J Cancer 2013 Sep49(14)2972-8
ReyonPharma
VM206RY
Heterologous prime-boost with a truncated HER2 sequence
HER2+ Stg IIIampIV BC
15
9
2 chemo
Plasmid DNA (pHM-GM-CSF expressing truncated HER2 amp GM-CSF) amp adenoviral vector (Ad-HM containing modified HER2) (2 4 and 8 mgpatientvisit) of pHM-GM-CSF 3x IM weeks 0 2 and 4 Ad-HM 3 times 109 virus particles at week 6
11 PR
4 pts 7 minor AEs
Unclear
Kim SB Ahn JH Kim J Jung KH A phase 1 study of a heterologous prime-boost vaccination involving a truncated HER2 sequence in patients with HER2-expressing breast cancer Mol Ther Methods Clin Dev 2015 Sep 30215031 doi 101038mtm201531 eCollection 2015
Rodon J Peacuterez-Fidalgo A Krop IE Burris H Guerrero-Zotano A Britten CD Becerra C Schellens J Richards DA Schuler M Abu-Khalaf M Johnson FM Ranson M Edenfield J Silva AP Hackl W Quadt C Demanse D Duval V Baselga J Phase 11b dose escalation and expansion study of BEZ235 a dual PI3KmTOR inhibitor in patients with advanced solid tumors including patients with advanced breast cancer Cancer Chemother Pharmacol 2018 Jun 7 doi 101007s00280-018-3610-z [Epub ahead of print]
Celgene(Abraxane)
Gemcitabine + Abraxane (nab-paclitaxel)
Chemo+ Chemo
OC BC NSCLC PC + LC OC BC KS
MBC
16
9
Adjuv chemo (100)chemo post-adjuv (33)
Gem (nucleoside metabolic inhibitor 1250 mgm2) on days 1 and 8 nab-Pac (microtubule inhibitor) starting dose of 180 mgm2 (cohort 1) 220 mgm2 (cohort 2) and 260 mgm2 (cohort 3) on day 1 of the 21-day cycle using a 3 + 3 design
0
MTD not reached29 Gr3 Neutropenia59 Gr1 Peripheralneuropathy
Yoshitomi S Taira N Doihara H Mizoo T Nogami T Iwamoto T Motoki T Shien T Ogasawara Y Matsuoka J Tsuji H Mitsuhashi T A phase 1 dose-finding and pharmacokinetic study of gemcitabine with nab-paclitaxel in patients with metastatic breast cancer Cancer Chemother Pharmacol 2016 Aug78(2)289-94
Eli Lilly
Erbituxreg (cetuximab) + Taxane
EGFR inhibitor antineoplastic agent + Chemo
Head amp NeckColorectal
TNBC
07-10
18
1 chemo
Cetuximab (epidermal growth factor receptor (EGFR) antagonist ) an initial loading dose of cetuximab 400 mgm2 followed by a weekly dose of 250 mgm2Paclitaxel (microtubule inhibitor) 80 mgm2 or Docetaxel at an initial dose of 30 mgm2 was administered weekly
56 CR 22 PR
83 Dermatologic toxicity11 Grade3+
Nechushtan H Vainer G Stainberg H Salmon AY Hamburger T Peretz T A phase 12 of a combination of cetuximab and taxane for triple negative breast cancer patients Breast 2014 Aug23(4)435-8
Polyphor
Balixafortide (POL6326) + eribulin
CXCR4 antagonist + tubulin-based antimitotic
Heavily pretreatedRelapsed MBC
14-16
56
3rd line 3 chemo
3+3 dose escalation The highest dose was established as eribulin 14 mgmsup2 on days 2 and 9 and balixafortide 55 mgkg on days 1minus3 and 8minus10 of the 21-day cycle
30 PR
41 Gr34 Neutropenia11 Gr34 Leucopenia11 Gr34 Febrileneutropenia2 Related mortalities
42018 Fast Track (HER2-MBC failed 2 prior regimens)
Pernas S Martin M Kaufman PA Gil-Martin M Gomez Pardo P Lopez-Tarruella S Manso L Ciruelos E Perez-Fidalgo JA Hernando C Ademuyiwa FO Weilbaecher K Mayer I Pluard TJ Martinez Garcia M Vahdat L Perez-Garcia J Wach A Barker D Fung S Romagnoli B Cortes J Balixafortide plus eribulin in HER2-negative metastatic breast cancer a phase 1 single-arm dose-escalation trial Lancet Oncol 2018 Jun19(6)812-824
1 PRndashbut only + letrozoleNo Resp on monotherapy
61 Gr34 Neutropenia39 Gr34 Leucopenia
$933M (1Q18)$31B (2017)
Tamura K Mukai H Naito Y Yonemori K Kodaira M Tanabe Y Yamamoto N Osera S Sasaki M Mori Y Hashigaki S Nagasawa T Umeyama Y Yoshino T Phase I study of palbociclib a cyclin-dependent kinase 46 inhibitor in Japanese patients Cancer Sci 2016 Jun107(6)755-63 doi 101111cas12932 Epub 2016 May 11
Pfizer
Ibrancereg (palbociclib)
CDK 46 Inhibitor
HR+ HER2- MBC
Heavily pretreatedRelapsed Met Cancer
04-08
41 (5 BC)
chemo naiumlve (17)1-2(51) 3(29) 3+(2)
Palbociclib 25-150 mg dose ranging
0
20 Gr34 Neutropenia23 Gr34 Leucopenia
$933M (1Q18)$31B (2017)
Flaherty KT Lorusso PM Demichele A Abramson VG Courtney R Randolph SS Shaik MN Wilner KD ODwyer PJ Schwartz GK Phase I dose-escalation trial of the oral cyclin-dependent kinase 46 inhibitor PD 0332991 administered using a 21-day schedule in patients with advanced cancer Clin Cancer Res 2012 Jan 1518(2)568-76 doi 1011581078-0432CCR-11-0509 Epub 2011 Nov 16
Novartis
Kisqalireg (ribociclib)
CDK 46 Inhibitor
Premenopausal HR+ HER2- MBC
Heavily pretreatedRelapsed Met Cancer
16
132 (20 BC)
0-1 (25) 2-3 (42)4+ (32)
Ribociclib 50 mg ranging up to 1200 mg dose escalation
23 PR-included 1 BC (5 of BC pts)
27 Gr34 Neutropenia17 Gr34 Leucopenia
Peak sales est at $25B
Infante JR Cassier PA Gerecitano JF Witteveen PO Chugh R Ribrag V Chakraborty A Matano A Dobson JR Crystal AS Parasuraman S Shapiro GI A Phase I Study of the Cyclin-Dependent Kinase 46 Inhibitor Ribociclib (LEE011) in Patients with Advanced Solid Tumors and Lymphomas Clin Cancer Res 2016 Dec 122(23)5696-5705 Epub 2016 Aug 19
Eli Lilly
Verzenioreg (abemaciclib)
CDK 46 Inhibitor
HR+HER2minusMBC
Heavily pretreatedRelapsed Met Cancer
16
12 (1 BC)
1 (312) 2 (212) 3+(7)
Abemaciclib 100 mg ranging up to 200 mg dose escalation
17 PR (included 1 BC)
17 Gr34 Neutropenia33 Gr34 Leucopenia
Peak sales est at $2B
Fujiwara Y Tamura K Kondo S Tanabe Y Iwasa S Shimomura A Kitano S Ogasawara K Turner PK Mori J Asou H Chan EM Yamamoto N Phase 1 study of abemaciclib an inhibitor of CDK 4 and 6 as a single agent for Japanese patients with advanced cancer Cancer Chemother Pharmacol 2016 Aug78(2)281-8 doi 101007s00280-016-3085-8 Epub 2016 Jun 16
Mukai H Saeki T Shimada K Naito Y Matsubara N Nakanishi T Obaishi H Namiki M Sasaki Y Phase 1 combination study of eribulin mesylate with trastuzumab for advanced or recurrent human epidermal growth factor receptor 2 positive breast cancer Invest New Drugs 2015 Feb33(1)119-27
AstraZeneca
Lynparza (Olaparib) + Cediranib
PARP inhibitor + inhibitor of VEGF receptor tyrosine kinases
HR+ HER2- MBC
BC amp OC
2013
28 (8 BC)
3 for BC
Olaparib (a poly (ADP-ribose) polymerase (PARP) inhibitor) amp Cediranib (Vascular endothelial growth factor receptor (VEGFR) 1 2 and 3 tyrosine kinase inhibitor)3 at dose level (DL) 0 (cediranib 20mg olaparib 100mg) 3 at DL1 (cediranib 20mg olaparib 200mg) 7 at DL2 (cediranib 30mg olaparib 200mg) 6 at DL3 (cediranib 30mg olaparib 400mg)
Liu JF Tolaney SM Birrer M Fleming GF Buss MK Dahlberg SE Lee H Whalen C Tyburski K Winer E Ivy P Matulonis UA A Phase 1 trial of the poly(ADP-ribose) polymerase inhibitor olaparib (AZD2281) in combination with the anti-angiogenic cediranib (AZD2171) in recurrent epithelial ovarian or triple-negative breast cancer Eur J Cancer 2013 Sep49(14)2972-8
Reyon Pharmaceutical
VM206RY
Heterologous prime-boost with a truncated HER2 sequence
HER2+ Stage IIIampIV BC
2015
9
2 chemo
Plasmid DNA (pHM-GM-CSF expressing truncated HER2 amp GM-CSF) amp adenoviral vector (Ad-HM containing modified HER2) (2 4 and 8 mgpatientvisit) of pHM-GM-CSF 3x IM weeks 0 2 and 4 Ad-HM 3 times 109 virus particles at week 6
11 PR
4 pts showed 7 minor AEs
Unclear
Kim SB Ahn JH Kim J Jung KH A phase 1 study of a heterologous prime-boost vaccination involving a truncated HER2 sequence in patients with HER2-expressing breast cancer Mol Ther Methods Clin Dev 2015 Sep 30215031 doi 101038mtm201531 eCollection 2015
Rodon J Peacuterez-Fidalgo A Krop IE Burris H Guerrero-Zotano A Britten CD Becerra C Schellens J Richards DA Schuler M Abu-Khalaf M Johnson FM Ranson M Edenfield J Silva AP Hackl W Quadt C Demanse D Duval V Baselga J Phase 11b dose escalation and expansion study of BEZ235 a dual PI3KmTOR inhibitor in patients with advanced solid tumors including patients with advanced breast cancer Cancer Chemother Pharmacol 2018 Jun 7 doi 101007s00280-018-3610-z [Epub ahead of print]
Celgene (Abraxane)
Gemcitabine + Abraxane (nab-paclitaxel)
Chemo + Chemo
OC BC NSCLC amp Panc cancer + Lung OC BC Kaposi sarcoma
MBC
2016
9
Adjuvant chemo (100)chemo post-adjuvant (33)
Gem (nucleoside metabolic inhibitor 1250 mgm2) on days 1 and 8 nab-Pac (microtubule inhibitor) starting dose of 180 mgm2 (cohort 1) 220 mgm2 (cohort 2) and 260 mgm2 (cohort 3) on day 1 of the 21-day cycle using a 3 + 3 design
0
MTD not reached29 Gr3 Neutropenia59 Gr1 Peripheralneuropathy
Yoshitomi S Taira N Doihara H Mizoo T Nogami T Iwamoto T Motoki T Shien T Ogasawara Y Matsuoka J Tsuji H Mitsuhashi T A phase 1 dose-finding and pharmacokinetic study of gemcitabine with nab-paclitaxel in patients with metastatic breast cancer Cancer Chemother Pharmacol 2016 Aug78(2)289-94
Eli Lilly
Erbituxreg (cetuximab) + Taxane
EGFR inhibitor antineoplastic agent + Chemo
Headamp Neck Colorectal Cancer
TNBC
2007-2010
18
1 chemo
Cetuximab (epidermal growth factor receptor (EGFR) antagonist ) an initial loading dose of cetuximab 400 mgm2 followed by a weekly dose of 250 mgm2Paclitaxel (microtubule inhibitor) 80 mgm2 or Docetaxel at an initial dose of 30 mgm2 was administered weekly
56 CR 22 PR
83 Dermatologic toxicity11 Grade3+
Nechushtan H Vainer G Stainberg H Salmon AY Hamburger T Peretz T A phase 12 of a combination of cetuximab and taxane for triple negative breast cancer patients Breast 2014 Aug23(4)435-8
Polyphor
Balixafortide (POL6326) + eribulin
CXCR4 antagonist + tubulin-based antimitotic
Heavily pretreated Relapsed MBC
2014-2016
56
3rd line 3 chemo
3+3 dose escalation The highest dose was established as eribulin 14 mgmsup2 on days 2 and 9 and balixafortide 55 mgkg on days 1minus3 and 8minus10 of the 21-day cycle
30 PR
41 Gr34 Neutropenia11 Gr34 Leucopenia11 Gr34 Febrileneutropenia2 Related mortalities
Apr 2018 Fast Track for HER2-MBC who have failed 2prior regimens
Pernas S Martin M Kaufman PA Gil-Martin M Gomez Pardo P Lopez-Tarruella S Manso L Ciruelos E Perez-Fidalgo JA Hernando C Ademuyiwa FO Weilbaecher K Mayer I Pluard TJ Martinez Garcia M Vahdat L Perez-Garcia J Wach A Barker D Fung S Romagnoli B Cortes J Balixafortide plus eribulin in HER2-negative metastatic breast cancer a phase 1 single-arm dose-escalation trial Lancet Oncol 2018 Jun19(6)812-824
11 PRndashbut only + letrozole (No Resp on monotherapy)
61 Gr34 Neutropenia39 Gr34 Leucopenia
$933M in 1Q2018 $31B in 2017
Tamura K Mukai H Naito Y Yonemori K Kodaira M Tanabe Y Yamamoto N Osera S Sasaki M Mori Y Hashigaki S Nagasawa T Umeyama Y Yoshino T Phase I study of palbociclib a cyclin-dependent kinase 46 inhibitor in Japanese patients Cancer Sci 2016 Jun107(6)755-63 doi 101111cas12932 Epub 2016 May 11
Pfizer
Ibrancereg (palbociclib)
CDK 46 Inhibitor
HR+ HER2- MBC
Heavily pretreated Relapsed Metastatic Cancer
2004-2008
41 (5 BC)
chemo naiumlve (17) 1-2 (51)3 (29) 3+ (2)
Palbociclib 25-150 mg dose ranging
0
20 Gr34 Neutropenia23 Gr34 Leucopenia
$933M in 1Q2018 $31B in 2017
Flaherty KT Lorusso PM Demichele A Abramson VG Courtney R Randolph SS Shaik MN Wilner KD ODwyer PJ Schwartz GK Phase I dose-escalation trial of the oral cyclin-dependent kinase 46 inhibitor PD 0332991 administered using a 21-day schedule in patients with advanced cancer Clin Cancer Res 2012 Jan 1518(2)568-76 doi 1011581078-0432CCR-11-0509 Epub 2011 Nov 16
Novartis
Kisqalireg (ribociclib)
CDK 46 Inhibitors
Premenopausal HR+ HER2- MBC
Heavily pretreated Relapsed Metastatic Cancer
2016
132 (20 BC)
0-1 (25) 2-3 (42) 4+ (32)
Ribociclib 50 mg ranging up to 1200 mg dose escalation
23 PRndashincluded 1 in BC (5 of BC pts)
27 Gr34 Neutropenia17 Gr34 Leucopenia
Peak sales projected at $25B
Infante JR Cassier PA Gerecitano JF Witteveen PO Chugh R Ribrag V Chakraborty A Matano A Dobson JR Crystal AS Parasuraman S Shapiro GI A Phase I Study of the Cyclin-Dependent Kinase 46 Inhibitor Ribociclib (LEE011) in Patients with Advanced Solid Tumors and Lymphomas Clin Cancer Res 2016 Dec 122(23)5696-5705 Epub 2016 Aug 19
Eli Lilly
Verzenioreg (abemaciclib)
CDK 46 Inhibitors
HR+HER2minusMBC
Heavily pretreated Relapsed Metastatic Cancer
2016
12 (1 BC)
1 (312) 2 (212) 3+ (7)
Abemaciclib 100 mg ranging up to 200 mg dose escalation
17 PR (included 1 in BC)
17 Gr34 Neutropenia33 Gr34 Leucopenia
Peak sales projected at $2B
Fujiwara Y Tamura K Kondo S Tanabe Y Iwasa S Shimomura A Kitano S Ogasawara K Turner PK Mori J Asou H Chan EM Yamamoto N Phase 1 study of abemaciclib an inhibitor of CDK 4 and 6 as a single agent for Japanese patients with advanced cancer Cancer Chemother Pharmacol 2016 Aug78(2)281-8 doi 101007s00280-016-3085-8 Epub 2016 Jun 16
Mukai H Saeki T Shimada K Naito Y Matsubara N Nakanishi T Obaishi H Namiki M Sasaki Y Phase 1 combination study of eribulin mesylate with trastuzumab for advanced or recurrent human epidermal growth factor receptor 2 positive breast cancer Invest New Drugs 2015 Feb33(1)119-27
AstraZeneca
Lynparza (Olaparib)+ Cediranib
PARP inhibitor+ inhibitor of VEGF RTK
HR+ HER2- MBC
BC amp OC
13
28 (8 BC)
3 for BC
Olaparib (a poly (ADP-ribose) polymerase (PARP) inhibitor) amp Cediranib (Vascular endothelial growth factor receptor (VEGFR) 1 2 and 3 tyrosine kinase inhibitor)3 at dose level (DL) 0 (cediranib 20mg olaparib 100mg) 3 at DL1 (cediranib 20mg olaparib 200mg) 7 at DL2 (cediranib 30mg olaparib 200mg) 6 at DL3 (cediranib 30mg olaparib 400mg)
Liu JF Tolaney SM Birrer M Fleming GF Buss MK Dahlberg SE Lee H Whalen C Tyburski K Winer E Ivy P Matulonis UA A Phase 1 trial of the poly(ADP-ribose) polymerase inhibitor olaparib (AZD2281) in combination with the anti-angiogenic cediranib (AZD2171) in recurrent epithelial ovarian or triple-negative breast cancer Eur J Cancer 2013 Sep49(14)2972-8
ReyonPharma
VM206RY
Heterologous prime-boost with a truncated HER2 sequence
HER2+ Stg IIIampIV BC
15
9
2 chemo
Plasmid DNA (pHM-GM-CSF expressing truncated HER2 amp GM-CSF) amp adenoviral vector (Ad-HM containing modified HER2) (2 4 and 8 mgpatientvisit) of pHM-GM-CSF 3x IM weeks 0 2 and 4 Ad-HM 3 times 109 virus particles at week 6
11 PR
4 pts 7 minor AEs
Unclear
Kim SB Ahn JH Kim J Jung KH A phase 1 study of a heterologous prime-boost vaccination involving a truncated HER2 sequence in patients with HER2-expressing breast cancer Mol Ther Methods Clin Dev 2015 Sep 30215031 doi 101038mtm201531 eCollection 2015
Rodon J Peacuterez-Fidalgo A Krop IE Burris H Guerrero-Zotano A Britten CD Becerra C Schellens J Richards DA Schuler M Abu-Khalaf M Johnson FM Ranson M Edenfield J Silva AP Hackl W Quadt C Demanse D Duval V Baselga J Phase 11b dose escalation and expansion study of BEZ235 a dual PI3KmTOR inhibitor in patients with advanced solid tumors including patients with advanced breast cancer Cancer Chemother Pharmacol 2018 Jun 7 doi 101007s00280-018-3610-z [Epub ahead of print]
Celgene(Abraxane)
Gemcitabine + Abraxane (nab-paclitaxel)
Chemo+ Chemo
OC BC NSCLC PC + LC OC BC KS
MBC
16
9
Adjuv chemo (100)chemo post-adjuv (33)
Gem (nucleoside metabolic inhibitor 1250 mgm2) on days 1 and 8 nab-Pac (microtubule inhibitor) starting dose of 180 mgm2 (cohort 1) 220 mgm2 (cohort 2) and 260 mgm2 (cohort 3) on day 1 of the 21-day cycle using a 3 + 3 design
0
MTD not reached29 Gr3 Neutropenia59 Gr1 Peripheralneuropathy
Yoshitomi S Taira N Doihara H Mizoo T Nogami T Iwamoto T Motoki T Shien T Ogasawara Y Matsuoka J Tsuji H Mitsuhashi T A phase 1 dose-finding and pharmacokinetic study of gemcitabine with nab-paclitaxel in patients with metastatic breast cancer Cancer Chemother Pharmacol 2016 Aug78(2)289-94
Eli Lilly
Erbituxreg (cetuximab) + Taxane
EGFR inhibitor antineoplastic agent + Chemo
Head amp NeckColorectal
TNBC
07-10
18
1 chemo
Cetuximab (epidermal growth factor receptor (EGFR) antagonist ) an initial loading dose of cetuximab 400 mgm2 followed by a weekly dose of 250 mgm2Paclitaxel (microtubule inhibitor) 80 mgm2 or Docetaxel at an initial dose of 30 mgm2 was administered weekly
56 CR 22 PR
83 Dermatologic toxicity11 Grade3+
Nechushtan H Vainer G Stainberg H Salmon AY Hamburger T Peretz T A phase 12 of a combination of cetuximab and taxane for triple negative breast cancer patients Breast 2014 Aug23(4)435-8
Polyphor
Balixafortide (POL6326) + eribulin
CXCR4 antagonist + tubulin-based antimitotic
Heavily pretreatedRelapsed MBC
14-16
56
3rd line 3 chemo
3+3 dose escalation The highest dose was established as eribulin 14 mgmsup2 on days 2 and 9 and balixafortide 55 mgkg on days 1minus3 and 8minus10 of the 21-day cycle
30 PR
41 Gr34 Neutropenia11 Gr34 Leucopenia11 Gr34 Febrileneutropenia2 Related mortalities
42018 Fast Track (HER2-MBC failed 2 prior regimens)
Pernas S Martin M Kaufman PA Gil-Martin M Gomez Pardo P Lopez-Tarruella S Manso L Ciruelos E Perez-Fidalgo JA Hernando C Ademuyiwa FO Weilbaecher K Mayer I Pluard TJ Martinez Garcia M Vahdat L Perez-Garcia J Wach A Barker D Fung S Romagnoli B Cortes J Balixafortide plus eribulin in HER2-negative metastatic breast cancer a phase 1 single-arm dose-escalation trial Lancet Oncol 2018 Jun19(6)812-824
1 PRndashbut only + letrozoleNo Resp on monotherapy
61 Gr34 Neutropenia39 Gr34 Leucopenia
$933M (1Q18)$31B (2017)
Tamura K Mukai H Naito Y Yonemori K Kodaira M Tanabe Y Yamamoto N Osera S Sasaki M Mori Y Hashigaki S Nagasawa T Umeyama Y Yoshino T Phase I study of palbociclib a cyclin-dependent kinase 46 inhibitor in Japanese patients Cancer Sci 2016 Jun107(6)755-63 doi 101111cas12932 Epub 2016 May 11
Pfizer
Ibrancereg (palbociclib)
CDK 46 Inhibitor
HR+ HER2- MBC
Heavily pretreatedRelapsed Met Cancer
04-08
41 (5 BC)
chemo naiumlve (17)1-2(51) 3(29) 3+(2)
Palbociclib 25-150 mg dose ranging
0
20 Gr34 Neutropenia23 Gr34 Leucopenia
$933M (1Q18)$31B (2017)
Flaherty KT Lorusso PM Demichele A Abramson VG Courtney R Randolph SS Shaik MN Wilner KD ODwyer PJ Schwartz GK Phase I dose-escalation trial of the oral cyclin-dependent kinase 46 inhibitor PD 0332991 administered using a 21-day schedule in patients with advanced cancer Clin Cancer Res 2012 Jan 1518(2)568-76 doi 1011581078-0432CCR-11-0509 Epub 2011 Nov 16
Novartis
Kisqalireg (ribociclib)
CDK 46 Inhibitor
Premenopausal HR+ HER2- MBC
Heavily pretreatedRelapsed Met Cancer
16
132 (20 BC)
0-1 (25) 2-3 (42)4+ (32)
Ribociclib 50 mg ranging up to 1200 mg dose escalation
23 PR-included 1 BC (5 of BC pts)
27 Gr34 Neutropenia17 Gr34 Leucopenia
Peak sales est at $25B
Infante JR Cassier PA Gerecitano JF Witteveen PO Chugh R Ribrag V Chakraborty A Matano A Dobson JR Crystal AS Parasuraman S Shapiro GI A Phase I Study of the Cyclin-Dependent Kinase 46 Inhibitor Ribociclib (LEE011) in Patients with Advanced Solid Tumors and Lymphomas Clin Cancer Res 2016 Dec 122(23)5696-5705 Epub 2016 Aug 19
Eli Lilly
Verzenioreg (abemaciclib)
CDK 46 Inhibitor
HR+HER2minusMBC
Heavily pretreatedRelapsed Met Cancer
16
12 (1 BC)
1 (312) 2 (212) 3+(7)
Abemaciclib 100 mg ranging up to 200 mg dose escalation
17 PR (included 1 BC)
17 Gr34 Neutropenia33 Gr34 Leucopenia
Peak sales est at $2B
Fujiwara Y Tamura K Kondo S Tanabe Y Iwasa S Shimomura A Kitano S Ogasawara K Turner PK Mori J Asou H Chan EM Yamamoto N Phase 1 study of abemaciclib an inhibitor of CDK 4 and 6 as a single agent for Japanese patients with advanced cancer Cancer Chemother Pharmacol 2016 Aug78(2)281-8 doi 101007s00280-016-3085-8 Epub 2016 Jun 16
41 Gr34 Neutropenia11 Gr34 Leucopenia11 Gr34 Febrileneutropenia2 Related mortalities
30 PRs in combination with Halaven
Bria-IMTTM
20
Injection site reactions No related SAEs or SUSARs
Tumor vol darr ampor darr circul tumor cells)All Comers 21(419) 26(519)One or More HLA matches 27(415) 33(515)Two or More HLA matches 50 (24) 75 (34))
Drug
Technology
Approved for
Market (US)
Ibrance (palbociclib)
CDK 46 Inhibitor
HR+HER2- MBC in combination with fluvestrant or aromatase inhibitor
$933M in 1Q2018 $3126M in 2017
Kisqali (ribociclib)
CDK 46 Inhibitor
2017 HR+HER2- MBC in combination with fluvestrant or aromatase inhibitor
Peak sales projected at $25B
Verzenio (abemaciclib)
CDK 46 Inhibitor
2017 HR+HER2- MBC in combination with fluvestrant or aromatase inhibitor
Peak sales projected at $2B
Lynparza (olaparib)
Poly (ADP-ribose) polymerase (PARP) inhibitor
2017 ovarian amp breast cancer
$997M in 2017
Halaven (eribulin mesylate)
Tubulin-based antimitotic
2H2017 3rd line MBC amp liposarcoma
$181M in 2017
balixafortide
CXCR4 antagonist
Fast track designation in 2018 for HER2- MBC who have failed 2 prior regimens
Bria-IMTtrade amp Bria-OTStradePotential Mechanisms of Action in Advanced Breast Cancer
Bria-IMTTM directly stimulates cancerfighting CD4+ and CD8+ T cells(further boosts the response)
Bria-IMTTM produces breastcancer antigens which aretaken up by dendritic cellsand ldquopresentedrdquo to CD4+and CD8+ T cells implicatedin tumor destruction
Bria-IMTTM secretes GM-CSF which further promotes dendritic cell-based antigen presentation (boosts the response) 7
Bria-IMTtradeHuman Proof-of-Concept Trials in Breast Cancer (Patient A002) Bria-IMTtrade Non-Personalized Immunotherapy ndash Given as Monotherapy
Second Proof-of-Concept Phase I (2005) 1 out of 4 patients responded with substantial tumor regression Patient A002 was the only patient with key HLA matches with Bria-IMTtrade
8
Bria-IMTtradeHuman Proof-of-Concept Trials in Breast Cancer (Patient A002) Approximately 3 months (106 days) after last inoculation Patient A002rsquos breast cancer returned and
spread to brain lung and other sites
Patient A002 was then re-treated with 10 inoculations of Bria-IMTtrade over 4 months
Repeat imaging studies showed normal findings on MRI and PET consistent with a completeremission of the previous multiple central nervous system metastases as shown in the brain scansbelow
Bria-IMTtrade and Bria-OTStrade shouldsynergize with existing approvedimmunotherapies as well as those stillunder development
This includes immune checkpointinhibitors such as antibodies to PD-1CTLA-4 GITR and CD73 inhibitors whicheliminate tumor immunosuppression Checkpoint Inhibitors were the
subject of the 2018 Nobel Prize inMedicine
In addition immunostimulatoryantibodies to molecules such as OX40should enhance responses to Bria-IMTtradeand Bria-OTStrade
13
Q3 2018 Data on first 20 Patients on Bria-IMTtrade Q3 2018 Initiate Combination Study of Bria-IMTtrade with Keytruda or Yervoy
Q4 2018 Switch to a novel frozen Bria-IMTtrade formulation Q4 2018 Safety Data (6 patients) of the Bria-IMTtrade - Keytrudareg Combination Study (SABC meeting) Q4 2018 Ongoing Corporate PartnershipCollaboration Discussions
Q1 2019 Efficacy Data (6 patients) of the Bria-IMTtrade - Keytrudareg Combination Study Q2 2019 Initiation of Bria-OTStrade GMP manufacturing (KBI BioPharma) Q2 2019 Additional Safety amp Efficacy data Monotherapy and Combination Studies (AACR meeting) Q2 2019 Final data for Monotherapy and Additional Data for the Combination Study (ASCO meeting) H1 2019 Candidate Selection for a PKCδ Inhibitor H1 2019 Initiate additional immunotherapy program H2 2019 Bria-OTStrade Authorization from FDA clearance for dosing H2 2019 Bria-OTStrade First Patient Dosed
Upcoming Milestones amp Catalysts
14
Involved in over 10 drugs brought to the market
Experienced Management Team
Management
William V Williams MD FACP President amp CEO VP Exploratory Development Incyte Corporation VP Experimental Medicine GlaxoSmithKline Head Rheumatology Research University of Pennsylvania Facilitated entry of over 20 compounds into the clinic including ruxolitinib (Jakafi)
baricitinib amp epacadostat NDAs including Jakafi Boniva Bexxar Author of over 120 peer-reviewed publications amp over 20 patents
Gadi Levin CA MBA CFO CFO of Labstyle Innovations Ltd VP of Finance for two Israeli investment houses in the fields of private equity
hedge funds and real estate Financial Consultant various firms Accountant Arthur Andersen
Markus Lacher PhD Senior Director RampD Founder T cell Therapeutics Inc an immuno-oncology company Sr Clinical Scientist Cesca Therapeutics Inc a clinical-stage autologous cell
therapy company Scientist at BioTime Inc and OncoCyte Corporation Editorial advisory board Recent Patents on Anti-Cancer Drug Discovery
Farrah Dean MSc MBA Manager Corp Development Investor relations CytRx Corporation amp CCG Investor Relations Senior Associate Equity Analyst Oppenheimer amp Co Rodman amp Renshaw amp
Brian Metcalf PhD Recently retired as CSO from Global Blood Therapeutics Former Head of Research amp Development Incyte Corporation Former Head of Medicinal Chemistry SmithKline Beecham
Douglas Faller MD PhD Professor of Medicine Pediatrics Biochemistry Microbiology Pathology and
Laboratory Medicine HematologistOncologist former Director of the Cancer Center Boston University School of Medicine
Founder of several successful biotechnology companies
Robert Williams PhD University Distinguished Professor of Chemistry Colorado State University Founder of several successful biotechnology companies including Microcide Xcyte
Therapies HemaQuest Arch Therapeutics and Cetya Therapeutics
Thomas Kieber-Emmons PhD Deputy Director University of Arkansas Cancer Center Expert in targeted cancer immunotherapies structural biology and computational
chemistry
Maria Trojanowska PhD Professor of Medicine Boston University School of Medicine Director The Arthritis Center
16
Veteran Board of Directors
Board of Directors
Saeid Babaei PhD MBA Chairman Entrepreneur 20 yrs of biotech leadership roles Current CEO AbCelex VP Bus Develop Lorus Therap Dir of Corp Develop Northern Therapeutics
Rahoul Sharan CA Director Chairman Potash Ridge Director of the Board Ansell Capital Corp Parallel Resources amp Galaxy Capital
Corporation
Martin Schmieg CPA Director CFO Sirna Therapeutics Inc amp Isolagen Inc CEO Freedom-2 Inc (now PharmaCyte Inc) Advisor Caladrius Biosciences Inc Beckman Coulter Genomics Calimmune
Charles Wiseman MD Co-Founder amp Director Director Immunotherapy Lab St Vincent Medical Center Chief Breast Cancer Basic Research Lab Univ of Texas MD Anderson Hospital amp
Tumour Institute Assist Prof Dept of Molecular Carcinogenesis amp Virology MD Anderson Acting Chief Div of Oncology White Memorial Medical Center LA
William V Williams MD FACP President amp CEO VP Exploratory Development Incyte Corporation VP Experimental Medicine GlaxoSmithKline Head Rheumatology Research University of Pennsylvania
Prior Affiliations
17
Drug Approvals by BriaCell Management Team
Bexxarreg (tositumomab and Iodine I131 tositumomab) Treatment of CD20 antigen-expressing relapsed or refractory low grade follicular or transformed non-Hodgkins lymphoma
Myleranreg (busulfan) for chronic myelogenous leukemia Defense of formulation change sNDA
Hycamtinreg (topotecan) for ovarian cancer Pediatric use sNDA
Navelbinereg (vinorelbine tartrate) for non-small cell lung cancer Pediatric use sNDA
Bonivareg (ibandronate) monthly oral treatment of osteoporosis
Bonivareg (ibandronate) quarterly intraveous treatment of osteoporosis
Zofranreg (ondansetron) for prevention of nausea and vomiting Pediatric use sNDA
Jakafireg (ruxolitinib) for myelofibrosis Jakafireg (ruxolitinib) for polycythemia vera
Olumiantreg (baricitinib) for rheumatoid arthritis Approved in USA Japan and Europe
18
Share Metrics
BCTV BCTXF 19
Data as of 1092018
Ticker TSX BCTV
US Ticker OTCQBBCTXF
Share Price (CAD) as of Oct 9 2018 $012
52-Week Range (CAD) $009-019
Shares Outstanding as of Oct 9 2018 1611M
Market Cap as of Oct 9 2018 (CAD) $193M
Cash and Short Term Investments as of July 31 2018 (CAD) $23M
Total Shareholders Equity as of July 31 2018 (CAD) $12M
Number of Warrants $014-$035 (CAD) as of Oct 9 2018 601M
Number of Compensation Warrants $014-$030 (CAD) as of Oct 9 2018 45M
Number of Options $014- $026 (CAD$) as of Oct 9 2018 93M
Developing Bria-OTStrade the First Off-the-Shelf Personalized Immunotherapy
Targeting Adv Breast Cancer Unmet medical need (42000 death in the US in 2017 ) $1 Bil- $5 Bil market opportunity depending on patient treatment stage
Impressive results in 2 proof-of-concept clinical trials Rapid Response Rate Repeated following re-treatment Excellent Safety Profile
Completed enrollment in Phase IIIa clinical trial of Bria-IMTtrade with outstanding safety amp efficacy data Initiated Phase IIa Combination Study of Bria-IMTtrade with Keytrudareg (Merck amp Co Inc)
Developing Bria-OTStrade along with BriaDXtrade its companion diagnostic test Ability to match and treat ~90 of patient population with Off-the-Shelf personalized immunotherapy
Experienced Management has been involved in over 10 drug approvals
Patient B001 Breast 70 No 1101 - 3501 4001 Negative -
Bria-IMTtradeHuman Proof-of-Concept Trials in Breast Cancer (Patient A002)
24
Proof-of-Concept Results Resulted in BriaCellrsquos Immunotherapy Strategy Use BriaDXtrade diagnostic to select only those patients matching Bria-IMTtrade Use BriaDXtrade diagnostic test to select Bria-OTStrade alleles matching ~90 of all patients
Bria-IMTtradeCurrent Phase IIIa Data Supports HLA Matching Hypothesis Six patients treated in 2017 Bria-IMTtrade was safe and well tolerated
Patient 01-002 73-year-old woman with breast cancer diagnosed in 1995 Developed liver metastases in2010 and lung metastases in 2017 Previously treated with 7 rounds of chemotherapy with 8 differentchemotherapy agents Received 5 cycles of Bria-IMTtrade over 3 months then monthly cycles (6 months total)Evaluated after 3 months and 6 months After 3 months despite the extensive prior therapy her scans notedthat ldquothere has been a clear response in the multiple bilateral pulmonary nodulesrdquo The response wasmaintained after 6 months of Bria-IMTtrade treatment She matches Bria-IMTtrade at 2 HLA alleles
The liver tumors were stable to slightly increased at 3 months and then progressed after 6 months
This supports our hypothesis of heightened anti-tumor activity in patients with a matched HLA types Clear path to develop BriaDXtrade to select the patients using HLA testing
1 RLL 29 Not Detectable Not Detectable2 LUL apical pleural based 34 tiny nodule lt 1mm scar tiny nodule lt 1mm scar3 xxx 39 Not Detectable Not Detectable4 40 Not Detectable Not Detectable5 RLL 45 Not Detectable Not Detectable6 LLL 49 Not Detectable Not Detectable7 xxx 52 Not Detectable Not Detectable8 RLL 52 Not Detectable Not Detectable9 RLL 56 Not Detectable Not Detectable
10 RLL costophrenic recess 56 Not Detectable Not Detectable11 XXX 58 Not Detectable Not Detectable12 LUL 60 Not Detectable Not Detectable13 XXX 67 15 1514 RUL 72 15 1515 LLL 76 Not Detectable Not Detectable16 RUL Noncalcified Nodule 77 Not Detectable Not Detectable17 RLL costophrenic recess 79 10 1018 RUL 82 Not Detectable Not Detectable19 RLL 90 Not Detectable Not Detectable20 RLL 91 lt 01 lt 0121 xxx xxx Not Detectable Not Detectable
27
Clinical Development Update ndash Summary 2018 September 26
Completed enrollment of Adv Breast cancer patients in the Phase IIIa ldquomonotherapyrdquo study of Bria-IMTtrade
We have confirmed our mechanism of action and achieved proof of concept
Initial safety data appears superior to that of the other advanced or approved drugs for breast cancer when they were at a similar clinical stage of development
Initial efficacy data is similar or superior to those of other advanced or approved drugs for breast cancer when they were at a similar clinical stage of development
Initiated Combination Study of Bria-IMTtrade with Keytrudareg or Yervoyreg in Adv breast cancer patients expecting even better response rates than those in the ldquomonotherapyrdquo study Initial safety data is expected in 4Q2018 Initial efficacy data is expected in 1Q2019
Bria-OTStrade the first off-the-shelf personalized treatment for advanced breast cancer is expected to enter the clinic in 2019
28
Bria-IMTtrade Excellent Safety Data - To Date
To date Bria-IMTtrade has been dosed in 24 patients (4 in 2004-2005 20 in 2017-2018)
Interim Data (20 patients)-Ongoing Phase IIIa Study (2017-2018)
Bria-IMTtrade has been very well tolerated (ge60 doses given to date) The majority of adverse events (AEs) were limited to expected minor local irritation at the
injection sites No related grade gt3 or unexpected AEs No related serious AEs No serious unexpected related AEs Most patients who have dropped out did so due to worsening of their underlying disease
Based on the current study Bria-IMTtrade has an excellent safety profile
29
Bria-IMTtrade - Efficacy as Predicted
Interim Data (19 patients)-Ongoing Phase IIIa Study (2017-2018) amp Original Study (2004-2005)
PD-L1 expression on circulating cancer cells amp cancer-associated cells in 100 of patients (to date) Strong rationale for combination with checkpoint inhibitors like Keytruda
30
Bria-IMTtrade appears to be most effective in patients who match with Bria-IMT trade at 2 HLA loci (types) further supporting our ldquoHLA Matching Hypothesisrdquo and the development of Bria-OTS trade to cover 90 of the patient population
Combination with immune checkpoint inhibitors may induce a more potent anti-cancer response leading to our strategy of combination studies of Bria-IMT trade with Keytruda or Yervoy
Patients (n) HLA Match
Tumor Shrinkage
Biological Response
4 ge2 50 7515 ge1 27 334 0 0 0
Biological response includes tumor shrinkage or lower circulating cancer associated cells
The confirmatory Bria-IMTtrade monotherapy Phase IIa trial has completed enrollment Additional Support for the HLA-matching hypothesis has been obtained
Bria-IMTtrade Combination Therapy study with immune checkpoint inhibitors Keytrudareg if PD-L12 positive (ge1) Yervoyreg if PD-L12 negative (lt1) Accepting patients from the monotherapy study who develop progressive disease Also enrolling patients directly into this study to enhance experience with the combination In discussion with other pharmaceutical companies to evaluate additional combinations with other
immunotherapies
Bria-OTStrade Off-the-Shelf Personalized Targeted Immunotherapy Developing Bria-OTStrade to co-express GM-CSF and interferon-α Pre-manufacture additional HLA alleles ndash Total of 15 alleles (8 Class I and 7 Class II) Co-development of BriaDXtrade companion diagnostic for HLA typing Combination therapy clinical trial with immune checkpoint inhibitors for non-responders using
information from the Bria-IMTtrade Combination Therapy Study
33
Development Timeline ndash Breast Cancer
20192018 2020 2021
Phase IIIaBria-IMTtrade
Monotherapy
Currently Enrolling Phase IIaBria-IMTtrade + Checkpoint
Currently in discussions with potential partnersPhase II Bria-IMTtrade plus Additional Combinations (1Q19 4Q22)(eg PD-1 Inhibitor PD-L1 inhibitor anti-CTLA4 anti-GITR anti-OX40)
1Q 2Q 3Q 4Q
2023
Bria-OTStrade Off-The-Shelf Personalized ImmunotherapyMonotherapy and Potential Partnered Combo Therapy
(2H19 Ongoing)
Bria-OTStradeOff-the-Shelf Cell Line cGMP Manufacturing
and BriaDXtrade(1Q18 1Q19)
Registration Studies (1Q20 2H22)Bria-IMTtrade with Checkpoint InhibitorsBria-OTStrade +- Checkpoint Inhibitors
34
Immuno-oncology Deals
Recent deals of small biotechs with big pharma in immuno-oncology
35
Date PartnershipDevelopment stage at the time of the deal Deal size
07122018 Immatics-Genmab Preclinical Up to $28B
04042018 OSE Immunotherapeutics-Boehringer Ingelheim Preclinical Up to euro113B ($139B)
02092018 Pieris Pharmaceuticals-Seattle Genetics Preclinical Up to $123B
2142018 Nektar-BMS Ph III Up to $36B
01222018 Juno-Celgene Ph II $9B (Acquisition)
11142017 Loxo-Bayer Larotrectinib (Ph II) LOXO-195 (Ph III) Up to $155B
1032017 CytomX-Amgen Preclinical Up to $15B
03202017 CytomX--BMS Ph III Up to $36B
6282016 Xencor-Novartis Preclinical Up to $24B
Early Stage Clinical Studies (Comparison)
We compared the interim data of Ph IIIa study of Bria-IMTtrade in advanced breast cancer with thedata in the early stage clinical studies of recently approved breast cancer drugs and one fasttracked product candidate
Apples to apples comparison Early Stage Clinical Studies in oncology are typically done in patientswith no other therapeutic options Thus the patients have very advanced disease and response ratesare typically quite low
The patients in our Ph IIIa study have been heavily pre-treated (median 45 prior regimens)Some recent studies of relevance in breast cancer are noted in the following slides
36
Breast Cancer Market Opportunity
Drug Technology Approved for Market (US)Ibrance (palbociclib) CDK 46 Inhibitor HR+HER2- MBC in combination with
fluvestrant or aromatase inhibitor$933M in 1Q2018 $3126M in 2017
Kisqali (ribociclib) CDK 46 Inhibitor 2017 HR+HER2- MBC in combination with fluvestrant or aromatase inhibitor
Peak sales projected at $25B
Verzenio (abemaciclib) CDK 46 Inhibitor 2017 HR+HER2- MBC in combination with fluvestrant or aromatase inhibitor
balixafortide CXCR4 antagonist Fast track designation in 2018 for HER2- MBC who have failed 2 prior regimens
The market for breast cancer drugs is a multibillion dollar market with new drugs being approvedon an ongoing basis indicating the shortage of safe and effective treatments for this deadly disease
37
Competitors- Phase III Clinical Data Bria-IMTtrade shows superior safety and similar to superior efficacy data compared with those of the multi-billion dollar drugs when they were at a similar early stage of clinical development
Injection site reactions No related SAEs or SUSARs
Tumor vol darr ampor darr circul tumor cellsAll Comers 21(419) 26(519)One or More HLA matches 27(415) 33(515)Two or More HLA matches 50 (24) 75 (34)
Sheet1 (3)
Comp -Slides
Data
HLA (2)
HLA
Data (Ph1-2+4Pt)
Competitors (2018)-Slide
Competitors (2018)
In the Pipeline Protein Kinase C delta (PKCδ) Inhibitors
30 of all human malignancies display activating RAS mutations Another 60 showing over-activity of Ras-signaling pathways
Ras has been termed ldquoundruggablerdquo (no one has been able to make a Ras inhibitor drug)
BriaCellrsquos novel proprietary PKCδ inhibitors have shown activity against multiple RAS transformed tumors Lung cancer Melanoma Breast cancer Neuroendocrine cancer Pancreatic cancer Colorectal cancer
This target has an attractive safety profile based on in vivo studies and knock out mouse studies
PKCδ inhibitors should qualify for an accelerated clinical development plan and regulatory pathway
Could be in clinic within 24 months
Cost-Effective Additional Shot-on-Goal and additional partnership opportunities
Early-Stage Preclinical Program
39
Protein Kinase C delta (PKCδ) Inhibitors
Activated PKCδ inhibits RAS degradation which in turn stimulates tumor growth
Koo et al Oncotarget 621328 2016
30 of all human malignancies display activating RASmutations with another 60 showing over-activity of Ras-signaling pathways
BriaCellrsquos novel proprietary PKCδ inhibitors have shownactivity against multiple RAS transformed tumors
This target has an attractive safety profile based on in vivostudies and knock out mouse studies
PKCδ also has potential activity as an immunotherapeuticby blocking TGFβ signaling
PKCδ inhibitors are applicable to specific niche tumor typeswhich provide an accelerated clinical development plan
Structural aspects of first generation inhibitor rottlerin and staurosporine (pan-PKC activator) were combined to create second generation inhibitor KAM1
Third generation inhibitors such as BJE6-106 have improved potency and selectivity Fourth generation inhibitors under development to optimize drug-like characteristics PKCδ inhibitors lack endothelial cell cytotoxicity amp PKCδ deficient mice develop normally and are fertile Potentially no marked intrinsic toxicity by inhibiting PKCδ
Mukai H Saeki T Shimada K Naito Y Matsubara N Nakanishi T Obaishi H Namiki M Sasaki Y Phase 1 combination study of eribulin mesylate with trastuzumab for advanced or recurrent human epidermal growth factor receptor 2 positive breast cancer Invest New Drugs 2015 Feb33(1)119-27
AstraZeneca
Lynparza (Olaparib) + Cediranib
PARP inhibitor + inhibitor of VEGF receptor tyrosine kinases
HR+ HER2- MBC
BC amp OC
2013
28 (8 BC)
3 for BC
Olaparib (a poly (ADP-ribose) polymerase (PARP) inhibitor) amp Cediranib (Vascular endothelial growth factor receptor (VEGFR) 1 2 and 3 tyrosine kinase inhibitor)3 at dose level (DL) 0 (cediranib 20mg olaparib 100mg) 3 at DL1 (cediranib 20mg olaparib 200mg) 7 at DL2 (cediranib 30mg olaparib 200mg) 6 at DL3 (cediranib 30mg olaparib 400mg)
Liu JF Tolaney SM Birrer M Fleming GF Buss MK Dahlberg SE Lee H Whalen C Tyburski K Winer E Ivy P Matulonis UA A Phase 1 trial of the poly(ADP-ribose) polymerase inhibitor olaparib (AZD2281) in combination with the anti-angiogenic cediranib (AZD2171) in recurrent epithelial ovarian or triple-negative breast cancer Eur J Cancer 2013 Sep49(14)2972-8
Reyon Pharmaceutical
VM206RY
Heterologous prime-boost with a truncated HER2 sequence
HER2+ Stage IIIampIV BC
2015
9
2 chemo
Plasmid DNA (pHM-GM-CSF expressing truncated HER2 amp GM-CSF) amp adenoviral vector (Ad-HM containing modified HER2) (2 4 and 8 mgpatientvisit) of pHM-GM-CSF 3x IM weeks 0 2 and 4 Ad-HM 3 times 109 virus particles at week 6
11 PR
4 pts showed 7 minor AEs
Unclear
Kim SB Ahn JH Kim J Jung KH A phase 1 study of a heterologous prime-boost vaccination involving a truncated HER2 sequence in patients with HER2-expressing breast cancer Mol Ther Methods Clin Dev 2015 Sep 30215031 doi 101038mtm201531 eCollection 2015
Rodon J Peacuterez-Fidalgo A Krop IE Burris H Guerrero-Zotano A Britten CD Becerra C Schellens J Richards DA Schuler M Abu-Khalaf M Johnson FM Ranson M Edenfield J Silva AP Hackl W Quadt C Demanse D Duval V Baselga J Phase 11b dose escalation and expansion study of BEZ235 a dual PI3KmTOR inhibitor in patients with advanced solid tumors including patients with advanced breast cancer Cancer Chemother Pharmacol 2018 Jun 7 doi 101007s00280-018-3610-z [Epub ahead of print]
Celgene (Abraxane)
Gemcitabine + Abraxane (nab-paclitaxel)
Chemo + Chemo
OC BC NSCLC amp Panc cancer + Lung OC BC Kaposi sarcoma
MBC
2016
9
Adjuvant chemo (100)chemo post-adjuvant (33)
Gem (nucleoside metabolic inhibitor 1250 mgm2) on days 1 and 8 nab-Pac (microtubule inhibitor) starting dose of 180 mgm2 (cohort 1) 220 mgm2 (cohort 2) and 260 mgm2 (cohort 3) on day 1 of the 21-day cycle using a 3 + 3 design
0
MTD not reached29 Gr3 Neutropenia59 Gr1 Peripheralneuropathy
Yoshitomi S Taira N Doihara H Mizoo T Nogami T Iwamoto T Motoki T Shien T Ogasawara Y Matsuoka J Tsuji H Mitsuhashi T A phase 1 dose-finding and pharmacokinetic study of gemcitabine with nab-paclitaxel in patients with metastatic breast cancer Cancer Chemother Pharmacol 2016 Aug78(2)289-94
Eli Lilly
Erbituxreg (cetuximab) + Taxane
EGFR inhibitor antineoplastic agent + Chemo
Headamp Neck Colorectal Cancer
TNBC
2007-2010
18
1 chemo
Cetuximab (epidermal growth factor receptor (EGFR) antagonist ) an initial loading dose of cetuximab 400 mgm2 followed by a weekly dose of 250 mgm2Paclitaxel (microtubule inhibitor) 80 mgm2 or Docetaxel at an initial dose of 30 mgm2 was administered weekly
56 CR 22 PR
83 Dermatologic toxicity11 Grade3+
Nechushtan H Vainer G Stainberg H Salmon AY Hamburger T Peretz T A phase 12 of a combination of cetuximab and taxane for triple negative breast cancer patients Breast 2014 Aug23(4)435-8
Polyphor
Balixafortide (POL6326) + eribulin
CXCR4 antagonist + tubulin-based antimitotic
Heavily pretreated Relapsed MBC
2014-2016
56
3rd line 3 chemo
3+3 dose escalation The highest dose was established as eribulin 14 mgmsup2 on days 2 and 9 and balixafortide 55 mgkg on days 1minus3 and 8minus10 of the 21-day cycle
30 PR
41 Gr34 Neutropenia11 Gr34 Leucopenia11 Gr34 Febrileneutropenia2 Related mortalities
Apr 2018 Fast Track for HER2-MBC who have failed 2prior regimens
Pernas S Martin M Kaufman PA Gil-Martin M Gomez Pardo P Lopez-Tarruella S Manso L Ciruelos E Perez-Fidalgo JA Hernando C Ademuyiwa FO Weilbaecher K Mayer I Pluard TJ Martinez Garcia M Vahdat L Perez-Garcia J Wach A Barker D Fung S Romagnoli B Cortes J Balixafortide plus eribulin in HER2-negative metastatic breast cancer a phase 1 single-arm dose-escalation trial Lancet Oncol 2018 Jun19(6)812-824
11 PRndashbut only + letrozole (No Resp on monotherapy)
61 Gr34 Neutropenia39 Gr34 Leucopenia
$933M in 1Q2018 $31B in 2017
Tamura K Mukai H Naito Y Yonemori K Kodaira M Tanabe Y Yamamoto N Osera S Sasaki M Mori Y Hashigaki S Nagasawa T Umeyama Y Yoshino T Phase I study of palbociclib a cyclin-dependent kinase 46 inhibitor in Japanese patients Cancer Sci 2016 Jun107(6)755-63 doi 101111cas12932 Epub 2016 May 11
Pfizer
Ibrancereg (palbociclib)
CDK 46 Inhibitor
HR+ HER2- MBC
Heavily pretreated Relapsed Metastatic Cancer
2004-2008
41 (5 BC)
chemo naiumlve (17) 1-2 (51)3 (29) 3+ (2)
Palbociclib 25-150 mg dose ranging
0
20 Gr34 Neutropenia23 Gr34 Leucopenia
$933M in 1Q2018 $31B in 2017
Flaherty KT Lorusso PM Demichele A Abramson VG Courtney R Randolph SS Shaik MN Wilner KD ODwyer PJ Schwartz GK Phase I dose-escalation trial of the oral cyclin-dependent kinase 46 inhibitor PD 0332991 administered using a 21-day schedule in patients with advanced cancer Clin Cancer Res 2012 Jan 1518(2)568-76 doi 1011581078-0432CCR-11-0509 Epub 2011 Nov 16
Novartis
Kisqalireg (ribociclib)
CDK 46 Inhibitors
Premenopausal HR+ HER2- MBC
Heavily pretreated Relapsed Metastatic Cancer
2016
132 (20 BC)
0-1 (25) 2-3 (42) 4+ (32)
Ribociclib 50 mg ranging up to 1200 mg dose escalation
23 PRndashincluded 1 in BC (5 of BC pts)
27 Gr34 Neutropenia17 Gr34 Leucopenia
Peak sales projected at $25B
Infante JR Cassier PA Gerecitano JF Witteveen PO Chugh R Ribrag V Chakraborty A Matano A Dobson JR Crystal AS Parasuraman S Shapiro GI A Phase I Study of the Cyclin-Dependent Kinase 46 Inhibitor Ribociclib (LEE011) in Patients with Advanced Solid Tumors and Lymphomas Clin Cancer Res 2016 Dec 122(23)5696-5705 Epub 2016 Aug 19
Eli Lilly
Verzenioreg (abemaciclib)
CDK 46 Inhibitors
HR+HER2minusMBC
Heavily pretreated Relapsed Metastatic Cancer
2016
12 (1 BC)
1 (312) 2 (212) 3+ (7)
Abemaciclib 100 mg ranging up to 200 mg dose escalation
17 PR (included 1 in BC)
17 Gr34 Neutropenia33 Gr34 Leucopenia
Peak sales projected at $2B
Fujiwara Y Tamura K Kondo S Tanabe Y Iwasa S Shimomura A Kitano S Ogasawara K Turner PK Mori J Asou H Chan EM Yamamoto N Phase 1 study of abemaciclib an inhibitor of CDK 4 and 6 as a single agent for Japanese patients with advanced cancer Cancer Chemother Pharmacol 2016 Aug78(2)281-8 doi 101007s00280-016-3085-8 Epub 2016 Jun 16
Mukai H Saeki T Shimada K Naito Y Matsubara N Nakanishi T Obaishi H Namiki M Sasaki Y Phase 1 combination study of eribulin mesylate with trastuzumab for advanced or recurrent human epidermal growth factor receptor 2 positive breast cancer Invest New Drugs 2015 Feb33(1)119-27
AstraZeneca
Lynparza (Olaparib)+ Cediranib
PARP inhibitor+ inhibitor of VEGF RTK
HR+ HER2- MBC
BC amp OC
13
28 (8 BC)
3 for BC
Olaparib (a poly (ADP-ribose) polymerase (PARP) inhibitor) amp Cediranib (Vascular endothelial growth factor receptor (VEGFR) 1 2 and 3 tyrosine kinase inhibitor)3 at dose level (DL) 0 (cediranib 20mg olaparib 100mg) 3 at DL1 (cediranib 20mg olaparib 200mg) 7 at DL2 (cediranib 30mg olaparib 200mg) 6 at DL3 (cediranib 30mg olaparib 400mg)
Liu JF Tolaney SM Birrer M Fleming GF Buss MK Dahlberg SE Lee H Whalen C Tyburski K Winer E Ivy P Matulonis UA A Phase 1 trial of the poly(ADP-ribose) polymerase inhibitor olaparib (AZD2281) in combination with the anti-angiogenic cediranib (AZD2171) in recurrent epithelial ovarian or triple-negative breast cancer Eur J Cancer 2013 Sep49(14)2972-8
ReyonPharma
VM206RY
Heterologous prime-boost with a truncated HER2 sequence
HER2+ Stg IIIampIV BC
15
9
2 chemo
Plasmid DNA (pHM-GM-CSF expressing truncated HER2 amp GM-CSF) amp adenoviral vector (Ad-HM containing modified HER2) (2 4 and 8 mgpatientvisit) of pHM-GM-CSF 3x IM weeks 0 2 and 4 Ad-HM 3 times 109 virus particles at week 6
11 PR
4 pts 7 minor AEs
Unclear
Kim SB Ahn JH Kim J Jung KH A phase 1 study of a heterologous prime-boost vaccination involving a truncated HER2 sequence in patients with HER2-expressing breast cancer Mol Ther Methods Clin Dev 2015 Sep 30215031 doi 101038mtm201531 eCollection 2015
Rodon J Peacuterez-Fidalgo A Krop IE Burris H Guerrero-Zotano A Britten CD Becerra C Schellens J Richards DA Schuler M Abu-Khalaf M Johnson FM Ranson M Edenfield J Silva AP Hackl W Quadt C Demanse D Duval V Baselga J Phase 11b dose escalation and expansion study of BEZ235 a dual PI3KmTOR inhibitor in patients with advanced solid tumors including patients with advanced breast cancer Cancer Chemother Pharmacol 2018 Jun 7 doi 101007s00280-018-3610-z [Epub ahead of print]
Celgene(Abraxane)
Gemcitabine + Abraxane (nab-paclitaxel)
Chemo+ Chemo
OC BC NSCLC PC + LC OC BC KS
MBC
16
9
Adjuv chemo (100)chemo post-adjuv (33)
Gem (nucleoside metabolic inhibitor 1250 mgm2) on days 1 and 8 nab-Pac (microtubule inhibitor) starting dose of 180 mgm2 (cohort 1) 220 mgm2 (cohort 2) and 260 mgm2 (cohort 3) on day 1 of the 21-day cycle using a 3 + 3 design
0
MTD not reached29 Gr3 Neutropenia59 Gr1 Peripheralneuropathy
Yoshitomi S Taira N Doihara H Mizoo T Nogami T Iwamoto T Motoki T Shien T Ogasawara Y Matsuoka J Tsuji H Mitsuhashi T A phase 1 dose-finding and pharmacokinetic study of gemcitabine with nab-paclitaxel in patients with metastatic breast cancer Cancer Chemother Pharmacol 2016 Aug78(2)289-94
Eli Lilly
Erbituxreg (cetuximab) + Taxane
EGFR inhibitor antineoplastic agent + Chemo
Head amp NeckColorectal
TNBC
07-10
18
1 chemo
Cetuximab (epidermal growth factor receptor (EGFR) antagonist ) an initial loading dose of cetuximab 400 mgm2 followed by a weekly dose of 250 mgm2Paclitaxel (microtubule inhibitor) 80 mgm2 or Docetaxel at an initial dose of 30 mgm2 was administered weekly
56 CR 22 PR
83 Dermatologic toxicity11 Grade3+
Nechushtan H Vainer G Stainberg H Salmon AY Hamburger T Peretz T A phase 12 of a combination of cetuximab and taxane for triple negative breast cancer patients Breast 2014 Aug23(4)435-8
Polyphor
Balixafortide (POL6326) + eribulin
CXCR4 antagonist + tubulin-based antimitotic
Heavily pretreatedRelapsed MBC
14-16
56
3rd line 3 chemo
3+3 dose escalation The highest dose was established as eribulin 14 mgmsup2 on days 2 and 9 and balixafortide 55 mgkg on days 1minus3 and 8minus10 of the 21-day cycle
30 PR
41 Gr34 Neutropenia11 Gr34 Leucopenia11 Gr34 Febrileneutropenia2 Related mortalities
42018 Fast Track (HER2-MBC failed 2 prior regimens)
Pernas S Martin M Kaufman PA Gil-Martin M Gomez Pardo P Lopez-Tarruella S Manso L Ciruelos E Perez-Fidalgo JA Hernando C Ademuyiwa FO Weilbaecher K Mayer I Pluard TJ Martinez Garcia M Vahdat L Perez-Garcia J Wach A Barker D Fung S Romagnoli B Cortes J Balixafortide plus eribulin in HER2-negative metastatic breast cancer a phase 1 single-arm dose-escalation trial Lancet Oncol 2018 Jun19(6)812-824
1 PRndashbut only + letrozoleNo Resp on monotherapy
61 Gr34 Neutropenia39 Gr34 Leucopenia
$933M (1Q18)$31B (2017)
Tamura K Mukai H Naito Y Yonemori K Kodaira M Tanabe Y Yamamoto N Osera S Sasaki M Mori Y Hashigaki S Nagasawa T Umeyama Y Yoshino T Phase I study of palbociclib a cyclin-dependent kinase 46 inhibitor in Japanese patients Cancer Sci 2016 Jun107(6)755-63 doi 101111cas12932 Epub 2016 May 11
Pfizer
Ibrancereg (palbociclib)
CDK 46 Inhibitor
HR+ HER2- MBC
Heavily pretreatedRelapsed Met Cancer
04-08
41 (5 BC)
chemo naiumlve (17)1-2(51) 3(29) 3+(2)
Palbociclib 25-150 mg dose ranging
0
20 Gr34 Neutropenia23 Gr34 Leucopenia
$933M (1Q18)$31B (2017)
Flaherty KT Lorusso PM Demichele A Abramson VG Courtney R Randolph SS Shaik MN Wilner KD ODwyer PJ Schwartz GK Phase I dose-escalation trial of the oral cyclin-dependent kinase 46 inhibitor PD 0332991 administered using a 21-day schedule in patients with advanced cancer Clin Cancer Res 2012 Jan 1518(2)568-76 doi 1011581078-0432CCR-11-0509 Epub 2011 Nov 16
Novartis
Kisqalireg (ribociclib)
CDK 46 Inhibitor
Premenopausal HR+ HER2- MBC
Heavily pretreatedRelapsed Met Cancer
16
132 (20 BC)
0-1 (25) 2-3 (42)4+ (32)
Ribociclib 50 mg ranging up to 1200 mg dose escalation
23 PR-included 1 BC (5 of BC pts)
27 Gr34 Neutropenia17 Gr34 Leucopenia
Peak sales est at $25B
Infante JR Cassier PA Gerecitano JF Witteveen PO Chugh R Ribrag V Chakraborty A Matano A Dobson JR Crystal AS Parasuraman S Shapiro GI A Phase I Study of the Cyclin-Dependent Kinase 46 Inhibitor Ribociclib (LEE011) in Patients with Advanced Solid Tumors and Lymphomas Clin Cancer Res 2016 Dec 122(23)5696-5705 Epub 2016 Aug 19
Eli Lilly
Verzenioreg (abemaciclib)
CDK 46 Inhibitor
HR+HER2minusMBC
Heavily pretreatedRelapsed Met Cancer
16
12 (1 BC)
1 (312) 2 (212) 3+(7)
Abemaciclib 100 mg ranging up to 200 mg dose escalation
17 PR (included 1 BC)
17 Gr34 Neutropenia33 Gr34 Leucopenia
Peak sales est at $2B
Fujiwara Y Tamura K Kondo S Tanabe Y Iwasa S Shimomura A Kitano S Ogasawara K Turner PK Mori J Asou H Chan EM Yamamoto N Phase 1 study of abemaciclib an inhibitor of CDK 4 and 6 as a single agent for Japanese patients with advanced cancer Cancer Chemother Pharmacol 2016 Aug78(2)281-8 doi 101007s00280-016-3085-8 Epub 2016 Jun 16
Mukai H Saeki T Shimada K Naito Y Matsubara N Nakanishi T Obaishi H Namiki M Sasaki Y Phase 1 combination study of eribulin mesylate with trastuzumab for advanced or recurrent human epidermal growth factor receptor 2 positive breast cancer Invest New Drugs 2015 Feb33(1)119-27
AstraZeneca
Lynparza (Olaparib) + Cediranib
PARP inhibitor + inhibitor of VEGF receptor tyrosine kinases
HR+ HER2- MBC
BC amp OC
2013
28 (8 BC)
3 for BC
Olaparib (a poly (ADP-ribose) polymerase (PARP) inhibitor) amp Cediranib (Vascular endothelial growth factor receptor (VEGFR) 1 2 and 3 tyrosine kinase inhibitor)3 at dose level (DL) 0 (cediranib 20mg olaparib 100mg) 3 at DL1 (cediranib 20mg olaparib 200mg) 7 at DL2 (cediranib 30mg olaparib 200mg) 6 at DL3 (cediranib 30mg olaparib 400mg)
Liu JF Tolaney SM Birrer M Fleming GF Buss MK Dahlberg SE Lee H Whalen C Tyburski K Winer E Ivy P Matulonis UA A Phase 1 trial of the poly(ADP-ribose) polymerase inhibitor olaparib (AZD2281) in combination with the anti-angiogenic cediranib (AZD2171) in recurrent epithelial ovarian or triple-negative breast cancer Eur J Cancer 2013 Sep49(14)2972-8
Reyon Pharmaceutical
VM206RY
Heterologous prime-boost with a truncated HER2 sequence
HER2+ Stage IIIampIV BC
2015
9
2 chemo
Plasmid DNA (pHM-GM-CSF expressing truncated HER2 amp GM-CSF) amp adenoviral vector (Ad-HM containing modified HER2) (2 4 and 8 mgpatientvisit) of pHM-GM-CSF 3x IM weeks 0 2 and 4 Ad-HM 3 times 109 virus particles at week 6
11 PR
4 pts showed 7 minor AEs
Unclear
Kim SB Ahn JH Kim J Jung KH A phase 1 study of a heterologous prime-boost vaccination involving a truncated HER2 sequence in patients with HER2-expressing breast cancer Mol Ther Methods Clin Dev 2015 Sep 30215031 doi 101038mtm201531 eCollection 2015
Rodon J Peacuterez-Fidalgo A Krop IE Burris H Guerrero-Zotano A Britten CD Becerra C Schellens J Richards DA Schuler M Abu-Khalaf M Johnson FM Ranson M Edenfield J Silva AP Hackl W Quadt C Demanse D Duval V Baselga J Phase 11b dose escalation and expansion study of BEZ235 a dual PI3KmTOR inhibitor in patients with advanced solid tumors including patients with advanced breast cancer Cancer Chemother Pharmacol 2018 Jun 7 doi 101007s00280-018-3610-z [Epub ahead of print]
Celgene (Abraxane)
Gemcitabine + Abraxane (nab-paclitaxel)
Chemo + Chemo
OC BC NSCLC amp Panc cancer + Lung OC BC Kaposi sarcoma
MBC
2016
9
Adjuvant chemo (100)chemo post-adjuvant (33)
Gem (nucleoside metabolic inhibitor 1250 mgm2) on days 1 and 8 nab-Pac (microtubule inhibitor) starting dose of 180 mgm2 (cohort 1) 220 mgm2 (cohort 2) and 260 mgm2 (cohort 3) on day 1 of the 21-day cycle using a 3 + 3 design
0
MTD not reached29 Gr3 Neutropenia59 Gr1 Peripheralneuropathy
Yoshitomi S Taira N Doihara H Mizoo T Nogami T Iwamoto T Motoki T Shien T Ogasawara Y Matsuoka J Tsuji H Mitsuhashi T A phase 1 dose-finding and pharmacokinetic study of gemcitabine with nab-paclitaxel in patients with metastatic breast cancer Cancer Chemother Pharmacol 2016 Aug78(2)289-94
Eli Lilly
Erbituxreg (cetuximab) + Taxane
EGFR inhibitor antineoplastic agent + Chemo
Headamp Neck Colorectal Cancer
TNBC
2007-2010
18
1 chemo
Cetuximab (epidermal growth factor receptor (EGFR) antagonist ) an initial loading dose of cetuximab 400 mgm2 followed by a weekly dose of 250 mgm2Paclitaxel (microtubule inhibitor) 80 mgm2 or Docetaxel at an initial dose of 30 mgm2 was administered weekly
56 CR 22 PR
83 Dermatologic toxicity11 Grade3+
Nechushtan H Vainer G Stainberg H Salmon AY Hamburger T Peretz T A phase 12 of a combination of cetuximab and taxane for triple negative breast cancer patients Breast 2014 Aug23(4)435-8
Polyphor
Balixafortide (POL6326) + eribulin
CXCR4 antagonist + tubulin-based antimitotic
Heavily pretreated Relapsed MBC
2014-2016
56
3rd line 3 chemo
3+3 dose escalation The highest dose was established as eribulin 14 mgmsup2 on days 2 and 9 and balixafortide 55 mgkg on days 1minus3 and 8minus10 of the 21-day cycle
30 PR
41 Gr34 Neutropenia11 Gr34 Leucopenia11 Gr34 Febrileneutropenia2 Related mortalities
Apr 2018 Fast Track for HER2-MBC who have failed 2prior regimens
Pernas S Martin M Kaufman PA Gil-Martin M Gomez Pardo P Lopez-Tarruella S Manso L Ciruelos E Perez-Fidalgo JA Hernando C Ademuyiwa FO Weilbaecher K Mayer I Pluard TJ Martinez Garcia M Vahdat L Perez-Garcia J Wach A Barker D Fung S Romagnoli B Cortes J Balixafortide plus eribulin in HER2-negative metastatic breast cancer a phase 1 single-arm dose-escalation trial Lancet Oncol 2018 Jun19(6)812-824
11 PRndashbut only + letrozole (No Resp on monotherapy)
61 Gr34 Neutropenia39 Gr34 Leucopenia
$933M in 1Q2018 $31B in 2017
Tamura K Mukai H Naito Y Yonemori K Kodaira M Tanabe Y Yamamoto N Osera S Sasaki M Mori Y Hashigaki S Nagasawa T Umeyama Y Yoshino T Phase I study of palbociclib a cyclin-dependent kinase 46 inhibitor in Japanese patients Cancer Sci 2016 Jun107(6)755-63 doi 101111cas12932 Epub 2016 May 11
Pfizer
Ibrancereg (palbociclib)
CDK 46 Inhibitor
HR+ HER2- MBC
Heavily pretreated Relapsed Metastatic Cancer
2004-2008
41 (5 BC)
chemo naiumlve (17) 1-2 (51)3 (29) 3+ (2)
Palbociclib 25-150 mg dose ranging
0
20 Gr34 Neutropenia23 Gr34 Leucopenia
$933M in 1Q2018 $31B in 2017
Flaherty KT Lorusso PM Demichele A Abramson VG Courtney R Randolph SS Shaik MN Wilner KD ODwyer PJ Schwartz GK Phase I dose-escalation trial of the oral cyclin-dependent kinase 46 inhibitor PD 0332991 administered using a 21-day schedule in patients with advanced cancer Clin Cancer Res 2012 Jan 1518(2)568-76 doi 1011581078-0432CCR-11-0509 Epub 2011 Nov 16
Novartis
Kisqalireg (ribociclib)
CDK 46 Inhibitors
Premenopausal HR+ HER2- MBC
Heavily pretreated Relapsed Metastatic Cancer
2016
132 (20 BC)
0-1 (25) 2-3 (42) 4+ (32)
Ribociclib 50 mg ranging up to 1200 mg dose escalation
23 PRndashincluded 1 in BC (5 of BC pts)
27 Gr34 Neutropenia17 Gr34 Leucopenia
Peak sales projected at $25B
Infante JR Cassier PA Gerecitano JF Witteveen PO Chugh R Ribrag V Chakraborty A Matano A Dobson JR Crystal AS Parasuraman S Shapiro GI A Phase I Study of the Cyclin-Dependent Kinase 46 Inhibitor Ribociclib (LEE011) in Patients with Advanced Solid Tumors and Lymphomas Clin Cancer Res 2016 Dec 122(23)5696-5705 Epub 2016 Aug 19
Eli Lilly
Verzenioreg (abemaciclib)
CDK 46 Inhibitors
HR+HER2minusMBC
Heavily pretreated Relapsed Metastatic Cancer
2016
12 (1 BC)
1 (312) 2 (212) 3+ (7)
Abemaciclib 100 mg ranging up to 200 mg dose escalation
17 PR (included 1 in BC)
17 Gr34 Neutropenia33 Gr34 Leucopenia
Peak sales projected at $2B
Fujiwara Y Tamura K Kondo S Tanabe Y Iwasa S Shimomura A Kitano S Ogasawara K Turner PK Mori J Asou H Chan EM Yamamoto N Phase 1 study of abemaciclib an inhibitor of CDK 4 and 6 as a single agent for Japanese patients with advanced cancer Cancer Chemother Pharmacol 2016 Aug78(2)281-8 doi 101007s00280-016-3085-8 Epub 2016 Jun 16
Mukai H Saeki T Shimada K Naito Y Matsubara N Nakanishi T Obaishi H Namiki M Sasaki Y Phase 1 combination study of eribulin mesylate with trastuzumab for advanced or recurrent human epidermal growth factor receptor 2 positive breast cancer Invest New Drugs 2015 Feb33(1)119-27
AstraZeneca
Lynparza (Olaparib)+ Cediranib
PARP inhibitor+ inhibitor of VEGF RTK
HR+ HER2- MBC
BC amp OC
13
28 (8 BC)
3 for BC
Olaparib (a poly (ADP-ribose) polymerase (PARP) inhibitor) amp Cediranib (Vascular endothelial growth factor receptor (VEGFR) 1 2 and 3 tyrosine kinase inhibitor)3 at dose level (DL) 0 (cediranib 20mg olaparib 100mg) 3 at DL1 (cediranib 20mg olaparib 200mg) 7 at DL2 (cediranib 30mg olaparib 200mg) 6 at DL3 (cediranib 30mg olaparib 400mg)
Liu JF Tolaney SM Birrer M Fleming GF Buss MK Dahlberg SE Lee H Whalen C Tyburski K Winer E Ivy P Matulonis UA A Phase 1 trial of the poly(ADP-ribose) polymerase inhibitor olaparib (AZD2281) in combination with the anti-angiogenic cediranib (AZD2171) in recurrent epithelial ovarian or triple-negative breast cancer Eur J Cancer 2013 Sep49(14)2972-8
ReyonPharma
VM206RY
Heterologous prime-boost with a truncated HER2 sequence
HER2+ Stg IIIampIV BC
15
9
2 chemo
Plasmid DNA (pHM-GM-CSF expressing truncated HER2 amp GM-CSF) amp adenoviral vector (Ad-HM containing modified HER2) (2 4 and 8 mgpatientvisit) of pHM-GM-CSF 3x IM weeks 0 2 and 4 Ad-HM 3 times 109 virus particles at week 6
11 PR
4 pts 7 minor AEs
Unclear
Kim SB Ahn JH Kim J Jung KH A phase 1 study of a heterologous prime-boost vaccination involving a truncated HER2 sequence in patients with HER2-expressing breast cancer Mol Ther Methods Clin Dev 2015 Sep 30215031 doi 101038mtm201531 eCollection 2015
Rodon J Peacuterez-Fidalgo A Krop IE Burris H Guerrero-Zotano A Britten CD Becerra C Schellens J Richards DA Schuler M Abu-Khalaf M Johnson FM Ranson M Edenfield J Silva AP Hackl W Quadt C Demanse D Duval V Baselga J Phase 11b dose escalation and expansion study of BEZ235 a dual PI3KmTOR inhibitor in patients with advanced solid tumors including patients with advanced breast cancer Cancer Chemother Pharmacol 2018 Jun 7 doi 101007s00280-018-3610-z [Epub ahead of print]
Celgene(Abraxane)
Gemcitabine + Abraxane (nab-paclitaxel)
Chemo+ Chemo
OC BC NSCLC PC + LC OC BC KS
MBC
16
9
Adjuv chemo (100)chemo post-adjuv (33)
Gem (nucleoside metabolic inhibitor 1250 mgm2) on days 1 and 8 nab-Pac (microtubule inhibitor) starting dose of 180 mgm2 (cohort 1) 220 mgm2 (cohort 2) and 260 mgm2 (cohort 3) on day 1 of the 21-day cycle using a 3 + 3 design
0
MTD not reached29 Gr3 Neutropenia59 Gr1 Peripheralneuropathy
Yoshitomi S Taira N Doihara H Mizoo T Nogami T Iwamoto T Motoki T Shien T Ogasawara Y Matsuoka J Tsuji H Mitsuhashi T A phase 1 dose-finding and pharmacokinetic study of gemcitabine with nab-paclitaxel in patients with metastatic breast cancer Cancer Chemother Pharmacol 2016 Aug78(2)289-94
Eli Lilly
Erbituxreg (cetuximab) + Taxane
EGFR inhibitor antineoplastic agent + Chemo
Head amp NeckColorectal
TNBC
07-10
18
1 chemo
Cetuximab (epidermal growth factor receptor (EGFR) antagonist ) an initial loading dose of cetuximab 400 mgm2 followed by a weekly dose of 250 mgm2Paclitaxel (microtubule inhibitor) 80 mgm2 or Docetaxel at an initial dose of 30 mgm2 was administered weekly
56 CR 22 PR
83 Dermatologic toxicity11 Grade3+
Nechushtan H Vainer G Stainberg H Salmon AY Hamburger T Peretz T A phase 12 of a combination of cetuximab and taxane for triple negative breast cancer patients Breast 2014 Aug23(4)435-8
Polyphor
Balixafortide (POL6326) + eribulin
CXCR4 antagonist + tubulin-based antimitotic
Heavily pretreatedRelapsed MBC
14-16
56
3rd line 3 chemo
3+3 dose escalation The highest dose was established as eribulin 14 mgmsup2 on days 2 and 9 and balixafortide 55 mgkg on days 1minus3 and 8minus10 of the 21-day cycle
30 PR
41 Gr34 Neutropenia11 Gr34 Leucopenia11 Gr34 Febrileneutropenia2 Related mortalities
42018 Fast Track (HER2-MBC failed 2 prior regimens)
Pernas S Martin M Kaufman PA Gil-Martin M Gomez Pardo P Lopez-Tarruella S Manso L Ciruelos E Perez-Fidalgo JA Hernando C Ademuyiwa FO Weilbaecher K Mayer I Pluard TJ Martinez Garcia M Vahdat L Perez-Garcia J Wach A Barker D Fung S Romagnoli B Cortes J Balixafortide plus eribulin in HER2-negative metastatic breast cancer a phase 1 single-arm dose-escalation trial Lancet Oncol 2018 Jun19(6)812-824
1 PRndashbut only + letrozoleNo Resp on monotherapy
61 Gr34 Neutropenia39 Gr34 Leucopenia
$933M (1Q18)$31B (2017)
Tamura K Mukai H Naito Y Yonemori K Kodaira M Tanabe Y Yamamoto N Osera S Sasaki M Mori Y Hashigaki S Nagasawa T Umeyama Y Yoshino T Phase I study of palbociclib a cyclin-dependent kinase 46 inhibitor in Japanese patients Cancer Sci 2016 Jun107(6)755-63 doi 101111cas12932 Epub 2016 May 11
Pfizer
Ibrancereg (palbociclib)
CDK 46 Inhibitor
HR+ HER2- MBC
Heavily pretreatedRelapsed Met Cancer
04-08
41 (5 BC)
chemo naiumlve (17)1-2(51) 3(29) 3+(2)
Palbociclib 25-150 mg dose ranging
0
20 Gr34 Neutropenia23 Gr34 Leucopenia
$933M (1Q18)$31B (2017)
Flaherty KT Lorusso PM Demichele A Abramson VG Courtney R Randolph SS Shaik MN Wilner KD ODwyer PJ Schwartz GK Phase I dose-escalation trial of the oral cyclin-dependent kinase 46 inhibitor PD 0332991 administered using a 21-day schedule in patients with advanced cancer Clin Cancer Res 2012 Jan 1518(2)568-76 doi 1011581078-0432CCR-11-0509 Epub 2011 Nov 16
Novartis
Kisqalireg (ribociclib)
CDK 46 Inhibitor
Premenopausal HR+ HER2- MBC
Heavily pretreatedRelapsed Met Cancer
16
132 (20 BC)
0-1 (25) 2-3 (42)4+ (32)
Ribociclib 50 mg ranging up to 1200 mg dose escalation
23 PR-included 1 BC (5 of BC pts)
27 Gr34 Neutropenia17 Gr34 Leucopenia
Peak sales est at $25B
Infante JR Cassier PA Gerecitano JF Witteveen PO Chugh R Ribrag V Chakraborty A Matano A Dobson JR Crystal AS Parasuraman S Shapiro GI A Phase I Study of the Cyclin-Dependent Kinase 46 Inhibitor Ribociclib (LEE011) in Patients with Advanced Solid Tumors and Lymphomas Clin Cancer Res 2016 Dec 122(23)5696-5705 Epub 2016 Aug 19
Eli Lilly
Verzenioreg (abemaciclib)
CDK 46 Inhibitor
HR+HER2minusMBC
Heavily pretreatedRelapsed Met Cancer
16
12 (1 BC)
1 (312) 2 (212) 3+(7)
Abemaciclib 100 mg ranging up to 200 mg dose escalation
17 PR (included 1 BC)
17 Gr34 Neutropenia33 Gr34 Leucopenia
Peak sales est at $2B
Fujiwara Y Tamura K Kondo S Tanabe Y Iwasa S Shimomura A Kitano S Ogasawara K Turner PK Mori J Asou H Chan EM Yamamoto N Phase 1 study of abemaciclib an inhibitor of CDK 4 and 6 as a single agent for Japanese patients with advanced cancer Cancer Chemother Pharmacol 2016 Aug78(2)281-8 doi 101007s00280-016-3085-8 Epub 2016 Jun 16
41 Gr34 Neutropenia11 Gr34 Leucopenia11 Gr34 Febrileneutropenia2 Related mortalities
30 PRs in combination with Halaven
Bria-IMTTM
20
Injection site reactions No related SAEs or SUSARs
Tumor vol darr ampor darr circul tumor cells)All Comers 21(419) 26(519)One or More HLA matches 27(415) 33(515)Two or More HLA matches 50 (24) 75 (34))
Drug
Technology
Approved for
Market (US)
Ibrance (palbociclib)
CDK 46 Inhibitor
HR+HER2- MBC in combination with fluvestrant or aromatase inhibitor
$933M in 1Q2018 $3126M in 2017
Kisqali (ribociclib)
CDK 46 Inhibitor
2017 HR+HER2- MBC in combination with fluvestrant or aromatase inhibitor
Peak sales projected at $25B
Verzenio (abemaciclib)
CDK 46 Inhibitor
2017 HR+HER2- MBC in combination with fluvestrant or aromatase inhibitor
Peak sales projected at $2B
Lynparza (olaparib)
Poly (ADP-ribose) polymerase (PARP) inhibitor
2017 ovarian amp breast cancer
$997M in 2017
Halaven (eribulin mesylate)
Tubulin-based antimitotic
2H2017 3rd line MBC amp liposarcoma
$181M in 2017
balixafortide
CXCR4 antagonist
Fast track designation in 2018 for HER2- MBC who have failed 2 prior regimens
Bria-IMTtradeHuman Proof-of-Concept Trials in Breast Cancer (Patient A002) Bria-IMTtrade Non-Personalized Immunotherapy ndash Given as Monotherapy
Second Proof-of-Concept Phase I (2005) 1 out of 4 patients responded with substantial tumor regression Patient A002 was the only patient with key HLA matches with Bria-IMTtrade
8
Bria-IMTtradeHuman Proof-of-Concept Trials in Breast Cancer (Patient A002) Approximately 3 months (106 days) after last inoculation Patient A002rsquos breast cancer returned and
spread to brain lung and other sites
Patient A002 was then re-treated with 10 inoculations of Bria-IMTtrade over 4 months
Repeat imaging studies showed normal findings on MRI and PET consistent with a completeremission of the previous multiple central nervous system metastases as shown in the brain scansbelow
Bria-IMTtrade and Bria-OTStrade shouldsynergize with existing approvedimmunotherapies as well as those stillunder development
This includes immune checkpointinhibitors such as antibodies to PD-1CTLA-4 GITR and CD73 inhibitors whicheliminate tumor immunosuppression Checkpoint Inhibitors were the
subject of the 2018 Nobel Prize inMedicine
In addition immunostimulatoryantibodies to molecules such as OX40should enhance responses to Bria-IMTtradeand Bria-OTStrade
13
Q3 2018 Data on first 20 Patients on Bria-IMTtrade Q3 2018 Initiate Combination Study of Bria-IMTtrade with Keytruda or Yervoy
Q4 2018 Switch to a novel frozen Bria-IMTtrade formulation Q4 2018 Safety Data (6 patients) of the Bria-IMTtrade - Keytrudareg Combination Study (SABC meeting) Q4 2018 Ongoing Corporate PartnershipCollaboration Discussions
Q1 2019 Efficacy Data (6 patients) of the Bria-IMTtrade - Keytrudareg Combination Study Q2 2019 Initiation of Bria-OTStrade GMP manufacturing (KBI BioPharma) Q2 2019 Additional Safety amp Efficacy data Monotherapy and Combination Studies (AACR meeting) Q2 2019 Final data for Monotherapy and Additional Data for the Combination Study (ASCO meeting) H1 2019 Candidate Selection for a PKCδ Inhibitor H1 2019 Initiate additional immunotherapy program H2 2019 Bria-OTStrade Authorization from FDA clearance for dosing H2 2019 Bria-OTStrade First Patient Dosed
Upcoming Milestones amp Catalysts
14
Involved in over 10 drugs brought to the market
Experienced Management Team
Management
William V Williams MD FACP President amp CEO VP Exploratory Development Incyte Corporation VP Experimental Medicine GlaxoSmithKline Head Rheumatology Research University of Pennsylvania Facilitated entry of over 20 compounds into the clinic including ruxolitinib (Jakafi)
baricitinib amp epacadostat NDAs including Jakafi Boniva Bexxar Author of over 120 peer-reviewed publications amp over 20 patents
Gadi Levin CA MBA CFO CFO of Labstyle Innovations Ltd VP of Finance for two Israeli investment houses in the fields of private equity
hedge funds and real estate Financial Consultant various firms Accountant Arthur Andersen
Markus Lacher PhD Senior Director RampD Founder T cell Therapeutics Inc an immuno-oncology company Sr Clinical Scientist Cesca Therapeutics Inc a clinical-stage autologous cell
therapy company Scientist at BioTime Inc and OncoCyte Corporation Editorial advisory board Recent Patents on Anti-Cancer Drug Discovery
Farrah Dean MSc MBA Manager Corp Development Investor relations CytRx Corporation amp CCG Investor Relations Senior Associate Equity Analyst Oppenheimer amp Co Rodman amp Renshaw amp
Brian Metcalf PhD Recently retired as CSO from Global Blood Therapeutics Former Head of Research amp Development Incyte Corporation Former Head of Medicinal Chemistry SmithKline Beecham
Douglas Faller MD PhD Professor of Medicine Pediatrics Biochemistry Microbiology Pathology and
Laboratory Medicine HematologistOncologist former Director of the Cancer Center Boston University School of Medicine
Founder of several successful biotechnology companies
Robert Williams PhD University Distinguished Professor of Chemistry Colorado State University Founder of several successful biotechnology companies including Microcide Xcyte
Therapies HemaQuest Arch Therapeutics and Cetya Therapeutics
Thomas Kieber-Emmons PhD Deputy Director University of Arkansas Cancer Center Expert in targeted cancer immunotherapies structural biology and computational
chemistry
Maria Trojanowska PhD Professor of Medicine Boston University School of Medicine Director The Arthritis Center
16
Veteran Board of Directors
Board of Directors
Saeid Babaei PhD MBA Chairman Entrepreneur 20 yrs of biotech leadership roles Current CEO AbCelex VP Bus Develop Lorus Therap Dir of Corp Develop Northern Therapeutics
Rahoul Sharan CA Director Chairman Potash Ridge Director of the Board Ansell Capital Corp Parallel Resources amp Galaxy Capital
Corporation
Martin Schmieg CPA Director CFO Sirna Therapeutics Inc amp Isolagen Inc CEO Freedom-2 Inc (now PharmaCyte Inc) Advisor Caladrius Biosciences Inc Beckman Coulter Genomics Calimmune
Charles Wiseman MD Co-Founder amp Director Director Immunotherapy Lab St Vincent Medical Center Chief Breast Cancer Basic Research Lab Univ of Texas MD Anderson Hospital amp
Tumour Institute Assist Prof Dept of Molecular Carcinogenesis amp Virology MD Anderson Acting Chief Div of Oncology White Memorial Medical Center LA
William V Williams MD FACP President amp CEO VP Exploratory Development Incyte Corporation VP Experimental Medicine GlaxoSmithKline Head Rheumatology Research University of Pennsylvania
Prior Affiliations
17
Drug Approvals by BriaCell Management Team
Bexxarreg (tositumomab and Iodine I131 tositumomab) Treatment of CD20 antigen-expressing relapsed or refractory low grade follicular or transformed non-Hodgkins lymphoma
Myleranreg (busulfan) for chronic myelogenous leukemia Defense of formulation change sNDA
Hycamtinreg (topotecan) for ovarian cancer Pediatric use sNDA
Navelbinereg (vinorelbine tartrate) for non-small cell lung cancer Pediatric use sNDA
Bonivareg (ibandronate) monthly oral treatment of osteoporosis
Bonivareg (ibandronate) quarterly intraveous treatment of osteoporosis
Zofranreg (ondansetron) for prevention of nausea and vomiting Pediatric use sNDA
Jakafireg (ruxolitinib) for myelofibrosis Jakafireg (ruxolitinib) for polycythemia vera
Olumiantreg (baricitinib) for rheumatoid arthritis Approved in USA Japan and Europe
18
Share Metrics
BCTV BCTXF 19
Data as of 1092018
Ticker TSX BCTV
US Ticker OTCQBBCTXF
Share Price (CAD) as of Oct 9 2018 $012
52-Week Range (CAD) $009-019
Shares Outstanding as of Oct 9 2018 1611M
Market Cap as of Oct 9 2018 (CAD) $193M
Cash and Short Term Investments as of July 31 2018 (CAD) $23M
Total Shareholders Equity as of July 31 2018 (CAD) $12M
Number of Warrants $014-$035 (CAD) as of Oct 9 2018 601M
Number of Compensation Warrants $014-$030 (CAD) as of Oct 9 2018 45M
Number of Options $014- $026 (CAD$) as of Oct 9 2018 93M
Developing Bria-OTStrade the First Off-the-Shelf Personalized Immunotherapy
Targeting Adv Breast Cancer Unmet medical need (42000 death in the US in 2017 ) $1 Bil- $5 Bil market opportunity depending on patient treatment stage
Impressive results in 2 proof-of-concept clinical trials Rapid Response Rate Repeated following re-treatment Excellent Safety Profile
Completed enrollment in Phase IIIa clinical trial of Bria-IMTtrade with outstanding safety amp efficacy data Initiated Phase IIa Combination Study of Bria-IMTtrade with Keytrudareg (Merck amp Co Inc)
Developing Bria-OTStrade along with BriaDXtrade its companion diagnostic test Ability to match and treat ~90 of patient population with Off-the-Shelf personalized immunotherapy
Experienced Management has been involved in over 10 drug approvals
Patient B001 Breast 70 No 1101 - 3501 4001 Negative -
Bria-IMTtradeHuman Proof-of-Concept Trials in Breast Cancer (Patient A002)
24
Proof-of-Concept Results Resulted in BriaCellrsquos Immunotherapy Strategy Use BriaDXtrade diagnostic to select only those patients matching Bria-IMTtrade Use BriaDXtrade diagnostic test to select Bria-OTStrade alleles matching ~90 of all patients
Bria-IMTtradeCurrent Phase IIIa Data Supports HLA Matching Hypothesis Six patients treated in 2017 Bria-IMTtrade was safe and well tolerated
Patient 01-002 73-year-old woman with breast cancer diagnosed in 1995 Developed liver metastases in2010 and lung metastases in 2017 Previously treated with 7 rounds of chemotherapy with 8 differentchemotherapy agents Received 5 cycles of Bria-IMTtrade over 3 months then monthly cycles (6 months total)Evaluated after 3 months and 6 months After 3 months despite the extensive prior therapy her scans notedthat ldquothere has been a clear response in the multiple bilateral pulmonary nodulesrdquo The response wasmaintained after 6 months of Bria-IMTtrade treatment She matches Bria-IMTtrade at 2 HLA alleles
The liver tumors were stable to slightly increased at 3 months and then progressed after 6 months
This supports our hypothesis of heightened anti-tumor activity in patients with a matched HLA types Clear path to develop BriaDXtrade to select the patients using HLA testing
1 RLL 29 Not Detectable Not Detectable2 LUL apical pleural based 34 tiny nodule lt 1mm scar tiny nodule lt 1mm scar3 xxx 39 Not Detectable Not Detectable4 40 Not Detectable Not Detectable5 RLL 45 Not Detectable Not Detectable6 LLL 49 Not Detectable Not Detectable7 xxx 52 Not Detectable Not Detectable8 RLL 52 Not Detectable Not Detectable9 RLL 56 Not Detectable Not Detectable
10 RLL costophrenic recess 56 Not Detectable Not Detectable11 XXX 58 Not Detectable Not Detectable12 LUL 60 Not Detectable Not Detectable13 XXX 67 15 1514 RUL 72 15 1515 LLL 76 Not Detectable Not Detectable16 RUL Noncalcified Nodule 77 Not Detectable Not Detectable17 RLL costophrenic recess 79 10 1018 RUL 82 Not Detectable Not Detectable19 RLL 90 Not Detectable Not Detectable20 RLL 91 lt 01 lt 0121 xxx xxx Not Detectable Not Detectable
27
Clinical Development Update ndash Summary 2018 September 26
Completed enrollment of Adv Breast cancer patients in the Phase IIIa ldquomonotherapyrdquo study of Bria-IMTtrade
We have confirmed our mechanism of action and achieved proof of concept
Initial safety data appears superior to that of the other advanced or approved drugs for breast cancer when they were at a similar clinical stage of development
Initial efficacy data is similar or superior to those of other advanced or approved drugs for breast cancer when they were at a similar clinical stage of development
Initiated Combination Study of Bria-IMTtrade with Keytrudareg or Yervoyreg in Adv breast cancer patients expecting even better response rates than those in the ldquomonotherapyrdquo study Initial safety data is expected in 4Q2018 Initial efficacy data is expected in 1Q2019
Bria-OTStrade the first off-the-shelf personalized treatment for advanced breast cancer is expected to enter the clinic in 2019
28
Bria-IMTtrade Excellent Safety Data - To Date
To date Bria-IMTtrade has been dosed in 24 patients (4 in 2004-2005 20 in 2017-2018)
Interim Data (20 patients)-Ongoing Phase IIIa Study (2017-2018)
Bria-IMTtrade has been very well tolerated (ge60 doses given to date) The majority of adverse events (AEs) were limited to expected minor local irritation at the
injection sites No related grade gt3 or unexpected AEs No related serious AEs No serious unexpected related AEs Most patients who have dropped out did so due to worsening of their underlying disease
Based on the current study Bria-IMTtrade has an excellent safety profile
29
Bria-IMTtrade - Efficacy as Predicted
Interim Data (19 patients)-Ongoing Phase IIIa Study (2017-2018) amp Original Study (2004-2005)
PD-L1 expression on circulating cancer cells amp cancer-associated cells in 100 of patients (to date) Strong rationale for combination with checkpoint inhibitors like Keytruda
30
Bria-IMTtrade appears to be most effective in patients who match with Bria-IMT trade at 2 HLA loci (types) further supporting our ldquoHLA Matching Hypothesisrdquo and the development of Bria-OTS trade to cover 90 of the patient population
Combination with immune checkpoint inhibitors may induce a more potent anti-cancer response leading to our strategy of combination studies of Bria-IMT trade with Keytruda or Yervoy
Patients (n) HLA Match
Tumor Shrinkage
Biological Response
4 ge2 50 7515 ge1 27 334 0 0 0
Biological response includes tumor shrinkage or lower circulating cancer associated cells
The confirmatory Bria-IMTtrade monotherapy Phase IIa trial has completed enrollment Additional Support for the HLA-matching hypothesis has been obtained
Bria-IMTtrade Combination Therapy study with immune checkpoint inhibitors Keytrudareg if PD-L12 positive (ge1) Yervoyreg if PD-L12 negative (lt1) Accepting patients from the monotherapy study who develop progressive disease Also enrolling patients directly into this study to enhance experience with the combination In discussion with other pharmaceutical companies to evaluate additional combinations with other
immunotherapies
Bria-OTStrade Off-the-Shelf Personalized Targeted Immunotherapy Developing Bria-OTStrade to co-express GM-CSF and interferon-α Pre-manufacture additional HLA alleles ndash Total of 15 alleles (8 Class I and 7 Class II) Co-development of BriaDXtrade companion diagnostic for HLA typing Combination therapy clinical trial with immune checkpoint inhibitors for non-responders using
information from the Bria-IMTtrade Combination Therapy Study
33
Development Timeline ndash Breast Cancer
20192018 2020 2021
Phase IIIaBria-IMTtrade
Monotherapy
Currently Enrolling Phase IIaBria-IMTtrade + Checkpoint
Currently in discussions with potential partnersPhase II Bria-IMTtrade plus Additional Combinations (1Q19 4Q22)(eg PD-1 Inhibitor PD-L1 inhibitor anti-CTLA4 anti-GITR anti-OX40)
1Q 2Q 3Q 4Q
2023
Bria-OTStrade Off-The-Shelf Personalized ImmunotherapyMonotherapy and Potential Partnered Combo Therapy
(2H19 Ongoing)
Bria-OTStradeOff-the-Shelf Cell Line cGMP Manufacturing
and BriaDXtrade(1Q18 1Q19)
Registration Studies (1Q20 2H22)Bria-IMTtrade with Checkpoint InhibitorsBria-OTStrade +- Checkpoint Inhibitors
34
Immuno-oncology Deals
Recent deals of small biotechs with big pharma in immuno-oncology
35
Date PartnershipDevelopment stage at the time of the deal Deal size
07122018 Immatics-Genmab Preclinical Up to $28B
04042018 OSE Immunotherapeutics-Boehringer Ingelheim Preclinical Up to euro113B ($139B)
02092018 Pieris Pharmaceuticals-Seattle Genetics Preclinical Up to $123B
2142018 Nektar-BMS Ph III Up to $36B
01222018 Juno-Celgene Ph II $9B (Acquisition)
11142017 Loxo-Bayer Larotrectinib (Ph II) LOXO-195 (Ph III) Up to $155B
1032017 CytomX-Amgen Preclinical Up to $15B
03202017 CytomX--BMS Ph III Up to $36B
6282016 Xencor-Novartis Preclinical Up to $24B
Early Stage Clinical Studies (Comparison)
We compared the interim data of Ph IIIa study of Bria-IMTtrade in advanced breast cancer with thedata in the early stage clinical studies of recently approved breast cancer drugs and one fasttracked product candidate
Apples to apples comparison Early Stage Clinical Studies in oncology are typically done in patientswith no other therapeutic options Thus the patients have very advanced disease and response ratesare typically quite low
The patients in our Ph IIIa study have been heavily pre-treated (median 45 prior regimens)Some recent studies of relevance in breast cancer are noted in the following slides
36
Breast Cancer Market Opportunity
Drug Technology Approved for Market (US)Ibrance (palbociclib) CDK 46 Inhibitor HR+HER2- MBC in combination with
fluvestrant or aromatase inhibitor$933M in 1Q2018 $3126M in 2017
Kisqali (ribociclib) CDK 46 Inhibitor 2017 HR+HER2- MBC in combination with fluvestrant or aromatase inhibitor
Peak sales projected at $25B
Verzenio (abemaciclib) CDK 46 Inhibitor 2017 HR+HER2- MBC in combination with fluvestrant or aromatase inhibitor
balixafortide CXCR4 antagonist Fast track designation in 2018 for HER2- MBC who have failed 2 prior regimens
The market for breast cancer drugs is a multibillion dollar market with new drugs being approvedon an ongoing basis indicating the shortage of safe and effective treatments for this deadly disease
37
Competitors- Phase III Clinical Data Bria-IMTtrade shows superior safety and similar to superior efficacy data compared with those of the multi-billion dollar drugs when they were at a similar early stage of clinical development
Injection site reactions No related SAEs or SUSARs
Tumor vol darr ampor darr circul tumor cellsAll Comers 21(419) 26(519)One or More HLA matches 27(415) 33(515)Two or More HLA matches 50 (24) 75 (34)
Sheet1 (3)
Comp -Slides
Data
HLA (2)
HLA
Data (Ph1-2+4Pt)
Competitors (2018)-Slide
Competitors (2018)
In the Pipeline Protein Kinase C delta (PKCδ) Inhibitors
30 of all human malignancies display activating RAS mutations Another 60 showing over-activity of Ras-signaling pathways
Ras has been termed ldquoundruggablerdquo (no one has been able to make a Ras inhibitor drug)
BriaCellrsquos novel proprietary PKCδ inhibitors have shown activity against multiple RAS transformed tumors Lung cancer Melanoma Breast cancer Neuroendocrine cancer Pancreatic cancer Colorectal cancer
This target has an attractive safety profile based on in vivo studies and knock out mouse studies
PKCδ inhibitors should qualify for an accelerated clinical development plan and regulatory pathway
Could be in clinic within 24 months
Cost-Effective Additional Shot-on-Goal and additional partnership opportunities
Early-Stage Preclinical Program
39
Protein Kinase C delta (PKCδ) Inhibitors
Activated PKCδ inhibits RAS degradation which in turn stimulates tumor growth
Koo et al Oncotarget 621328 2016
30 of all human malignancies display activating RASmutations with another 60 showing over-activity of Ras-signaling pathways
BriaCellrsquos novel proprietary PKCδ inhibitors have shownactivity against multiple RAS transformed tumors
This target has an attractive safety profile based on in vivostudies and knock out mouse studies
PKCδ also has potential activity as an immunotherapeuticby blocking TGFβ signaling
PKCδ inhibitors are applicable to specific niche tumor typeswhich provide an accelerated clinical development plan
Structural aspects of first generation inhibitor rottlerin and staurosporine (pan-PKC activator) were combined to create second generation inhibitor KAM1
Third generation inhibitors such as BJE6-106 have improved potency and selectivity Fourth generation inhibitors under development to optimize drug-like characteristics PKCδ inhibitors lack endothelial cell cytotoxicity amp PKCδ deficient mice develop normally and are fertile Potentially no marked intrinsic toxicity by inhibiting PKCδ
Mukai H Saeki T Shimada K Naito Y Matsubara N Nakanishi T Obaishi H Namiki M Sasaki Y Phase 1 combination study of eribulin mesylate with trastuzumab for advanced or recurrent human epidermal growth factor receptor 2 positive breast cancer Invest New Drugs 2015 Feb33(1)119-27
AstraZeneca
Lynparza (Olaparib) + Cediranib
PARP inhibitor + inhibitor of VEGF receptor tyrosine kinases
HR+ HER2- MBC
BC amp OC
2013
28 (8 BC)
3 for BC
Olaparib (a poly (ADP-ribose) polymerase (PARP) inhibitor) amp Cediranib (Vascular endothelial growth factor receptor (VEGFR) 1 2 and 3 tyrosine kinase inhibitor)3 at dose level (DL) 0 (cediranib 20mg olaparib 100mg) 3 at DL1 (cediranib 20mg olaparib 200mg) 7 at DL2 (cediranib 30mg olaparib 200mg) 6 at DL3 (cediranib 30mg olaparib 400mg)
Liu JF Tolaney SM Birrer M Fleming GF Buss MK Dahlberg SE Lee H Whalen C Tyburski K Winer E Ivy P Matulonis UA A Phase 1 trial of the poly(ADP-ribose) polymerase inhibitor olaparib (AZD2281) in combination with the anti-angiogenic cediranib (AZD2171) in recurrent epithelial ovarian or triple-negative breast cancer Eur J Cancer 2013 Sep49(14)2972-8
Reyon Pharmaceutical
VM206RY
Heterologous prime-boost with a truncated HER2 sequence
HER2+ Stage IIIampIV BC
2015
9
2 chemo
Plasmid DNA (pHM-GM-CSF expressing truncated HER2 amp GM-CSF) amp adenoviral vector (Ad-HM containing modified HER2) (2 4 and 8 mgpatientvisit) of pHM-GM-CSF 3x IM weeks 0 2 and 4 Ad-HM 3 times 109 virus particles at week 6
11 PR
4 pts showed 7 minor AEs
Unclear
Kim SB Ahn JH Kim J Jung KH A phase 1 study of a heterologous prime-boost vaccination involving a truncated HER2 sequence in patients with HER2-expressing breast cancer Mol Ther Methods Clin Dev 2015 Sep 30215031 doi 101038mtm201531 eCollection 2015
Rodon J Peacuterez-Fidalgo A Krop IE Burris H Guerrero-Zotano A Britten CD Becerra C Schellens J Richards DA Schuler M Abu-Khalaf M Johnson FM Ranson M Edenfield J Silva AP Hackl W Quadt C Demanse D Duval V Baselga J Phase 11b dose escalation and expansion study of BEZ235 a dual PI3KmTOR inhibitor in patients with advanced solid tumors including patients with advanced breast cancer Cancer Chemother Pharmacol 2018 Jun 7 doi 101007s00280-018-3610-z [Epub ahead of print]
Celgene (Abraxane)
Gemcitabine + Abraxane (nab-paclitaxel)
Chemo + Chemo
OC BC NSCLC amp Panc cancer + Lung OC BC Kaposi sarcoma
MBC
2016
9
Adjuvant chemo (100)chemo post-adjuvant (33)
Gem (nucleoside metabolic inhibitor 1250 mgm2) on days 1 and 8 nab-Pac (microtubule inhibitor) starting dose of 180 mgm2 (cohort 1) 220 mgm2 (cohort 2) and 260 mgm2 (cohort 3) on day 1 of the 21-day cycle using a 3 + 3 design
0
MTD not reached29 Gr3 Neutropenia59 Gr1 Peripheralneuropathy
Yoshitomi S Taira N Doihara H Mizoo T Nogami T Iwamoto T Motoki T Shien T Ogasawara Y Matsuoka J Tsuji H Mitsuhashi T A phase 1 dose-finding and pharmacokinetic study of gemcitabine with nab-paclitaxel in patients with metastatic breast cancer Cancer Chemother Pharmacol 2016 Aug78(2)289-94
Eli Lilly
Erbituxreg (cetuximab) + Taxane
EGFR inhibitor antineoplastic agent + Chemo
Headamp Neck Colorectal Cancer
TNBC
2007-2010
18
1 chemo
Cetuximab (epidermal growth factor receptor (EGFR) antagonist ) an initial loading dose of cetuximab 400 mgm2 followed by a weekly dose of 250 mgm2Paclitaxel (microtubule inhibitor) 80 mgm2 or Docetaxel at an initial dose of 30 mgm2 was administered weekly
56 CR 22 PR
83 Dermatologic toxicity11 Grade3+
Nechushtan H Vainer G Stainberg H Salmon AY Hamburger T Peretz T A phase 12 of a combination of cetuximab and taxane for triple negative breast cancer patients Breast 2014 Aug23(4)435-8
Polyphor
Balixafortide (POL6326) + eribulin
CXCR4 antagonist + tubulin-based antimitotic
Heavily pretreated Relapsed MBC
2014-2016
56
3rd line 3 chemo
3+3 dose escalation The highest dose was established as eribulin 14 mgmsup2 on days 2 and 9 and balixafortide 55 mgkg on days 1minus3 and 8minus10 of the 21-day cycle
30 PR
41 Gr34 Neutropenia11 Gr34 Leucopenia11 Gr34 Febrileneutropenia2 Related mortalities
Apr 2018 Fast Track for HER2-MBC who have failed 2prior regimens
Pernas S Martin M Kaufman PA Gil-Martin M Gomez Pardo P Lopez-Tarruella S Manso L Ciruelos E Perez-Fidalgo JA Hernando C Ademuyiwa FO Weilbaecher K Mayer I Pluard TJ Martinez Garcia M Vahdat L Perez-Garcia J Wach A Barker D Fung S Romagnoli B Cortes J Balixafortide plus eribulin in HER2-negative metastatic breast cancer a phase 1 single-arm dose-escalation trial Lancet Oncol 2018 Jun19(6)812-824
11 PRndashbut only + letrozole (No Resp on monotherapy)
61 Gr34 Neutropenia39 Gr34 Leucopenia
$933M in 1Q2018 $31B in 2017
Tamura K Mukai H Naito Y Yonemori K Kodaira M Tanabe Y Yamamoto N Osera S Sasaki M Mori Y Hashigaki S Nagasawa T Umeyama Y Yoshino T Phase I study of palbociclib a cyclin-dependent kinase 46 inhibitor in Japanese patients Cancer Sci 2016 Jun107(6)755-63 doi 101111cas12932 Epub 2016 May 11
Pfizer
Ibrancereg (palbociclib)
CDK 46 Inhibitor
HR+ HER2- MBC
Heavily pretreated Relapsed Metastatic Cancer
2004-2008
41 (5 BC)
chemo naiumlve (17) 1-2 (51)3 (29) 3+ (2)
Palbociclib 25-150 mg dose ranging
0
20 Gr34 Neutropenia23 Gr34 Leucopenia
$933M in 1Q2018 $31B in 2017
Flaherty KT Lorusso PM Demichele A Abramson VG Courtney R Randolph SS Shaik MN Wilner KD ODwyer PJ Schwartz GK Phase I dose-escalation trial of the oral cyclin-dependent kinase 46 inhibitor PD 0332991 administered using a 21-day schedule in patients with advanced cancer Clin Cancer Res 2012 Jan 1518(2)568-76 doi 1011581078-0432CCR-11-0509 Epub 2011 Nov 16
Novartis
Kisqalireg (ribociclib)
CDK 46 Inhibitors
Premenopausal HR+ HER2- MBC
Heavily pretreated Relapsed Metastatic Cancer
2016
132 (20 BC)
0-1 (25) 2-3 (42) 4+ (32)
Ribociclib 50 mg ranging up to 1200 mg dose escalation
23 PRndashincluded 1 in BC (5 of BC pts)
27 Gr34 Neutropenia17 Gr34 Leucopenia
Peak sales projected at $25B
Infante JR Cassier PA Gerecitano JF Witteveen PO Chugh R Ribrag V Chakraborty A Matano A Dobson JR Crystal AS Parasuraman S Shapiro GI A Phase I Study of the Cyclin-Dependent Kinase 46 Inhibitor Ribociclib (LEE011) in Patients with Advanced Solid Tumors and Lymphomas Clin Cancer Res 2016 Dec 122(23)5696-5705 Epub 2016 Aug 19
Eli Lilly
Verzenioreg (abemaciclib)
CDK 46 Inhibitors
HR+HER2minusMBC
Heavily pretreated Relapsed Metastatic Cancer
2016
12 (1 BC)
1 (312) 2 (212) 3+ (7)
Abemaciclib 100 mg ranging up to 200 mg dose escalation
17 PR (included 1 in BC)
17 Gr34 Neutropenia33 Gr34 Leucopenia
Peak sales projected at $2B
Fujiwara Y Tamura K Kondo S Tanabe Y Iwasa S Shimomura A Kitano S Ogasawara K Turner PK Mori J Asou H Chan EM Yamamoto N Phase 1 study of abemaciclib an inhibitor of CDK 4 and 6 as a single agent for Japanese patients with advanced cancer Cancer Chemother Pharmacol 2016 Aug78(2)281-8 doi 101007s00280-016-3085-8 Epub 2016 Jun 16
Mukai H Saeki T Shimada K Naito Y Matsubara N Nakanishi T Obaishi H Namiki M Sasaki Y Phase 1 combination study of eribulin mesylate with trastuzumab for advanced or recurrent human epidermal growth factor receptor 2 positive breast cancer Invest New Drugs 2015 Feb33(1)119-27
AstraZeneca
Lynparza (Olaparib)+ Cediranib
PARP inhibitor+ inhibitor of VEGF RTK
HR+ HER2- MBC
BC amp OC
13
28 (8 BC)
3 for BC
Olaparib (a poly (ADP-ribose) polymerase (PARP) inhibitor) amp Cediranib (Vascular endothelial growth factor receptor (VEGFR) 1 2 and 3 tyrosine kinase inhibitor)3 at dose level (DL) 0 (cediranib 20mg olaparib 100mg) 3 at DL1 (cediranib 20mg olaparib 200mg) 7 at DL2 (cediranib 30mg olaparib 200mg) 6 at DL3 (cediranib 30mg olaparib 400mg)
Liu JF Tolaney SM Birrer M Fleming GF Buss MK Dahlberg SE Lee H Whalen C Tyburski K Winer E Ivy P Matulonis UA A Phase 1 trial of the poly(ADP-ribose) polymerase inhibitor olaparib (AZD2281) in combination with the anti-angiogenic cediranib (AZD2171) in recurrent epithelial ovarian or triple-negative breast cancer Eur J Cancer 2013 Sep49(14)2972-8
ReyonPharma
VM206RY
Heterologous prime-boost with a truncated HER2 sequence
HER2+ Stg IIIampIV BC
15
9
2 chemo
Plasmid DNA (pHM-GM-CSF expressing truncated HER2 amp GM-CSF) amp adenoviral vector (Ad-HM containing modified HER2) (2 4 and 8 mgpatientvisit) of pHM-GM-CSF 3x IM weeks 0 2 and 4 Ad-HM 3 times 109 virus particles at week 6
11 PR
4 pts 7 minor AEs
Unclear
Kim SB Ahn JH Kim J Jung KH A phase 1 study of a heterologous prime-boost vaccination involving a truncated HER2 sequence in patients with HER2-expressing breast cancer Mol Ther Methods Clin Dev 2015 Sep 30215031 doi 101038mtm201531 eCollection 2015
Rodon J Peacuterez-Fidalgo A Krop IE Burris H Guerrero-Zotano A Britten CD Becerra C Schellens J Richards DA Schuler M Abu-Khalaf M Johnson FM Ranson M Edenfield J Silva AP Hackl W Quadt C Demanse D Duval V Baselga J Phase 11b dose escalation and expansion study of BEZ235 a dual PI3KmTOR inhibitor in patients with advanced solid tumors including patients with advanced breast cancer Cancer Chemother Pharmacol 2018 Jun 7 doi 101007s00280-018-3610-z [Epub ahead of print]
Celgene(Abraxane)
Gemcitabine + Abraxane (nab-paclitaxel)
Chemo+ Chemo
OC BC NSCLC PC + LC OC BC KS
MBC
16
9
Adjuv chemo (100)chemo post-adjuv (33)
Gem (nucleoside metabolic inhibitor 1250 mgm2) on days 1 and 8 nab-Pac (microtubule inhibitor) starting dose of 180 mgm2 (cohort 1) 220 mgm2 (cohort 2) and 260 mgm2 (cohort 3) on day 1 of the 21-day cycle using a 3 + 3 design
0
MTD not reached29 Gr3 Neutropenia59 Gr1 Peripheralneuropathy
Yoshitomi S Taira N Doihara H Mizoo T Nogami T Iwamoto T Motoki T Shien T Ogasawara Y Matsuoka J Tsuji H Mitsuhashi T A phase 1 dose-finding and pharmacokinetic study of gemcitabine with nab-paclitaxel in patients with metastatic breast cancer Cancer Chemother Pharmacol 2016 Aug78(2)289-94
Eli Lilly
Erbituxreg (cetuximab) + Taxane
EGFR inhibitor antineoplastic agent + Chemo
Head amp NeckColorectal
TNBC
07-10
18
1 chemo
Cetuximab (epidermal growth factor receptor (EGFR) antagonist ) an initial loading dose of cetuximab 400 mgm2 followed by a weekly dose of 250 mgm2Paclitaxel (microtubule inhibitor) 80 mgm2 or Docetaxel at an initial dose of 30 mgm2 was administered weekly
56 CR 22 PR
83 Dermatologic toxicity11 Grade3+
Nechushtan H Vainer G Stainberg H Salmon AY Hamburger T Peretz T A phase 12 of a combination of cetuximab and taxane for triple negative breast cancer patients Breast 2014 Aug23(4)435-8
Polyphor
Balixafortide (POL6326) + eribulin
CXCR4 antagonist + tubulin-based antimitotic
Heavily pretreatedRelapsed MBC
14-16
56
3rd line 3 chemo
3+3 dose escalation The highest dose was established as eribulin 14 mgmsup2 on days 2 and 9 and balixafortide 55 mgkg on days 1minus3 and 8minus10 of the 21-day cycle
30 PR
41 Gr34 Neutropenia11 Gr34 Leucopenia11 Gr34 Febrileneutropenia2 Related mortalities
42018 Fast Track (HER2-MBC failed 2 prior regimens)
Pernas S Martin M Kaufman PA Gil-Martin M Gomez Pardo P Lopez-Tarruella S Manso L Ciruelos E Perez-Fidalgo JA Hernando C Ademuyiwa FO Weilbaecher K Mayer I Pluard TJ Martinez Garcia M Vahdat L Perez-Garcia J Wach A Barker D Fung S Romagnoli B Cortes J Balixafortide plus eribulin in HER2-negative metastatic breast cancer a phase 1 single-arm dose-escalation trial Lancet Oncol 2018 Jun19(6)812-824
1 PRndashbut only + letrozoleNo Resp on monotherapy
61 Gr34 Neutropenia39 Gr34 Leucopenia
$933M (1Q18)$31B (2017)
Tamura K Mukai H Naito Y Yonemori K Kodaira M Tanabe Y Yamamoto N Osera S Sasaki M Mori Y Hashigaki S Nagasawa T Umeyama Y Yoshino T Phase I study of palbociclib a cyclin-dependent kinase 46 inhibitor in Japanese patients Cancer Sci 2016 Jun107(6)755-63 doi 101111cas12932 Epub 2016 May 11
Pfizer
Ibrancereg (palbociclib)
CDK 46 Inhibitor
HR+ HER2- MBC
Heavily pretreatedRelapsed Met Cancer
04-08
41 (5 BC)
chemo naiumlve (17)1-2(51) 3(29) 3+(2)
Palbociclib 25-150 mg dose ranging
0
20 Gr34 Neutropenia23 Gr34 Leucopenia
$933M (1Q18)$31B (2017)
Flaherty KT Lorusso PM Demichele A Abramson VG Courtney R Randolph SS Shaik MN Wilner KD ODwyer PJ Schwartz GK Phase I dose-escalation trial of the oral cyclin-dependent kinase 46 inhibitor PD 0332991 administered using a 21-day schedule in patients with advanced cancer Clin Cancer Res 2012 Jan 1518(2)568-76 doi 1011581078-0432CCR-11-0509 Epub 2011 Nov 16
Novartis
Kisqalireg (ribociclib)
CDK 46 Inhibitor
Premenopausal HR+ HER2- MBC
Heavily pretreatedRelapsed Met Cancer
16
132 (20 BC)
0-1 (25) 2-3 (42)4+ (32)
Ribociclib 50 mg ranging up to 1200 mg dose escalation
23 PR-included 1 BC (5 of BC pts)
27 Gr34 Neutropenia17 Gr34 Leucopenia
Peak sales est at $25B
Infante JR Cassier PA Gerecitano JF Witteveen PO Chugh R Ribrag V Chakraborty A Matano A Dobson JR Crystal AS Parasuraman S Shapiro GI A Phase I Study of the Cyclin-Dependent Kinase 46 Inhibitor Ribociclib (LEE011) in Patients with Advanced Solid Tumors and Lymphomas Clin Cancer Res 2016 Dec 122(23)5696-5705 Epub 2016 Aug 19
Eli Lilly
Verzenioreg (abemaciclib)
CDK 46 Inhibitor
HR+HER2minusMBC
Heavily pretreatedRelapsed Met Cancer
16
12 (1 BC)
1 (312) 2 (212) 3+(7)
Abemaciclib 100 mg ranging up to 200 mg dose escalation
17 PR (included 1 BC)
17 Gr34 Neutropenia33 Gr34 Leucopenia
Peak sales est at $2B
Fujiwara Y Tamura K Kondo S Tanabe Y Iwasa S Shimomura A Kitano S Ogasawara K Turner PK Mori J Asou H Chan EM Yamamoto N Phase 1 study of abemaciclib an inhibitor of CDK 4 and 6 as a single agent for Japanese patients with advanced cancer Cancer Chemother Pharmacol 2016 Aug78(2)281-8 doi 101007s00280-016-3085-8 Epub 2016 Jun 16
Mukai H Saeki T Shimada K Naito Y Matsubara N Nakanishi T Obaishi H Namiki M Sasaki Y Phase 1 combination study of eribulin mesylate with trastuzumab for advanced or recurrent human epidermal growth factor receptor 2 positive breast cancer Invest New Drugs 2015 Feb33(1)119-27
AstraZeneca
Lynparza (Olaparib) + Cediranib
PARP inhibitor + inhibitor of VEGF receptor tyrosine kinases
HR+ HER2- MBC
BC amp OC
2013
28 (8 BC)
3 for BC
Olaparib (a poly (ADP-ribose) polymerase (PARP) inhibitor) amp Cediranib (Vascular endothelial growth factor receptor (VEGFR) 1 2 and 3 tyrosine kinase inhibitor)3 at dose level (DL) 0 (cediranib 20mg olaparib 100mg) 3 at DL1 (cediranib 20mg olaparib 200mg) 7 at DL2 (cediranib 30mg olaparib 200mg) 6 at DL3 (cediranib 30mg olaparib 400mg)
Liu JF Tolaney SM Birrer M Fleming GF Buss MK Dahlberg SE Lee H Whalen C Tyburski K Winer E Ivy P Matulonis UA A Phase 1 trial of the poly(ADP-ribose) polymerase inhibitor olaparib (AZD2281) in combination with the anti-angiogenic cediranib (AZD2171) in recurrent epithelial ovarian or triple-negative breast cancer Eur J Cancer 2013 Sep49(14)2972-8
Reyon Pharmaceutical
VM206RY
Heterologous prime-boost with a truncated HER2 sequence
HER2+ Stage IIIampIV BC
2015
9
2 chemo
Plasmid DNA (pHM-GM-CSF expressing truncated HER2 amp GM-CSF) amp adenoviral vector (Ad-HM containing modified HER2) (2 4 and 8 mgpatientvisit) of pHM-GM-CSF 3x IM weeks 0 2 and 4 Ad-HM 3 times 109 virus particles at week 6
11 PR
4 pts showed 7 minor AEs
Unclear
Kim SB Ahn JH Kim J Jung KH A phase 1 study of a heterologous prime-boost vaccination involving a truncated HER2 sequence in patients with HER2-expressing breast cancer Mol Ther Methods Clin Dev 2015 Sep 30215031 doi 101038mtm201531 eCollection 2015
Rodon J Peacuterez-Fidalgo A Krop IE Burris H Guerrero-Zotano A Britten CD Becerra C Schellens J Richards DA Schuler M Abu-Khalaf M Johnson FM Ranson M Edenfield J Silva AP Hackl W Quadt C Demanse D Duval V Baselga J Phase 11b dose escalation and expansion study of BEZ235 a dual PI3KmTOR inhibitor in patients with advanced solid tumors including patients with advanced breast cancer Cancer Chemother Pharmacol 2018 Jun 7 doi 101007s00280-018-3610-z [Epub ahead of print]
Celgene (Abraxane)
Gemcitabine + Abraxane (nab-paclitaxel)
Chemo + Chemo
OC BC NSCLC amp Panc cancer + Lung OC BC Kaposi sarcoma
MBC
2016
9
Adjuvant chemo (100)chemo post-adjuvant (33)
Gem (nucleoside metabolic inhibitor 1250 mgm2) on days 1 and 8 nab-Pac (microtubule inhibitor) starting dose of 180 mgm2 (cohort 1) 220 mgm2 (cohort 2) and 260 mgm2 (cohort 3) on day 1 of the 21-day cycle using a 3 + 3 design
0
MTD not reached29 Gr3 Neutropenia59 Gr1 Peripheralneuropathy
Yoshitomi S Taira N Doihara H Mizoo T Nogami T Iwamoto T Motoki T Shien T Ogasawara Y Matsuoka J Tsuji H Mitsuhashi T A phase 1 dose-finding and pharmacokinetic study of gemcitabine with nab-paclitaxel in patients with metastatic breast cancer Cancer Chemother Pharmacol 2016 Aug78(2)289-94
Eli Lilly
Erbituxreg (cetuximab) + Taxane
EGFR inhibitor antineoplastic agent + Chemo
Headamp Neck Colorectal Cancer
TNBC
2007-2010
18
1 chemo
Cetuximab (epidermal growth factor receptor (EGFR) antagonist ) an initial loading dose of cetuximab 400 mgm2 followed by a weekly dose of 250 mgm2Paclitaxel (microtubule inhibitor) 80 mgm2 or Docetaxel at an initial dose of 30 mgm2 was administered weekly
56 CR 22 PR
83 Dermatologic toxicity11 Grade3+
Nechushtan H Vainer G Stainberg H Salmon AY Hamburger T Peretz T A phase 12 of a combination of cetuximab and taxane for triple negative breast cancer patients Breast 2014 Aug23(4)435-8
Polyphor
Balixafortide (POL6326) + eribulin
CXCR4 antagonist + tubulin-based antimitotic
Heavily pretreated Relapsed MBC
2014-2016
56
3rd line 3 chemo
3+3 dose escalation The highest dose was established as eribulin 14 mgmsup2 on days 2 and 9 and balixafortide 55 mgkg on days 1minus3 and 8minus10 of the 21-day cycle
30 PR
41 Gr34 Neutropenia11 Gr34 Leucopenia11 Gr34 Febrileneutropenia2 Related mortalities
Apr 2018 Fast Track for HER2-MBC who have failed 2prior regimens
Pernas S Martin M Kaufman PA Gil-Martin M Gomez Pardo P Lopez-Tarruella S Manso L Ciruelos E Perez-Fidalgo JA Hernando C Ademuyiwa FO Weilbaecher K Mayer I Pluard TJ Martinez Garcia M Vahdat L Perez-Garcia J Wach A Barker D Fung S Romagnoli B Cortes J Balixafortide plus eribulin in HER2-negative metastatic breast cancer a phase 1 single-arm dose-escalation trial Lancet Oncol 2018 Jun19(6)812-824
11 PRndashbut only + letrozole (No Resp on monotherapy)
61 Gr34 Neutropenia39 Gr34 Leucopenia
$933M in 1Q2018 $31B in 2017
Tamura K Mukai H Naito Y Yonemori K Kodaira M Tanabe Y Yamamoto N Osera S Sasaki M Mori Y Hashigaki S Nagasawa T Umeyama Y Yoshino T Phase I study of palbociclib a cyclin-dependent kinase 46 inhibitor in Japanese patients Cancer Sci 2016 Jun107(6)755-63 doi 101111cas12932 Epub 2016 May 11
Pfizer
Ibrancereg (palbociclib)
CDK 46 Inhibitor
HR+ HER2- MBC
Heavily pretreated Relapsed Metastatic Cancer
2004-2008
41 (5 BC)
chemo naiumlve (17) 1-2 (51)3 (29) 3+ (2)
Palbociclib 25-150 mg dose ranging
0
20 Gr34 Neutropenia23 Gr34 Leucopenia
$933M in 1Q2018 $31B in 2017
Flaherty KT Lorusso PM Demichele A Abramson VG Courtney R Randolph SS Shaik MN Wilner KD ODwyer PJ Schwartz GK Phase I dose-escalation trial of the oral cyclin-dependent kinase 46 inhibitor PD 0332991 administered using a 21-day schedule in patients with advanced cancer Clin Cancer Res 2012 Jan 1518(2)568-76 doi 1011581078-0432CCR-11-0509 Epub 2011 Nov 16
Novartis
Kisqalireg (ribociclib)
CDK 46 Inhibitors
Premenopausal HR+ HER2- MBC
Heavily pretreated Relapsed Metastatic Cancer
2016
132 (20 BC)
0-1 (25) 2-3 (42) 4+ (32)
Ribociclib 50 mg ranging up to 1200 mg dose escalation
23 PRndashincluded 1 in BC (5 of BC pts)
27 Gr34 Neutropenia17 Gr34 Leucopenia
Peak sales projected at $25B
Infante JR Cassier PA Gerecitano JF Witteveen PO Chugh R Ribrag V Chakraborty A Matano A Dobson JR Crystal AS Parasuraman S Shapiro GI A Phase I Study of the Cyclin-Dependent Kinase 46 Inhibitor Ribociclib (LEE011) in Patients with Advanced Solid Tumors and Lymphomas Clin Cancer Res 2016 Dec 122(23)5696-5705 Epub 2016 Aug 19
Eli Lilly
Verzenioreg (abemaciclib)
CDK 46 Inhibitors
HR+HER2minusMBC
Heavily pretreated Relapsed Metastatic Cancer
2016
12 (1 BC)
1 (312) 2 (212) 3+ (7)
Abemaciclib 100 mg ranging up to 200 mg dose escalation
17 PR (included 1 in BC)
17 Gr34 Neutropenia33 Gr34 Leucopenia
Peak sales projected at $2B
Fujiwara Y Tamura K Kondo S Tanabe Y Iwasa S Shimomura A Kitano S Ogasawara K Turner PK Mori J Asou H Chan EM Yamamoto N Phase 1 study of abemaciclib an inhibitor of CDK 4 and 6 as a single agent for Japanese patients with advanced cancer Cancer Chemother Pharmacol 2016 Aug78(2)281-8 doi 101007s00280-016-3085-8 Epub 2016 Jun 16
Mukai H Saeki T Shimada K Naito Y Matsubara N Nakanishi T Obaishi H Namiki M Sasaki Y Phase 1 combination study of eribulin mesylate with trastuzumab for advanced or recurrent human epidermal growth factor receptor 2 positive breast cancer Invest New Drugs 2015 Feb33(1)119-27
AstraZeneca
Lynparza (Olaparib)+ Cediranib
PARP inhibitor+ inhibitor of VEGF RTK
HR+ HER2- MBC
BC amp OC
13
28 (8 BC)
3 for BC
Olaparib (a poly (ADP-ribose) polymerase (PARP) inhibitor) amp Cediranib (Vascular endothelial growth factor receptor (VEGFR) 1 2 and 3 tyrosine kinase inhibitor)3 at dose level (DL) 0 (cediranib 20mg olaparib 100mg) 3 at DL1 (cediranib 20mg olaparib 200mg) 7 at DL2 (cediranib 30mg olaparib 200mg) 6 at DL3 (cediranib 30mg olaparib 400mg)
Liu JF Tolaney SM Birrer M Fleming GF Buss MK Dahlberg SE Lee H Whalen C Tyburski K Winer E Ivy P Matulonis UA A Phase 1 trial of the poly(ADP-ribose) polymerase inhibitor olaparib (AZD2281) in combination with the anti-angiogenic cediranib (AZD2171) in recurrent epithelial ovarian or triple-negative breast cancer Eur J Cancer 2013 Sep49(14)2972-8
ReyonPharma
VM206RY
Heterologous prime-boost with a truncated HER2 sequence
HER2+ Stg IIIampIV BC
15
9
2 chemo
Plasmid DNA (pHM-GM-CSF expressing truncated HER2 amp GM-CSF) amp adenoviral vector (Ad-HM containing modified HER2) (2 4 and 8 mgpatientvisit) of pHM-GM-CSF 3x IM weeks 0 2 and 4 Ad-HM 3 times 109 virus particles at week 6
11 PR
4 pts 7 minor AEs
Unclear
Kim SB Ahn JH Kim J Jung KH A phase 1 study of a heterologous prime-boost vaccination involving a truncated HER2 sequence in patients with HER2-expressing breast cancer Mol Ther Methods Clin Dev 2015 Sep 30215031 doi 101038mtm201531 eCollection 2015
Rodon J Peacuterez-Fidalgo A Krop IE Burris H Guerrero-Zotano A Britten CD Becerra C Schellens J Richards DA Schuler M Abu-Khalaf M Johnson FM Ranson M Edenfield J Silva AP Hackl W Quadt C Demanse D Duval V Baselga J Phase 11b dose escalation and expansion study of BEZ235 a dual PI3KmTOR inhibitor in patients with advanced solid tumors including patients with advanced breast cancer Cancer Chemother Pharmacol 2018 Jun 7 doi 101007s00280-018-3610-z [Epub ahead of print]
Celgene(Abraxane)
Gemcitabine + Abraxane (nab-paclitaxel)
Chemo+ Chemo
OC BC NSCLC PC + LC OC BC KS
MBC
16
9
Adjuv chemo (100)chemo post-adjuv (33)
Gem (nucleoside metabolic inhibitor 1250 mgm2) on days 1 and 8 nab-Pac (microtubule inhibitor) starting dose of 180 mgm2 (cohort 1) 220 mgm2 (cohort 2) and 260 mgm2 (cohort 3) on day 1 of the 21-day cycle using a 3 + 3 design
0
MTD not reached29 Gr3 Neutropenia59 Gr1 Peripheralneuropathy
Yoshitomi S Taira N Doihara H Mizoo T Nogami T Iwamoto T Motoki T Shien T Ogasawara Y Matsuoka J Tsuji H Mitsuhashi T A phase 1 dose-finding and pharmacokinetic study of gemcitabine with nab-paclitaxel in patients with metastatic breast cancer Cancer Chemother Pharmacol 2016 Aug78(2)289-94
Eli Lilly
Erbituxreg (cetuximab) + Taxane
EGFR inhibitor antineoplastic agent + Chemo
Head amp NeckColorectal
TNBC
07-10
18
1 chemo
Cetuximab (epidermal growth factor receptor (EGFR) antagonist ) an initial loading dose of cetuximab 400 mgm2 followed by a weekly dose of 250 mgm2Paclitaxel (microtubule inhibitor) 80 mgm2 or Docetaxel at an initial dose of 30 mgm2 was administered weekly
56 CR 22 PR
83 Dermatologic toxicity11 Grade3+
Nechushtan H Vainer G Stainberg H Salmon AY Hamburger T Peretz T A phase 12 of a combination of cetuximab and taxane for triple negative breast cancer patients Breast 2014 Aug23(4)435-8
Polyphor
Balixafortide (POL6326) + eribulin
CXCR4 antagonist + tubulin-based antimitotic
Heavily pretreatedRelapsed MBC
14-16
56
3rd line 3 chemo
3+3 dose escalation The highest dose was established as eribulin 14 mgmsup2 on days 2 and 9 and balixafortide 55 mgkg on days 1minus3 and 8minus10 of the 21-day cycle
30 PR
41 Gr34 Neutropenia11 Gr34 Leucopenia11 Gr34 Febrileneutropenia2 Related mortalities
42018 Fast Track (HER2-MBC failed 2 prior regimens)
Pernas S Martin M Kaufman PA Gil-Martin M Gomez Pardo P Lopez-Tarruella S Manso L Ciruelos E Perez-Fidalgo JA Hernando C Ademuyiwa FO Weilbaecher K Mayer I Pluard TJ Martinez Garcia M Vahdat L Perez-Garcia J Wach A Barker D Fung S Romagnoli B Cortes J Balixafortide plus eribulin in HER2-negative metastatic breast cancer a phase 1 single-arm dose-escalation trial Lancet Oncol 2018 Jun19(6)812-824
1 PRndashbut only + letrozoleNo Resp on monotherapy
61 Gr34 Neutropenia39 Gr34 Leucopenia
$933M (1Q18)$31B (2017)
Tamura K Mukai H Naito Y Yonemori K Kodaira M Tanabe Y Yamamoto N Osera S Sasaki M Mori Y Hashigaki S Nagasawa T Umeyama Y Yoshino T Phase I study of palbociclib a cyclin-dependent kinase 46 inhibitor in Japanese patients Cancer Sci 2016 Jun107(6)755-63 doi 101111cas12932 Epub 2016 May 11
Pfizer
Ibrancereg (palbociclib)
CDK 46 Inhibitor
HR+ HER2- MBC
Heavily pretreatedRelapsed Met Cancer
04-08
41 (5 BC)
chemo naiumlve (17)1-2(51) 3(29) 3+(2)
Palbociclib 25-150 mg dose ranging
0
20 Gr34 Neutropenia23 Gr34 Leucopenia
$933M (1Q18)$31B (2017)
Flaherty KT Lorusso PM Demichele A Abramson VG Courtney R Randolph SS Shaik MN Wilner KD ODwyer PJ Schwartz GK Phase I dose-escalation trial of the oral cyclin-dependent kinase 46 inhibitor PD 0332991 administered using a 21-day schedule in patients with advanced cancer Clin Cancer Res 2012 Jan 1518(2)568-76 doi 1011581078-0432CCR-11-0509 Epub 2011 Nov 16
Novartis
Kisqalireg (ribociclib)
CDK 46 Inhibitor
Premenopausal HR+ HER2- MBC
Heavily pretreatedRelapsed Met Cancer
16
132 (20 BC)
0-1 (25) 2-3 (42)4+ (32)
Ribociclib 50 mg ranging up to 1200 mg dose escalation
23 PR-included 1 BC (5 of BC pts)
27 Gr34 Neutropenia17 Gr34 Leucopenia
Peak sales est at $25B
Infante JR Cassier PA Gerecitano JF Witteveen PO Chugh R Ribrag V Chakraborty A Matano A Dobson JR Crystal AS Parasuraman S Shapiro GI A Phase I Study of the Cyclin-Dependent Kinase 46 Inhibitor Ribociclib (LEE011) in Patients with Advanced Solid Tumors and Lymphomas Clin Cancer Res 2016 Dec 122(23)5696-5705 Epub 2016 Aug 19
Eli Lilly
Verzenioreg (abemaciclib)
CDK 46 Inhibitor
HR+HER2minusMBC
Heavily pretreatedRelapsed Met Cancer
16
12 (1 BC)
1 (312) 2 (212) 3+(7)
Abemaciclib 100 mg ranging up to 200 mg dose escalation
17 PR (included 1 BC)
17 Gr34 Neutropenia33 Gr34 Leucopenia
Peak sales est at $2B
Fujiwara Y Tamura K Kondo S Tanabe Y Iwasa S Shimomura A Kitano S Ogasawara K Turner PK Mori J Asou H Chan EM Yamamoto N Phase 1 study of abemaciclib an inhibitor of CDK 4 and 6 as a single agent for Japanese patients with advanced cancer Cancer Chemother Pharmacol 2016 Aug78(2)281-8 doi 101007s00280-016-3085-8 Epub 2016 Jun 16
41 Gr34 Neutropenia11 Gr34 Leucopenia11 Gr34 Febrileneutropenia2 Related mortalities
30 PRs in combination with Halaven
Bria-IMTTM
20
Injection site reactions No related SAEs or SUSARs
Tumor vol darr ampor darr circul tumor cells)All Comers 21(419) 26(519)One or More HLA matches 27(415) 33(515)Two or More HLA matches 50 (24) 75 (34))
Drug
Technology
Approved for
Market (US)
Ibrance (palbociclib)
CDK 46 Inhibitor
HR+HER2- MBC in combination with fluvestrant or aromatase inhibitor
$933M in 1Q2018 $3126M in 2017
Kisqali (ribociclib)
CDK 46 Inhibitor
2017 HR+HER2- MBC in combination with fluvestrant or aromatase inhibitor
Peak sales projected at $25B
Verzenio (abemaciclib)
CDK 46 Inhibitor
2017 HR+HER2- MBC in combination with fluvestrant or aromatase inhibitor
Peak sales projected at $2B
Lynparza (olaparib)
Poly (ADP-ribose) polymerase (PARP) inhibitor
2017 ovarian amp breast cancer
$997M in 2017
Halaven (eribulin mesylate)
Tubulin-based antimitotic
2H2017 3rd line MBC amp liposarcoma
$181M in 2017
balixafortide
CXCR4 antagonist
Fast track designation in 2018 for HER2- MBC who have failed 2 prior regimens
Bria-IMTtradeHuman Proof-of-Concept Trials in Breast Cancer (Patient A002) Approximately 3 months (106 days) after last inoculation Patient A002rsquos breast cancer returned and
spread to brain lung and other sites
Patient A002 was then re-treated with 10 inoculations of Bria-IMTtrade over 4 months
Repeat imaging studies showed normal findings on MRI and PET consistent with a completeremission of the previous multiple central nervous system metastases as shown in the brain scansbelow
Bria-IMTtrade and Bria-OTStrade shouldsynergize with existing approvedimmunotherapies as well as those stillunder development
This includes immune checkpointinhibitors such as antibodies to PD-1CTLA-4 GITR and CD73 inhibitors whicheliminate tumor immunosuppression Checkpoint Inhibitors were the
subject of the 2018 Nobel Prize inMedicine
In addition immunostimulatoryantibodies to molecules such as OX40should enhance responses to Bria-IMTtradeand Bria-OTStrade
13
Q3 2018 Data on first 20 Patients on Bria-IMTtrade Q3 2018 Initiate Combination Study of Bria-IMTtrade with Keytruda or Yervoy
Q4 2018 Switch to a novel frozen Bria-IMTtrade formulation Q4 2018 Safety Data (6 patients) of the Bria-IMTtrade - Keytrudareg Combination Study (SABC meeting) Q4 2018 Ongoing Corporate PartnershipCollaboration Discussions
Q1 2019 Efficacy Data (6 patients) of the Bria-IMTtrade - Keytrudareg Combination Study Q2 2019 Initiation of Bria-OTStrade GMP manufacturing (KBI BioPharma) Q2 2019 Additional Safety amp Efficacy data Monotherapy and Combination Studies (AACR meeting) Q2 2019 Final data for Monotherapy and Additional Data for the Combination Study (ASCO meeting) H1 2019 Candidate Selection for a PKCδ Inhibitor H1 2019 Initiate additional immunotherapy program H2 2019 Bria-OTStrade Authorization from FDA clearance for dosing H2 2019 Bria-OTStrade First Patient Dosed
Upcoming Milestones amp Catalysts
14
Involved in over 10 drugs brought to the market
Experienced Management Team
Management
William V Williams MD FACP President amp CEO VP Exploratory Development Incyte Corporation VP Experimental Medicine GlaxoSmithKline Head Rheumatology Research University of Pennsylvania Facilitated entry of over 20 compounds into the clinic including ruxolitinib (Jakafi)
baricitinib amp epacadostat NDAs including Jakafi Boniva Bexxar Author of over 120 peer-reviewed publications amp over 20 patents
Gadi Levin CA MBA CFO CFO of Labstyle Innovations Ltd VP of Finance for two Israeli investment houses in the fields of private equity
hedge funds and real estate Financial Consultant various firms Accountant Arthur Andersen
Markus Lacher PhD Senior Director RampD Founder T cell Therapeutics Inc an immuno-oncology company Sr Clinical Scientist Cesca Therapeutics Inc a clinical-stage autologous cell
therapy company Scientist at BioTime Inc and OncoCyte Corporation Editorial advisory board Recent Patents on Anti-Cancer Drug Discovery
Farrah Dean MSc MBA Manager Corp Development Investor relations CytRx Corporation amp CCG Investor Relations Senior Associate Equity Analyst Oppenheimer amp Co Rodman amp Renshaw amp
Brian Metcalf PhD Recently retired as CSO from Global Blood Therapeutics Former Head of Research amp Development Incyte Corporation Former Head of Medicinal Chemistry SmithKline Beecham
Douglas Faller MD PhD Professor of Medicine Pediatrics Biochemistry Microbiology Pathology and
Laboratory Medicine HematologistOncologist former Director of the Cancer Center Boston University School of Medicine
Founder of several successful biotechnology companies
Robert Williams PhD University Distinguished Professor of Chemistry Colorado State University Founder of several successful biotechnology companies including Microcide Xcyte
Therapies HemaQuest Arch Therapeutics and Cetya Therapeutics
Thomas Kieber-Emmons PhD Deputy Director University of Arkansas Cancer Center Expert in targeted cancer immunotherapies structural biology and computational
chemistry
Maria Trojanowska PhD Professor of Medicine Boston University School of Medicine Director The Arthritis Center
16
Veteran Board of Directors
Board of Directors
Saeid Babaei PhD MBA Chairman Entrepreneur 20 yrs of biotech leadership roles Current CEO AbCelex VP Bus Develop Lorus Therap Dir of Corp Develop Northern Therapeutics
Rahoul Sharan CA Director Chairman Potash Ridge Director of the Board Ansell Capital Corp Parallel Resources amp Galaxy Capital
Corporation
Martin Schmieg CPA Director CFO Sirna Therapeutics Inc amp Isolagen Inc CEO Freedom-2 Inc (now PharmaCyte Inc) Advisor Caladrius Biosciences Inc Beckman Coulter Genomics Calimmune
Charles Wiseman MD Co-Founder amp Director Director Immunotherapy Lab St Vincent Medical Center Chief Breast Cancer Basic Research Lab Univ of Texas MD Anderson Hospital amp
Tumour Institute Assist Prof Dept of Molecular Carcinogenesis amp Virology MD Anderson Acting Chief Div of Oncology White Memorial Medical Center LA
William V Williams MD FACP President amp CEO VP Exploratory Development Incyte Corporation VP Experimental Medicine GlaxoSmithKline Head Rheumatology Research University of Pennsylvania
Prior Affiliations
17
Drug Approvals by BriaCell Management Team
Bexxarreg (tositumomab and Iodine I131 tositumomab) Treatment of CD20 antigen-expressing relapsed or refractory low grade follicular or transformed non-Hodgkins lymphoma
Myleranreg (busulfan) for chronic myelogenous leukemia Defense of formulation change sNDA
Hycamtinreg (topotecan) for ovarian cancer Pediatric use sNDA
Navelbinereg (vinorelbine tartrate) for non-small cell lung cancer Pediatric use sNDA
Bonivareg (ibandronate) monthly oral treatment of osteoporosis
Bonivareg (ibandronate) quarterly intraveous treatment of osteoporosis
Zofranreg (ondansetron) for prevention of nausea and vomiting Pediatric use sNDA
Jakafireg (ruxolitinib) for myelofibrosis Jakafireg (ruxolitinib) for polycythemia vera
Olumiantreg (baricitinib) for rheumatoid arthritis Approved in USA Japan and Europe
18
Share Metrics
BCTV BCTXF 19
Data as of 1092018
Ticker TSX BCTV
US Ticker OTCQBBCTXF
Share Price (CAD) as of Oct 9 2018 $012
52-Week Range (CAD) $009-019
Shares Outstanding as of Oct 9 2018 1611M
Market Cap as of Oct 9 2018 (CAD) $193M
Cash and Short Term Investments as of July 31 2018 (CAD) $23M
Total Shareholders Equity as of July 31 2018 (CAD) $12M
Number of Warrants $014-$035 (CAD) as of Oct 9 2018 601M
Number of Compensation Warrants $014-$030 (CAD) as of Oct 9 2018 45M
Number of Options $014- $026 (CAD$) as of Oct 9 2018 93M
Developing Bria-OTStrade the First Off-the-Shelf Personalized Immunotherapy
Targeting Adv Breast Cancer Unmet medical need (42000 death in the US in 2017 ) $1 Bil- $5 Bil market opportunity depending on patient treatment stage
Impressive results in 2 proof-of-concept clinical trials Rapid Response Rate Repeated following re-treatment Excellent Safety Profile
Completed enrollment in Phase IIIa clinical trial of Bria-IMTtrade with outstanding safety amp efficacy data Initiated Phase IIa Combination Study of Bria-IMTtrade with Keytrudareg (Merck amp Co Inc)
Developing Bria-OTStrade along with BriaDXtrade its companion diagnostic test Ability to match and treat ~90 of patient population with Off-the-Shelf personalized immunotherapy
Experienced Management has been involved in over 10 drug approvals
Patient B001 Breast 70 No 1101 - 3501 4001 Negative -
Bria-IMTtradeHuman Proof-of-Concept Trials in Breast Cancer (Patient A002)
24
Proof-of-Concept Results Resulted in BriaCellrsquos Immunotherapy Strategy Use BriaDXtrade diagnostic to select only those patients matching Bria-IMTtrade Use BriaDXtrade diagnostic test to select Bria-OTStrade alleles matching ~90 of all patients
Bria-IMTtradeCurrent Phase IIIa Data Supports HLA Matching Hypothesis Six patients treated in 2017 Bria-IMTtrade was safe and well tolerated
Patient 01-002 73-year-old woman with breast cancer diagnosed in 1995 Developed liver metastases in2010 and lung metastases in 2017 Previously treated with 7 rounds of chemotherapy with 8 differentchemotherapy agents Received 5 cycles of Bria-IMTtrade over 3 months then monthly cycles (6 months total)Evaluated after 3 months and 6 months After 3 months despite the extensive prior therapy her scans notedthat ldquothere has been a clear response in the multiple bilateral pulmonary nodulesrdquo The response wasmaintained after 6 months of Bria-IMTtrade treatment She matches Bria-IMTtrade at 2 HLA alleles
The liver tumors were stable to slightly increased at 3 months and then progressed after 6 months
This supports our hypothesis of heightened anti-tumor activity in patients with a matched HLA types Clear path to develop BriaDXtrade to select the patients using HLA testing
1 RLL 29 Not Detectable Not Detectable2 LUL apical pleural based 34 tiny nodule lt 1mm scar tiny nodule lt 1mm scar3 xxx 39 Not Detectable Not Detectable4 40 Not Detectable Not Detectable5 RLL 45 Not Detectable Not Detectable6 LLL 49 Not Detectable Not Detectable7 xxx 52 Not Detectable Not Detectable8 RLL 52 Not Detectable Not Detectable9 RLL 56 Not Detectable Not Detectable
10 RLL costophrenic recess 56 Not Detectable Not Detectable11 XXX 58 Not Detectable Not Detectable12 LUL 60 Not Detectable Not Detectable13 XXX 67 15 1514 RUL 72 15 1515 LLL 76 Not Detectable Not Detectable16 RUL Noncalcified Nodule 77 Not Detectable Not Detectable17 RLL costophrenic recess 79 10 1018 RUL 82 Not Detectable Not Detectable19 RLL 90 Not Detectable Not Detectable20 RLL 91 lt 01 lt 0121 xxx xxx Not Detectable Not Detectable
27
Clinical Development Update ndash Summary 2018 September 26
Completed enrollment of Adv Breast cancer patients in the Phase IIIa ldquomonotherapyrdquo study of Bria-IMTtrade
We have confirmed our mechanism of action and achieved proof of concept
Initial safety data appears superior to that of the other advanced or approved drugs for breast cancer when they were at a similar clinical stage of development
Initial efficacy data is similar or superior to those of other advanced or approved drugs for breast cancer when they were at a similar clinical stage of development
Initiated Combination Study of Bria-IMTtrade with Keytrudareg or Yervoyreg in Adv breast cancer patients expecting even better response rates than those in the ldquomonotherapyrdquo study Initial safety data is expected in 4Q2018 Initial efficacy data is expected in 1Q2019
Bria-OTStrade the first off-the-shelf personalized treatment for advanced breast cancer is expected to enter the clinic in 2019
28
Bria-IMTtrade Excellent Safety Data - To Date
To date Bria-IMTtrade has been dosed in 24 patients (4 in 2004-2005 20 in 2017-2018)
Interim Data (20 patients)-Ongoing Phase IIIa Study (2017-2018)
Bria-IMTtrade has been very well tolerated (ge60 doses given to date) The majority of adverse events (AEs) were limited to expected minor local irritation at the
injection sites No related grade gt3 or unexpected AEs No related serious AEs No serious unexpected related AEs Most patients who have dropped out did so due to worsening of their underlying disease
Based on the current study Bria-IMTtrade has an excellent safety profile
29
Bria-IMTtrade - Efficacy as Predicted
Interim Data (19 patients)-Ongoing Phase IIIa Study (2017-2018) amp Original Study (2004-2005)
PD-L1 expression on circulating cancer cells amp cancer-associated cells in 100 of patients (to date) Strong rationale for combination with checkpoint inhibitors like Keytruda
30
Bria-IMTtrade appears to be most effective in patients who match with Bria-IMT trade at 2 HLA loci (types) further supporting our ldquoHLA Matching Hypothesisrdquo and the development of Bria-OTS trade to cover 90 of the patient population
Combination with immune checkpoint inhibitors may induce a more potent anti-cancer response leading to our strategy of combination studies of Bria-IMT trade with Keytruda or Yervoy
Patients (n) HLA Match
Tumor Shrinkage
Biological Response
4 ge2 50 7515 ge1 27 334 0 0 0
Biological response includes tumor shrinkage or lower circulating cancer associated cells
The confirmatory Bria-IMTtrade monotherapy Phase IIa trial has completed enrollment Additional Support for the HLA-matching hypothesis has been obtained
Bria-IMTtrade Combination Therapy study with immune checkpoint inhibitors Keytrudareg if PD-L12 positive (ge1) Yervoyreg if PD-L12 negative (lt1) Accepting patients from the monotherapy study who develop progressive disease Also enrolling patients directly into this study to enhance experience with the combination In discussion with other pharmaceutical companies to evaluate additional combinations with other
immunotherapies
Bria-OTStrade Off-the-Shelf Personalized Targeted Immunotherapy Developing Bria-OTStrade to co-express GM-CSF and interferon-α Pre-manufacture additional HLA alleles ndash Total of 15 alleles (8 Class I and 7 Class II) Co-development of BriaDXtrade companion diagnostic for HLA typing Combination therapy clinical trial with immune checkpoint inhibitors for non-responders using
information from the Bria-IMTtrade Combination Therapy Study
33
Development Timeline ndash Breast Cancer
20192018 2020 2021
Phase IIIaBria-IMTtrade
Monotherapy
Currently Enrolling Phase IIaBria-IMTtrade + Checkpoint
Currently in discussions with potential partnersPhase II Bria-IMTtrade plus Additional Combinations (1Q19 4Q22)(eg PD-1 Inhibitor PD-L1 inhibitor anti-CTLA4 anti-GITR anti-OX40)
1Q 2Q 3Q 4Q
2023
Bria-OTStrade Off-The-Shelf Personalized ImmunotherapyMonotherapy and Potential Partnered Combo Therapy
(2H19 Ongoing)
Bria-OTStradeOff-the-Shelf Cell Line cGMP Manufacturing
and BriaDXtrade(1Q18 1Q19)
Registration Studies (1Q20 2H22)Bria-IMTtrade with Checkpoint InhibitorsBria-OTStrade +- Checkpoint Inhibitors
34
Immuno-oncology Deals
Recent deals of small biotechs with big pharma in immuno-oncology
35
Date PartnershipDevelopment stage at the time of the deal Deal size
07122018 Immatics-Genmab Preclinical Up to $28B
04042018 OSE Immunotherapeutics-Boehringer Ingelheim Preclinical Up to euro113B ($139B)
02092018 Pieris Pharmaceuticals-Seattle Genetics Preclinical Up to $123B
2142018 Nektar-BMS Ph III Up to $36B
01222018 Juno-Celgene Ph II $9B (Acquisition)
11142017 Loxo-Bayer Larotrectinib (Ph II) LOXO-195 (Ph III) Up to $155B
1032017 CytomX-Amgen Preclinical Up to $15B
03202017 CytomX--BMS Ph III Up to $36B
6282016 Xencor-Novartis Preclinical Up to $24B
Early Stage Clinical Studies (Comparison)
We compared the interim data of Ph IIIa study of Bria-IMTtrade in advanced breast cancer with thedata in the early stage clinical studies of recently approved breast cancer drugs and one fasttracked product candidate
Apples to apples comparison Early Stage Clinical Studies in oncology are typically done in patientswith no other therapeutic options Thus the patients have very advanced disease and response ratesare typically quite low
The patients in our Ph IIIa study have been heavily pre-treated (median 45 prior regimens)Some recent studies of relevance in breast cancer are noted in the following slides
36
Breast Cancer Market Opportunity
Drug Technology Approved for Market (US)Ibrance (palbociclib) CDK 46 Inhibitor HR+HER2- MBC in combination with
fluvestrant or aromatase inhibitor$933M in 1Q2018 $3126M in 2017
Kisqali (ribociclib) CDK 46 Inhibitor 2017 HR+HER2- MBC in combination with fluvestrant or aromatase inhibitor
Peak sales projected at $25B
Verzenio (abemaciclib) CDK 46 Inhibitor 2017 HR+HER2- MBC in combination with fluvestrant or aromatase inhibitor
balixafortide CXCR4 antagonist Fast track designation in 2018 for HER2- MBC who have failed 2 prior regimens
The market for breast cancer drugs is a multibillion dollar market with new drugs being approvedon an ongoing basis indicating the shortage of safe and effective treatments for this deadly disease
37
Competitors- Phase III Clinical Data Bria-IMTtrade shows superior safety and similar to superior efficacy data compared with those of the multi-billion dollar drugs when they were at a similar early stage of clinical development
Injection site reactions No related SAEs or SUSARs
Tumor vol darr ampor darr circul tumor cellsAll Comers 21(419) 26(519)One or More HLA matches 27(415) 33(515)Two or More HLA matches 50 (24) 75 (34)
Sheet1 (3)
Comp -Slides
Data
HLA (2)
HLA
Data (Ph1-2+4Pt)
Competitors (2018)-Slide
Competitors (2018)
In the Pipeline Protein Kinase C delta (PKCδ) Inhibitors
30 of all human malignancies display activating RAS mutations Another 60 showing over-activity of Ras-signaling pathways
Ras has been termed ldquoundruggablerdquo (no one has been able to make a Ras inhibitor drug)
BriaCellrsquos novel proprietary PKCδ inhibitors have shown activity against multiple RAS transformed tumors Lung cancer Melanoma Breast cancer Neuroendocrine cancer Pancreatic cancer Colorectal cancer
This target has an attractive safety profile based on in vivo studies and knock out mouse studies
PKCδ inhibitors should qualify for an accelerated clinical development plan and regulatory pathway
Could be in clinic within 24 months
Cost-Effective Additional Shot-on-Goal and additional partnership opportunities
Early-Stage Preclinical Program
39
Protein Kinase C delta (PKCδ) Inhibitors
Activated PKCδ inhibits RAS degradation which in turn stimulates tumor growth
Koo et al Oncotarget 621328 2016
30 of all human malignancies display activating RASmutations with another 60 showing over-activity of Ras-signaling pathways
BriaCellrsquos novel proprietary PKCδ inhibitors have shownactivity against multiple RAS transformed tumors
This target has an attractive safety profile based on in vivostudies and knock out mouse studies
PKCδ also has potential activity as an immunotherapeuticby blocking TGFβ signaling
PKCδ inhibitors are applicable to specific niche tumor typeswhich provide an accelerated clinical development plan
Structural aspects of first generation inhibitor rottlerin and staurosporine (pan-PKC activator) were combined to create second generation inhibitor KAM1
Third generation inhibitors such as BJE6-106 have improved potency and selectivity Fourth generation inhibitors under development to optimize drug-like characteristics PKCδ inhibitors lack endothelial cell cytotoxicity amp PKCδ deficient mice develop normally and are fertile Potentially no marked intrinsic toxicity by inhibiting PKCδ
Mukai H Saeki T Shimada K Naito Y Matsubara N Nakanishi T Obaishi H Namiki M Sasaki Y Phase 1 combination study of eribulin mesylate with trastuzumab for advanced or recurrent human epidermal growth factor receptor 2 positive breast cancer Invest New Drugs 2015 Feb33(1)119-27
AstraZeneca
Lynparza (Olaparib) + Cediranib
PARP inhibitor + inhibitor of VEGF receptor tyrosine kinases
HR+ HER2- MBC
BC amp OC
2013
28 (8 BC)
3 for BC
Olaparib (a poly (ADP-ribose) polymerase (PARP) inhibitor) amp Cediranib (Vascular endothelial growth factor receptor (VEGFR) 1 2 and 3 tyrosine kinase inhibitor)3 at dose level (DL) 0 (cediranib 20mg olaparib 100mg) 3 at DL1 (cediranib 20mg olaparib 200mg) 7 at DL2 (cediranib 30mg olaparib 200mg) 6 at DL3 (cediranib 30mg olaparib 400mg)
Liu JF Tolaney SM Birrer M Fleming GF Buss MK Dahlberg SE Lee H Whalen C Tyburski K Winer E Ivy P Matulonis UA A Phase 1 trial of the poly(ADP-ribose) polymerase inhibitor olaparib (AZD2281) in combination with the anti-angiogenic cediranib (AZD2171) in recurrent epithelial ovarian or triple-negative breast cancer Eur J Cancer 2013 Sep49(14)2972-8
Reyon Pharmaceutical
VM206RY
Heterologous prime-boost with a truncated HER2 sequence
HER2+ Stage IIIampIV BC
2015
9
2 chemo
Plasmid DNA (pHM-GM-CSF expressing truncated HER2 amp GM-CSF) amp adenoviral vector (Ad-HM containing modified HER2) (2 4 and 8 mgpatientvisit) of pHM-GM-CSF 3x IM weeks 0 2 and 4 Ad-HM 3 times 109 virus particles at week 6
11 PR
4 pts showed 7 minor AEs
Unclear
Kim SB Ahn JH Kim J Jung KH A phase 1 study of a heterologous prime-boost vaccination involving a truncated HER2 sequence in patients with HER2-expressing breast cancer Mol Ther Methods Clin Dev 2015 Sep 30215031 doi 101038mtm201531 eCollection 2015
Rodon J Peacuterez-Fidalgo A Krop IE Burris H Guerrero-Zotano A Britten CD Becerra C Schellens J Richards DA Schuler M Abu-Khalaf M Johnson FM Ranson M Edenfield J Silva AP Hackl W Quadt C Demanse D Duval V Baselga J Phase 11b dose escalation and expansion study of BEZ235 a dual PI3KmTOR inhibitor in patients with advanced solid tumors including patients with advanced breast cancer Cancer Chemother Pharmacol 2018 Jun 7 doi 101007s00280-018-3610-z [Epub ahead of print]
Celgene (Abraxane)
Gemcitabine + Abraxane (nab-paclitaxel)
Chemo + Chemo
OC BC NSCLC amp Panc cancer + Lung OC BC Kaposi sarcoma
MBC
2016
9
Adjuvant chemo (100)chemo post-adjuvant (33)
Gem (nucleoside metabolic inhibitor 1250 mgm2) on days 1 and 8 nab-Pac (microtubule inhibitor) starting dose of 180 mgm2 (cohort 1) 220 mgm2 (cohort 2) and 260 mgm2 (cohort 3) on day 1 of the 21-day cycle using a 3 + 3 design
0
MTD not reached29 Gr3 Neutropenia59 Gr1 Peripheralneuropathy
Yoshitomi S Taira N Doihara H Mizoo T Nogami T Iwamoto T Motoki T Shien T Ogasawara Y Matsuoka J Tsuji H Mitsuhashi T A phase 1 dose-finding and pharmacokinetic study of gemcitabine with nab-paclitaxel in patients with metastatic breast cancer Cancer Chemother Pharmacol 2016 Aug78(2)289-94
Eli Lilly
Erbituxreg (cetuximab) + Taxane
EGFR inhibitor antineoplastic agent + Chemo
Headamp Neck Colorectal Cancer
TNBC
2007-2010
18
1 chemo
Cetuximab (epidermal growth factor receptor (EGFR) antagonist ) an initial loading dose of cetuximab 400 mgm2 followed by a weekly dose of 250 mgm2Paclitaxel (microtubule inhibitor) 80 mgm2 or Docetaxel at an initial dose of 30 mgm2 was administered weekly
56 CR 22 PR
83 Dermatologic toxicity11 Grade3+
Nechushtan H Vainer G Stainberg H Salmon AY Hamburger T Peretz T A phase 12 of a combination of cetuximab and taxane for triple negative breast cancer patients Breast 2014 Aug23(4)435-8
Polyphor
Balixafortide (POL6326) + eribulin
CXCR4 antagonist + tubulin-based antimitotic
Heavily pretreated Relapsed MBC
2014-2016
56
3rd line 3 chemo
3+3 dose escalation The highest dose was established as eribulin 14 mgmsup2 on days 2 and 9 and balixafortide 55 mgkg on days 1minus3 and 8minus10 of the 21-day cycle
30 PR
41 Gr34 Neutropenia11 Gr34 Leucopenia11 Gr34 Febrileneutropenia2 Related mortalities
Apr 2018 Fast Track for HER2-MBC who have failed 2prior regimens
Pernas S Martin M Kaufman PA Gil-Martin M Gomez Pardo P Lopez-Tarruella S Manso L Ciruelos E Perez-Fidalgo JA Hernando C Ademuyiwa FO Weilbaecher K Mayer I Pluard TJ Martinez Garcia M Vahdat L Perez-Garcia J Wach A Barker D Fung S Romagnoli B Cortes J Balixafortide plus eribulin in HER2-negative metastatic breast cancer a phase 1 single-arm dose-escalation trial Lancet Oncol 2018 Jun19(6)812-824
11 PRndashbut only + letrozole (No Resp on monotherapy)
61 Gr34 Neutropenia39 Gr34 Leucopenia
$933M in 1Q2018 $31B in 2017
Tamura K Mukai H Naito Y Yonemori K Kodaira M Tanabe Y Yamamoto N Osera S Sasaki M Mori Y Hashigaki S Nagasawa T Umeyama Y Yoshino T Phase I study of palbociclib a cyclin-dependent kinase 46 inhibitor in Japanese patients Cancer Sci 2016 Jun107(6)755-63 doi 101111cas12932 Epub 2016 May 11
Pfizer
Ibrancereg (palbociclib)
CDK 46 Inhibitor
HR+ HER2- MBC
Heavily pretreated Relapsed Metastatic Cancer
2004-2008
41 (5 BC)
chemo naiumlve (17) 1-2 (51)3 (29) 3+ (2)
Palbociclib 25-150 mg dose ranging
0
20 Gr34 Neutropenia23 Gr34 Leucopenia
$933M in 1Q2018 $31B in 2017
Flaherty KT Lorusso PM Demichele A Abramson VG Courtney R Randolph SS Shaik MN Wilner KD ODwyer PJ Schwartz GK Phase I dose-escalation trial of the oral cyclin-dependent kinase 46 inhibitor PD 0332991 administered using a 21-day schedule in patients with advanced cancer Clin Cancer Res 2012 Jan 1518(2)568-76 doi 1011581078-0432CCR-11-0509 Epub 2011 Nov 16
Novartis
Kisqalireg (ribociclib)
CDK 46 Inhibitors
Premenopausal HR+ HER2- MBC
Heavily pretreated Relapsed Metastatic Cancer
2016
132 (20 BC)
0-1 (25) 2-3 (42) 4+ (32)
Ribociclib 50 mg ranging up to 1200 mg dose escalation
23 PRndashincluded 1 in BC (5 of BC pts)
27 Gr34 Neutropenia17 Gr34 Leucopenia
Peak sales projected at $25B
Infante JR Cassier PA Gerecitano JF Witteveen PO Chugh R Ribrag V Chakraborty A Matano A Dobson JR Crystal AS Parasuraman S Shapiro GI A Phase I Study of the Cyclin-Dependent Kinase 46 Inhibitor Ribociclib (LEE011) in Patients with Advanced Solid Tumors and Lymphomas Clin Cancer Res 2016 Dec 122(23)5696-5705 Epub 2016 Aug 19
Eli Lilly
Verzenioreg (abemaciclib)
CDK 46 Inhibitors
HR+HER2minusMBC
Heavily pretreated Relapsed Metastatic Cancer
2016
12 (1 BC)
1 (312) 2 (212) 3+ (7)
Abemaciclib 100 mg ranging up to 200 mg dose escalation
17 PR (included 1 in BC)
17 Gr34 Neutropenia33 Gr34 Leucopenia
Peak sales projected at $2B
Fujiwara Y Tamura K Kondo S Tanabe Y Iwasa S Shimomura A Kitano S Ogasawara K Turner PK Mori J Asou H Chan EM Yamamoto N Phase 1 study of abemaciclib an inhibitor of CDK 4 and 6 as a single agent for Japanese patients with advanced cancer Cancer Chemother Pharmacol 2016 Aug78(2)281-8 doi 101007s00280-016-3085-8 Epub 2016 Jun 16
Mukai H Saeki T Shimada K Naito Y Matsubara N Nakanishi T Obaishi H Namiki M Sasaki Y Phase 1 combination study of eribulin mesylate with trastuzumab for advanced or recurrent human epidermal growth factor receptor 2 positive breast cancer Invest New Drugs 2015 Feb33(1)119-27
AstraZeneca
Lynparza (Olaparib)+ Cediranib
PARP inhibitor+ inhibitor of VEGF RTK
HR+ HER2- MBC
BC amp OC
13
28 (8 BC)
3 for BC
Olaparib (a poly (ADP-ribose) polymerase (PARP) inhibitor) amp Cediranib (Vascular endothelial growth factor receptor (VEGFR) 1 2 and 3 tyrosine kinase inhibitor)3 at dose level (DL) 0 (cediranib 20mg olaparib 100mg) 3 at DL1 (cediranib 20mg olaparib 200mg) 7 at DL2 (cediranib 30mg olaparib 200mg) 6 at DL3 (cediranib 30mg olaparib 400mg)
Liu JF Tolaney SM Birrer M Fleming GF Buss MK Dahlberg SE Lee H Whalen C Tyburski K Winer E Ivy P Matulonis UA A Phase 1 trial of the poly(ADP-ribose) polymerase inhibitor olaparib (AZD2281) in combination with the anti-angiogenic cediranib (AZD2171) in recurrent epithelial ovarian or triple-negative breast cancer Eur J Cancer 2013 Sep49(14)2972-8
ReyonPharma
VM206RY
Heterologous prime-boost with a truncated HER2 sequence
HER2+ Stg IIIampIV BC
15
9
2 chemo
Plasmid DNA (pHM-GM-CSF expressing truncated HER2 amp GM-CSF) amp adenoviral vector (Ad-HM containing modified HER2) (2 4 and 8 mgpatientvisit) of pHM-GM-CSF 3x IM weeks 0 2 and 4 Ad-HM 3 times 109 virus particles at week 6
11 PR
4 pts 7 minor AEs
Unclear
Kim SB Ahn JH Kim J Jung KH A phase 1 study of a heterologous prime-boost vaccination involving a truncated HER2 sequence in patients with HER2-expressing breast cancer Mol Ther Methods Clin Dev 2015 Sep 30215031 doi 101038mtm201531 eCollection 2015
Rodon J Peacuterez-Fidalgo A Krop IE Burris H Guerrero-Zotano A Britten CD Becerra C Schellens J Richards DA Schuler M Abu-Khalaf M Johnson FM Ranson M Edenfield J Silva AP Hackl W Quadt C Demanse D Duval V Baselga J Phase 11b dose escalation and expansion study of BEZ235 a dual PI3KmTOR inhibitor in patients with advanced solid tumors including patients with advanced breast cancer Cancer Chemother Pharmacol 2018 Jun 7 doi 101007s00280-018-3610-z [Epub ahead of print]
Celgene(Abraxane)
Gemcitabine + Abraxane (nab-paclitaxel)
Chemo+ Chemo
OC BC NSCLC PC + LC OC BC KS
MBC
16
9
Adjuv chemo (100)chemo post-adjuv (33)
Gem (nucleoside metabolic inhibitor 1250 mgm2) on days 1 and 8 nab-Pac (microtubule inhibitor) starting dose of 180 mgm2 (cohort 1) 220 mgm2 (cohort 2) and 260 mgm2 (cohort 3) on day 1 of the 21-day cycle using a 3 + 3 design
0
MTD not reached29 Gr3 Neutropenia59 Gr1 Peripheralneuropathy
Yoshitomi S Taira N Doihara H Mizoo T Nogami T Iwamoto T Motoki T Shien T Ogasawara Y Matsuoka J Tsuji H Mitsuhashi T A phase 1 dose-finding and pharmacokinetic study of gemcitabine with nab-paclitaxel in patients with metastatic breast cancer Cancer Chemother Pharmacol 2016 Aug78(2)289-94
Eli Lilly
Erbituxreg (cetuximab) + Taxane
EGFR inhibitor antineoplastic agent + Chemo
Head amp NeckColorectal
TNBC
07-10
18
1 chemo
Cetuximab (epidermal growth factor receptor (EGFR) antagonist ) an initial loading dose of cetuximab 400 mgm2 followed by a weekly dose of 250 mgm2Paclitaxel (microtubule inhibitor) 80 mgm2 or Docetaxel at an initial dose of 30 mgm2 was administered weekly
56 CR 22 PR
83 Dermatologic toxicity11 Grade3+
Nechushtan H Vainer G Stainberg H Salmon AY Hamburger T Peretz T A phase 12 of a combination of cetuximab and taxane for triple negative breast cancer patients Breast 2014 Aug23(4)435-8
Polyphor
Balixafortide (POL6326) + eribulin
CXCR4 antagonist + tubulin-based antimitotic
Heavily pretreatedRelapsed MBC
14-16
56
3rd line 3 chemo
3+3 dose escalation The highest dose was established as eribulin 14 mgmsup2 on days 2 and 9 and balixafortide 55 mgkg on days 1minus3 and 8minus10 of the 21-day cycle
30 PR
41 Gr34 Neutropenia11 Gr34 Leucopenia11 Gr34 Febrileneutropenia2 Related mortalities
42018 Fast Track (HER2-MBC failed 2 prior regimens)
Pernas S Martin M Kaufman PA Gil-Martin M Gomez Pardo P Lopez-Tarruella S Manso L Ciruelos E Perez-Fidalgo JA Hernando C Ademuyiwa FO Weilbaecher K Mayer I Pluard TJ Martinez Garcia M Vahdat L Perez-Garcia J Wach A Barker D Fung S Romagnoli B Cortes J Balixafortide plus eribulin in HER2-negative metastatic breast cancer a phase 1 single-arm dose-escalation trial Lancet Oncol 2018 Jun19(6)812-824
1 PRndashbut only + letrozoleNo Resp on monotherapy
61 Gr34 Neutropenia39 Gr34 Leucopenia
$933M (1Q18)$31B (2017)
Tamura K Mukai H Naito Y Yonemori K Kodaira M Tanabe Y Yamamoto N Osera S Sasaki M Mori Y Hashigaki S Nagasawa T Umeyama Y Yoshino T Phase I study of palbociclib a cyclin-dependent kinase 46 inhibitor in Japanese patients Cancer Sci 2016 Jun107(6)755-63 doi 101111cas12932 Epub 2016 May 11
Pfizer
Ibrancereg (palbociclib)
CDK 46 Inhibitor
HR+ HER2- MBC
Heavily pretreatedRelapsed Met Cancer
04-08
41 (5 BC)
chemo naiumlve (17)1-2(51) 3(29) 3+(2)
Palbociclib 25-150 mg dose ranging
0
20 Gr34 Neutropenia23 Gr34 Leucopenia
$933M (1Q18)$31B (2017)
Flaherty KT Lorusso PM Demichele A Abramson VG Courtney R Randolph SS Shaik MN Wilner KD ODwyer PJ Schwartz GK Phase I dose-escalation trial of the oral cyclin-dependent kinase 46 inhibitor PD 0332991 administered using a 21-day schedule in patients with advanced cancer Clin Cancer Res 2012 Jan 1518(2)568-76 doi 1011581078-0432CCR-11-0509 Epub 2011 Nov 16
Novartis
Kisqalireg (ribociclib)
CDK 46 Inhibitor
Premenopausal HR+ HER2- MBC
Heavily pretreatedRelapsed Met Cancer
16
132 (20 BC)
0-1 (25) 2-3 (42)4+ (32)
Ribociclib 50 mg ranging up to 1200 mg dose escalation
23 PR-included 1 BC (5 of BC pts)
27 Gr34 Neutropenia17 Gr34 Leucopenia
Peak sales est at $25B
Infante JR Cassier PA Gerecitano JF Witteveen PO Chugh R Ribrag V Chakraborty A Matano A Dobson JR Crystal AS Parasuraman S Shapiro GI A Phase I Study of the Cyclin-Dependent Kinase 46 Inhibitor Ribociclib (LEE011) in Patients with Advanced Solid Tumors and Lymphomas Clin Cancer Res 2016 Dec 122(23)5696-5705 Epub 2016 Aug 19
Eli Lilly
Verzenioreg (abemaciclib)
CDK 46 Inhibitor
HR+HER2minusMBC
Heavily pretreatedRelapsed Met Cancer
16
12 (1 BC)
1 (312) 2 (212) 3+(7)
Abemaciclib 100 mg ranging up to 200 mg dose escalation
17 PR (included 1 BC)
17 Gr34 Neutropenia33 Gr34 Leucopenia
Peak sales est at $2B
Fujiwara Y Tamura K Kondo S Tanabe Y Iwasa S Shimomura A Kitano S Ogasawara K Turner PK Mori J Asou H Chan EM Yamamoto N Phase 1 study of abemaciclib an inhibitor of CDK 4 and 6 as a single agent for Japanese patients with advanced cancer Cancer Chemother Pharmacol 2016 Aug78(2)281-8 doi 101007s00280-016-3085-8 Epub 2016 Jun 16
Mukai H Saeki T Shimada K Naito Y Matsubara N Nakanishi T Obaishi H Namiki M Sasaki Y Phase 1 combination study of eribulin mesylate with trastuzumab for advanced or recurrent human epidermal growth factor receptor 2 positive breast cancer Invest New Drugs 2015 Feb33(1)119-27
AstraZeneca
Lynparza (Olaparib) + Cediranib
PARP inhibitor + inhibitor of VEGF receptor tyrosine kinases
HR+ HER2- MBC
BC amp OC
2013
28 (8 BC)
3 for BC
Olaparib (a poly (ADP-ribose) polymerase (PARP) inhibitor) amp Cediranib (Vascular endothelial growth factor receptor (VEGFR) 1 2 and 3 tyrosine kinase inhibitor)3 at dose level (DL) 0 (cediranib 20mg olaparib 100mg) 3 at DL1 (cediranib 20mg olaparib 200mg) 7 at DL2 (cediranib 30mg olaparib 200mg) 6 at DL3 (cediranib 30mg olaparib 400mg)
Liu JF Tolaney SM Birrer M Fleming GF Buss MK Dahlberg SE Lee H Whalen C Tyburski K Winer E Ivy P Matulonis UA A Phase 1 trial of the poly(ADP-ribose) polymerase inhibitor olaparib (AZD2281) in combination with the anti-angiogenic cediranib (AZD2171) in recurrent epithelial ovarian or triple-negative breast cancer Eur J Cancer 2013 Sep49(14)2972-8
Reyon Pharmaceutical
VM206RY
Heterologous prime-boost with a truncated HER2 sequence
HER2+ Stage IIIampIV BC
2015
9
2 chemo
Plasmid DNA (pHM-GM-CSF expressing truncated HER2 amp GM-CSF) amp adenoviral vector (Ad-HM containing modified HER2) (2 4 and 8 mgpatientvisit) of pHM-GM-CSF 3x IM weeks 0 2 and 4 Ad-HM 3 times 109 virus particles at week 6
11 PR
4 pts showed 7 minor AEs
Unclear
Kim SB Ahn JH Kim J Jung KH A phase 1 study of a heterologous prime-boost vaccination involving a truncated HER2 sequence in patients with HER2-expressing breast cancer Mol Ther Methods Clin Dev 2015 Sep 30215031 doi 101038mtm201531 eCollection 2015
Rodon J Peacuterez-Fidalgo A Krop IE Burris H Guerrero-Zotano A Britten CD Becerra C Schellens J Richards DA Schuler M Abu-Khalaf M Johnson FM Ranson M Edenfield J Silva AP Hackl W Quadt C Demanse D Duval V Baselga J Phase 11b dose escalation and expansion study of BEZ235 a dual PI3KmTOR inhibitor in patients with advanced solid tumors including patients with advanced breast cancer Cancer Chemother Pharmacol 2018 Jun 7 doi 101007s00280-018-3610-z [Epub ahead of print]
Celgene (Abraxane)
Gemcitabine + Abraxane (nab-paclitaxel)
Chemo + Chemo
OC BC NSCLC amp Panc cancer + Lung OC BC Kaposi sarcoma
MBC
2016
9
Adjuvant chemo (100)chemo post-adjuvant (33)
Gem (nucleoside metabolic inhibitor 1250 mgm2) on days 1 and 8 nab-Pac (microtubule inhibitor) starting dose of 180 mgm2 (cohort 1) 220 mgm2 (cohort 2) and 260 mgm2 (cohort 3) on day 1 of the 21-day cycle using a 3 + 3 design
0
MTD not reached29 Gr3 Neutropenia59 Gr1 Peripheralneuropathy
Yoshitomi S Taira N Doihara H Mizoo T Nogami T Iwamoto T Motoki T Shien T Ogasawara Y Matsuoka J Tsuji H Mitsuhashi T A phase 1 dose-finding and pharmacokinetic study of gemcitabine with nab-paclitaxel in patients with metastatic breast cancer Cancer Chemother Pharmacol 2016 Aug78(2)289-94
Eli Lilly
Erbituxreg (cetuximab) + Taxane
EGFR inhibitor antineoplastic agent + Chemo
Headamp Neck Colorectal Cancer
TNBC
2007-2010
18
1 chemo
Cetuximab (epidermal growth factor receptor (EGFR) antagonist ) an initial loading dose of cetuximab 400 mgm2 followed by a weekly dose of 250 mgm2Paclitaxel (microtubule inhibitor) 80 mgm2 or Docetaxel at an initial dose of 30 mgm2 was administered weekly
56 CR 22 PR
83 Dermatologic toxicity11 Grade3+
Nechushtan H Vainer G Stainberg H Salmon AY Hamburger T Peretz T A phase 12 of a combination of cetuximab and taxane for triple negative breast cancer patients Breast 2014 Aug23(4)435-8
Polyphor
Balixafortide (POL6326) + eribulin
CXCR4 antagonist + tubulin-based antimitotic
Heavily pretreated Relapsed MBC
2014-2016
56
3rd line 3 chemo
3+3 dose escalation The highest dose was established as eribulin 14 mgmsup2 on days 2 and 9 and balixafortide 55 mgkg on days 1minus3 and 8minus10 of the 21-day cycle
30 PR
41 Gr34 Neutropenia11 Gr34 Leucopenia11 Gr34 Febrileneutropenia2 Related mortalities
Apr 2018 Fast Track for HER2-MBC who have failed 2prior regimens
Pernas S Martin M Kaufman PA Gil-Martin M Gomez Pardo P Lopez-Tarruella S Manso L Ciruelos E Perez-Fidalgo JA Hernando C Ademuyiwa FO Weilbaecher K Mayer I Pluard TJ Martinez Garcia M Vahdat L Perez-Garcia J Wach A Barker D Fung S Romagnoli B Cortes J Balixafortide plus eribulin in HER2-negative metastatic breast cancer a phase 1 single-arm dose-escalation trial Lancet Oncol 2018 Jun19(6)812-824
11 PRndashbut only + letrozole (No Resp on monotherapy)
61 Gr34 Neutropenia39 Gr34 Leucopenia
$933M in 1Q2018 $31B in 2017
Tamura K Mukai H Naito Y Yonemori K Kodaira M Tanabe Y Yamamoto N Osera S Sasaki M Mori Y Hashigaki S Nagasawa T Umeyama Y Yoshino T Phase I study of palbociclib a cyclin-dependent kinase 46 inhibitor in Japanese patients Cancer Sci 2016 Jun107(6)755-63 doi 101111cas12932 Epub 2016 May 11
Pfizer
Ibrancereg (palbociclib)
CDK 46 Inhibitor
HR+ HER2- MBC
Heavily pretreated Relapsed Metastatic Cancer
2004-2008
41 (5 BC)
chemo naiumlve (17) 1-2 (51)3 (29) 3+ (2)
Palbociclib 25-150 mg dose ranging
0
20 Gr34 Neutropenia23 Gr34 Leucopenia
$933M in 1Q2018 $31B in 2017
Flaherty KT Lorusso PM Demichele A Abramson VG Courtney R Randolph SS Shaik MN Wilner KD ODwyer PJ Schwartz GK Phase I dose-escalation trial of the oral cyclin-dependent kinase 46 inhibitor PD 0332991 administered using a 21-day schedule in patients with advanced cancer Clin Cancer Res 2012 Jan 1518(2)568-76 doi 1011581078-0432CCR-11-0509 Epub 2011 Nov 16
Novartis
Kisqalireg (ribociclib)
CDK 46 Inhibitors
Premenopausal HR+ HER2- MBC
Heavily pretreated Relapsed Metastatic Cancer
2016
132 (20 BC)
0-1 (25) 2-3 (42) 4+ (32)
Ribociclib 50 mg ranging up to 1200 mg dose escalation
23 PRndashincluded 1 in BC (5 of BC pts)
27 Gr34 Neutropenia17 Gr34 Leucopenia
Peak sales projected at $25B
Infante JR Cassier PA Gerecitano JF Witteveen PO Chugh R Ribrag V Chakraborty A Matano A Dobson JR Crystal AS Parasuraman S Shapiro GI A Phase I Study of the Cyclin-Dependent Kinase 46 Inhibitor Ribociclib (LEE011) in Patients with Advanced Solid Tumors and Lymphomas Clin Cancer Res 2016 Dec 122(23)5696-5705 Epub 2016 Aug 19
Eli Lilly
Verzenioreg (abemaciclib)
CDK 46 Inhibitors
HR+HER2minusMBC
Heavily pretreated Relapsed Metastatic Cancer
2016
12 (1 BC)
1 (312) 2 (212) 3+ (7)
Abemaciclib 100 mg ranging up to 200 mg dose escalation
17 PR (included 1 in BC)
17 Gr34 Neutropenia33 Gr34 Leucopenia
Peak sales projected at $2B
Fujiwara Y Tamura K Kondo S Tanabe Y Iwasa S Shimomura A Kitano S Ogasawara K Turner PK Mori J Asou H Chan EM Yamamoto N Phase 1 study of abemaciclib an inhibitor of CDK 4 and 6 as a single agent for Japanese patients with advanced cancer Cancer Chemother Pharmacol 2016 Aug78(2)281-8 doi 101007s00280-016-3085-8 Epub 2016 Jun 16
Mukai H Saeki T Shimada K Naito Y Matsubara N Nakanishi T Obaishi H Namiki M Sasaki Y Phase 1 combination study of eribulin mesylate with trastuzumab for advanced or recurrent human epidermal growth factor receptor 2 positive breast cancer Invest New Drugs 2015 Feb33(1)119-27
AstraZeneca
Lynparza (Olaparib)+ Cediranib
PARP inhibitor+ inhibitor of VEGF RTK
HR+ HER2- MBC
BC amp OC
13
28 (8 BC)
3 for BC
Olaparib (a poly (ADP-ribose) polymerase (PARP) inhibitor) amp Cediranib (Vascular endothelial growth factor receptor (VEGFR) 1 2 and 3 tyrosine kinase inhibitor)3 at dose level (DL) 0 (cediranib 20mg olaparib 100mg) 3 at DL1 (cediranib 20mg olaparib 200mg) 7 at DL2 (cediranib 30mg olaparib 200mg) 6 at DL3 (cediranib 30mg olaparib 400mg)
Liu JF Tolaney SM Birrer M Fleming GF Buss MK Dahlberg SE Lee H Whalen C Tyburski K Winer E Ivy P Matulonis UA A Phase 1 trial of the poly(ADP-ribose) polymerase inhibitor olaparib (AZD2281) in combination with the anti-angiogenic cediranib (AZD2171) in recurrent epithelial ovarian or triple-negative breast cancer Eur J Cancer 2013 Sep49(14)2972-8
ReyonPharma
VM206RY
Heterologous prime-boost with a truncated HER2 sequence
HER2+ Stg IIIampIV BC
15
9
2 chemo
Plasmid DNA (pHM-GM-CSF expressing truncated HER2 amp GM-CSF) amp adenoviral vector (Ad-HM containing modified HER2) (2 4 and 8 mgpatientvisit) of pHM-GM-CSF 3x IM weeks 0 2 and 4 Ad-HM 3 times 109 virus particles at week 6
11 PR
4 pts 7 minor AEs
Unclear
Kim SB Ahn JH Kim J Jung KH A phase 1 study of a heterologous prime-boost vaccination involving a truncated HER2 sequence in patients with HER2-expressing breast cancer Mol Ther Methods Clin Dev 2015 Sep 30215031 doi 101038mtm201531 eCollection 2015
Rodon J Peacuterez-Fidalgo A Krop IE Burris H Guerrero-Zotano A Britten CD Becerra C Schellens J Richards DA Schuler M Abu-Khalaf M Johnson FM Ranson M Edenfield J Silva AP Hackl W Quadt C Demanse D Duval V Baselga J Phase 11b dose escalation and expansion study of BEZ235 a dual PI3KmTOR inhibitor in patients with advanced solid tumors including patients with advanced breast cancer Cancer Chemother Pharmacol 2018 Jun 7 doi 101007s00280-018-3610-z [Epub ahead of print]
Celgene(Abraxane)
Gemcitabine + Abraxane (nab-paclitaxel)
Chemo+ Chemo
OC BC NSCLC PC + LC OC BC KS
MBC
16
9
Adjuv chemo (100)chemo post-adjuv (33)
Gem (nucleoside metabolic inhibitor 1250 mgm2) on days 1 and 8 nab-Pac (microtubule inhibitor) starting dose of 180 mgm2 (cohort 1) 220 mgm2 (cohort 2) and 260 mgm2 (cohort 3) on day 1 of the 21-day cycle using a 3 + 3 design
0
MTD not reached29 Gr3 Neutropenia59 Gr1 Peripheralneuropathy
Yoshitomi S Taira N Doihara H Mizoo T Nogami T Iwamoto T Motoki T Shien T Ogasawara Y Matsuoka J Tsuji H Mitsuhashi T A phase 1 dose-finding and pharmacokinetic study of gemcitabine with nab-paclitaxel in patients with metastatic breast cancer Cancer Chemother Pharmacol 2016 Aug78(2)289-94
Eli Lilly
Erbituxreg (cetuximab) + Taxane
EGFR inhibitor antineoplastic agent + Chemo
Head amp NeckColorectal
TNBC
07-10
18
1 chemo
Cetuximab (epidermal growth factor receptor (EGFR) antagonist ) an initial loading dose of cetuximab 400 mgm2 followed by a weekly dose of 250 mgm2Paclitaxel (microtubule inhibitor) 80 mgm2 or Docetaxel at an initial dose of 30 mgm2 was administered weekly
56 CR 22 PR
83 Dermatologic toxicity11 Grade3+
Nechushtan H Vainer G Stainberg H Salmon AY Hamburger T Peretz T A phase 12 of a combination of cetuximab and taxane for triple negative breast cancer patients Breast 2014 Aug23(4)435-8
Polyphor
Balixafortide (POL6326) + eribulin
CXCR4 antagonist + tubulin-based antimitotic
Heavily pretreatedRelapsed MBC
14-16
56
3rd line 3 chemo
3+3 dose escalation The highest dose was established as eribulin 14 mgmsup2 on days 2 and 9 and balixafortide 55 mgkg on days 1minus3 and 8minus10 of the 21-day cycle
30 PR
41 Gr34 Neutropenia11 Gr34 Leucopenia11 Gr34 Febrileneutropenia2 Related mortalities
42018 Fast Track (HER2-MBC failed 2 prior regimens)
Pernas S Martin M Kaufman PA Gil-Martin M Gomez Pardo P Lopez-Tarruella S Manso L Ciruelos E Perez-Fidalgo JA Hernando C Ademuyiwa FO Weilbaecher K Mayer I Pluard TJ Martinez Garcia M Vahdat L Perez-Garcia J Wach A Barker D Fung S Romagnoli B Cortes J Balixafortide plus eribulin in HER2-negative metastatic breast cancer a phase 1 single-arm dose-escalation trial Lancet Oncol 2018 Jun19(6)812-824
1 PRndashbut only + letrozoleNo Resp on monotherapy
61 Gr34 Neutropenia39 Gr34 Leucopenia
$933M (1Q18)$31B (2017)
Tamura K Mukai H Naito Y Yonemori K Kodaira M Tanabe Y Yamamoto N Osera S Sasaki M Mori Y Hashigaki S Nagasawa T Umeyama Y Yoshino T Phase I study of palbociclib a cyclin-dependent kinase 46 inhibitor in Japanese patients Cancer Sci 2016 Jun107(6)755-63 doi 101111cas12932 Epub 2016 May 11
Pfizer
Ibrancereg (palbociclib)
CDK 46 Inhibitor
HR+ HER2- MBC
Heavily pretreatedRelapsed Met Cancer
04-08
41 (5 BC)
chemo naiumlve (17)1-2(51) 3(29) 3+(2)
Palbociclib 25-150 mg dose ranging
0
20 Gr34 Neutropenia23 Gr34 Leucopenia
$933M (1Q18)$31B (2017)
Flaherty KT Lorusso PM Demichele A Abramson VG Courtney R Randolph SS Shaik MN Wilner KD ODwyer PJ Schwartz GK Phase I dose-escalation trial of the oral cyclin-dependent kinase 46 inhibitor PD 0332991 administered using a 21-day schedule in patients with advanced cancer Clin Cancer Res 2012 Jan 1518(2)568-76 doi 1011581078-0432CCR-11-0509 Epub 2011 Nov 16
Novartis
Kisqalireg (ribociclib)
CDK 46 Inhibitor
Premenopausal HR+ HER2- MBC
Heavily pretreatedRelapsed Met Cancer
16
132 (20 BC)
0-1 (25) 2-3 (42)4+ (32)
Ribociclib 50 mg ranging up to 1200 mg dose escalation
23 PR-included 1 BC (5 of BC pts)
27 Gr34 Neutropenia17 Gr34 Leucopenia
Peak sales est at $25B
Infante JR Cassier PA Gerecitano JF Witteveen PO Chugh R Ribrag V Chakraborty A Matano A Dobson JR Crystal AS Parasuraman S Shapiro GI A Phase I Study of the Cyclin-Dependent Kinase 46 Inhibitor Ribociclib (LEE011) in Patients with Advanced Solid Tumors and Lymphomas Clin Cancer Res 2016 Dec 122(23)5696-5705 Epub 2016 Aug 19
Eli Lilly
Verzenioreg (abemaciclib)
CDK 46 Inhibitor
HR+HER2minusMBC
Heavily pretreatedRelapsed Met Cancer
16
12 (1 BC)
1 (312) 2 (212) 3+(7)
Abemaciclib 100 mg ranging up to 200 mg dose escalation
17 PR (included 1 BC)
17 Gr34 Neutropenia33 Gr34 Leucopenia
Peak sales est at $2B
Fujiwara Y Tamura K Kondo S Tanabe Y Iwasa S Shimomura A Kitano S Ogasawara K Turner PK Mori J Asou H Chan EM Yamamoto N Phase 1 study of abemaciclib an inhibitor of CDK 4 and 6 as a single agent for Japanese patients with advanced cancer Cancer Chemother Pharmacol 2016 Aug78(2)281-8 doi 101007s00280-016-3085-8 Epub 2016 Jun 16
Bria-IMTtrade and Bria-OTStrade shouldsynergize with existing approvedimmunotherapies as well as those stillunder development
This includes immune checkpointinhibitors such as antibodies to PD-1CTLA-4 GITR and CD73 inhibitors whicheliminate tumor immunosuppression Checkpoint Inhibitors were the
subject of the 2018 Nobel Prize inMedicine
In addition immunostimulatoryantibodies to molecules such as OX40should enhance responses to Bria-IMTtradeand Bria-OTStrade
13
Q3 2018 Data on first 20 Patients on Bria-IMTtrade Q3 2018 Initiate Combination Study of Bria-IMTtrade with Keytruda or Yervoy
Q4 2018 Switch to a novel frozen Bria-IMTtrade formulation Q4 2018 Safety Data (6 patients) of the Bria-IMTtrade - Keytrudareg Combination Study (SABC meeting) Q4 2018 Ongoing Corporate PartnershipCollaboration Discussions
Q1 2019 Efficacy Data (6 patients) of the Bria-IMTtrade - Keytrudareg Combination Study Q2 2019 Initiation of Bria-OTStrade GMP manufacturing (KBI BioPharma) Q2 2019 Additional Safety amp Efficacy data Monotherapy and Combination Studies (AACR meeting) Q2 2019 Final data for Monotherapy and Additional Data for the Combination Study (ASCO meeting) H1 2019 Candidate Selection for a PKCδ Inhibitor H1 2019 Initiate additional immunotherapy program H2 2019 Bria-OTStrade Authorization from FDA clearance for dosing H2 2019 Bria-OTStrade First Patient Dosed
Upcoming Milestones amp Catalysts
14
Involved in over 10 drugs brought to the market
Experienced Management Team
Management
William V Williams MD FACP President amp CEO VP Exploratory Development Incyte Corporation VP Experimental Medicine GlaxoSmithKline Head Rheumatology Research University of Pennsylvania Facilitated entry of over 20 compounds into the clinic including ruxolitinib (Jakafi)
baricitinib amp epacadostat NDAs including Jakafi Boniva Bexxar Author of over 120 peer-reviewed publications amp over 20 patents
Gadi Levin CA MBA CFO CFO of Labstyle Innovations Ltd VP of Finance for two Israeli investment houses in the fields of private equity
hedge funds and real estate Financial Consultant various firms Accountant Arthur Andersen
Markus Lacher PhD Senior Director RampD Founder T cell Therapeutics Inc an immuno-oncology company Sr Clinical Scientist Cesca Therapeutics Inc a clinical-stage autologous cell
therapy company Scientist at BioTime Inc and OncoCyte Corporation Editorial advisory board Recent Patents on Anti-Cancer Drug Discovery
Farrah Dean MSc MBA Manager Corp Development Investor relations CytRx Corporation amp CCG Investor Relations Senior Associate Equity Analyst Oppenheimer amp Co Rodman amp Renshaw amp
Brian Metcalf PhD Recently retired as CSO from Global Blood Therapeutics Former Head of Research amp Development Incyte Corporation Former Head of Medicinal Chemistry SmithKline Beecham
Douglas Faller MD PhD Professor of Medicine Pediatrics Biochemistry Microbiology Pathology and
Laboratory Medicine HematologistOncologist former Director of the Cancer Center Boston University School of Medicine
Founder of several successful biotechnology companies
Robert Williams PhD University Distinguished Professor of Chemistry Colorado State University Founder of several successful biotechnology companies including Microcide Xcyte
Therapies HemaQuest Arch Therapeutics and Cetya Therapeutics
Thomas Kieber-Emmons PhD Deputy Director University of Arkansas Cancer Center Expert in targeted cancer immunotherapies structural biology and computational
chemistry
Maria Trojanowska PhD Professor of Medicine Boston University School of Medicine Director The Arthritis Center
16
Veteran Board of Directors
Board of Directors
Saeid Babaei PhD MBA Chairman Entrepreneur 20 yrs of biotech leadership roles Current CEO AbCelex VP Bus Develop Lorus Therap Dir of Corp Develop Northern Therapeutics
Rahoul Sharan CA Director Chairman Potash Ridge Director of the Board Ansell Capital Corp Parallel Resources amp Galaxy Capital
Corporation
Martin Schmieg CPA Director CFO Sirna Therapeutics Inc amp Isolagen Inc CEO Freedom-2 Inc (now PharmaCyte Inc) Advisor Caladrius Biosciences Inc Beckman Coulter Genomics Calimmune
Charles Wiseman MD Co-Founder amp Director Director Immunotherapy Lab St Vincent Medical Center Chief Breast Cancer Basic Research Lab Univ of Texas MD Anderson Hospital amp
Tumour Institute Assist Prof Dept of Molecular Carcinogenesis amp Virology MD Anderson Acting Chief Div of Oncology White Memorial Medical Center LA
William V Williams MD FACP President amp CEO VP Exploratory Development Incyte Corporation VP Experimental Medicine GlaxoSmithKline Head Rheumatology Research University of Pennsylvania
Prior Affiliations
17
Drug Approvals by BriaCell Management Team
Bexxarreg (tositumomab and Iodine I131 tositumomab) Treatment of CD20 antigen-expressing relapsed or refractory low grade follicular or transformed non-Hodgkins lymphoma
Myleranreg (busulfan) for chronic myelogenous leukemia Defense of formulation change sNDA
Hycamtinreg (topotecan) for ovarian cancer Pediatric use sNDA
Navelbinereg (vinorelbine tartrate) for non-small cell lung cancer Pediatric use sNDA
Bonivareg (ibandronate) monthly oral treatment of osteoporosis
Bonivareg (ibandronate) quarterly intraveous treatment of osteoporosis
Zofranreg (ondansetron) for prevention of nausea and vomiting Pediatric use sNDA
Jakafireg (ruxolitinib) for myelofibrosis Jakafireg (ruxolitinib) for polycythemia vera
Olumiantreg (baricitinib) for rheumatoid arthritis Approved in USA Japan and Europe
18
Share Metrics
BCTV BCTXF 19
Data as of 1092018
Ticker TSX BCTV
US Ticker OTCQBBCTXF
Share Price (CAD) as of Oct 9 2018 $012
52-Week Range (CAD) $009-019
Shares Outstanding as of Oct 9 2018 1611M
Market Cap as of Oct 9 2018 (CAD) $193M
Cash and Short Term Investments as of July 31 2018 (CAD) $23M
Total Shareholders Equity as of July 31 2018 (CAD) $12M
Number of Warrants $014-$035 (CAD) as of Oct 9 2018 601M
Number of Compensation Warrants $014-$030 (CAD) as of Oct 9 2018 45M
Number of Options $014- $026 (CAD$) as of Oct 9 2018 93M
Developing Bria-OTStrade the First Off-the-Shelf Personalized Immunotherapy
Targeting Adv Breast Cancer Unmet medical need (42000 death in the US in 2017 ) $1 Bil- $5 Bil market opportunity depending on patient treatment stage
Impressive results in 2 proof-of-concept clinical trials Rapid Response Rate Repeated following re-treatment Excellent Safety Profile
Completed enrollment in Phase IIIa clinical trial of Bria-IMTtrade with outstanding safety amp efficacy data Initiated Phase IIa Combination Study of Bria-IMTtrade with Keytrudareg (Merck amp Co Inc)
Developing Bria-OTStrade along with BriaDXtrade its companion diagnostic test Ability to match and treat ~90 of patient population with Off-the-Shelf personalized immunotherapy
Experienced Management has been involved in over 10 drug approvals
Patient B001 Breast 70 No 1101 - 3501 4001 Negative -
Bria-IMTtradeHuman Proof-of-Concept Trials in Breast Cancer (Patient A002)
24
Proof-of-Concept Results Resulted in BriaCellrsquos Immunotherapy Strategy Use BriaDXtrade diagnostic to select only those patients matching Bria-IMTtrade Use BriaDXtrade diagnostic test to select Bria-OTStrade alleles matching ~90 of all patients
Bria-IMTtradeCurrent Phase IIIa Data Supports HLA Matching Hypothesis Six patients treated in 2017 Bria-IMTtrade was safe and well tolerated
Patient 01-002 73-year-old woman with breast cancer diagnosed in 1995 Developed liver metastases in2010 and lung metastases in 2017 Previously treated with 7 rounds of chemotherapy with 8 differentchemotherapy agents Received 5 cycles of Bria-IMTtrade over 3 months then monthly cycles (6 months total)Evaluated after 3 months and 6 months After 3 months despite the extensive prior therapy her scans notedthat ldquothere has been a clear response in the multiple bilateral pulmonary nodulesrdquo The response wasmaintained after 6 months of Bria-IMTtrade treatment She matches Bria-IMTtrade at 2 HLA alleles
The liver tumors were stable to slightly increased at 3 months and then progressed after 6 months
This supports our hypothesis of heightened anti-tumor activity in patients with a matched HLA types Clear path to develop BriaDXtrade to select the patients using HLA testing
1 RLL 29 Not Detectable Not Detectable2 LUL apical pleural based 34 tiny nodule lt 1mm scar tiny nodule lt 1mm scar3 xxx 39 Not Detectable Not Detectable4 40 Not Detectable Not Detectable5 RLL 45 Not Detectable Not Detectable6 LLL 49 Not Detectable Not Detectable7 xxx 52 Not Detectable Not Detectable8 RLL 52 Not Detectable Not Detectable9 RLL 56 Not Detectable Not Detectable
10 RLL costophrenic recess 56 Not Detectable Not Detectable11 XXX 58 Not Detectable Not Detectable12 LUL 60 Not Detectable Not Detectable13 XXX 67 15 1514 RUL 72 15 1515 LLL 76 Not Detectable Not Detectable16 RUL Noncalcified Nodule 77 Not Detectable Not Detectable17 RLL costophrenic recess 79 10 1018 RUL 82 Not Detectable Not Detectable19 RLL 90 Not Detectable Not Detectable20 RLL 91 lt 01 lt 0121 xxx xxx Not Detectable Not Detectable
27
Clinical Development Update ndash Summary 2018 September 26
Completed enrollment of Adv Breast cancer patients in the Phase IIIa ldquomonotherapyrdquo study of Bria-IMTtrade
We have confirmed our mechanism of action and achieved proof of concept
Initial safety data appears superior to that of the other advanced or approved drugs for breast cancer when they were at a similar clinical stage of development
Initial efficacy data is similar or superior to those of other advanced or approved drugs for breast cancer when they were at a similar clinical stage of development
Initiated Combination Study of Bria-IMTtrade with Keytrudareg or Yervoyreg in Adv breast cancer patients expecting even better response rates than those in the ldquomonotherapyrdquo study Initial safety data is expected in 4Q2018 Initial efficacy data is expected in 1Q2019
Bria-OTStrade the first off-the-shelf personalized treatment for advanced breast cancer is expected to enter the clinic in 2019
28
Bria-IMTtrade Excellent Safety Data - To Date
To date Bria-IMTtrade has been dosed in 24 patients (4 in 2004-2005 20 in 2017-2018)
Interim Data (20 patients)-Ongoing Phase IIIa Study (2017-2018)
Bria-IMTtrade has been very well tolerated (ge60 doses given to date) The majority of adverse events (AEs) were limited to expected minor local irritation at the
injection sites No related grade gt3 or unexpected AEs No related serious AEs No serious unexpected related AEs Most patients who have dropped out did so due to worsening of their underlying disease
Based on the current study Bria-IMTtrade has an excellent safety profile
29
Bria-IMTtrade - Efficacy as Predicted
Interim Data (19 patients)-Ongoing Phase IIIa Study (2017-2018) amp Original Study (2004-2005)
PD-L1 expression on circulating cancer cells amp cancer-associated cells in 100 of patients (to date) Strong rationale for combination with checkpoint inhibitors like Keytruda
30
Bria-IMTtrade appears to be most effective in patients who match with Bria-IMT trade at 2 HLA loci (types) further supporting our ldquoHLA Matching Hypothesisrdquo and the development of Bria-OTS trade to cover 90 of the patient population
Combination with immune checkpoint inhibitors may induce a more potent anti-cancer response leading to our strategy of combination studies of Bria-IMT trade with Keytruda or Yervoy
Patients (n) HLA Match
Tumor Shrinkage
Biological Response
4 ge2 50 7515 ge1 27 334 0 0 0
Biological response includes tumor shrinkage or lower circulating cancer associated cells
The confirmatory Bria-IMTtrade monotherapy Phase IIa trial has completed enrollment Additional Support for the HLA-matching hypothesis has been obtained
Bria-IMTtrade Combination Therapy study with immune checkpoint inhibitors Keytrudareg if PD-L12 positive (ge1) Yervoyreg if PD-L12 negative (lt1) Accepting patients from the monotherapy study who develop progressive disease Also enrolling patients directly into this study to enhance experience with the combination In discussion with other pharmaceutical companies to evaluate additional combinations with other
immunotherapies
Bria-OTStrade Off-the-Shelf Personalized Targeted Immunotherapy Developing Bria-OTStrade to co-express GM-CSF and interferon-α Pre-manufacture additional HLA alleles ndash Total of 15 alleles (8 Class I and 7 Class II) Co-development of BriaDXtrade companion diagnostic for HLA typing Combination therapy clinical trial with immune checkpoint inhibitors for non-responders using
information from the Bria-IMTtrade Combination Therapy Study
33
Development Timeline ndash Breast Cancer
20192018 2020 2021
Phase IIIaBria-IMTtrade
Monotherapy
Currently Enrolling Phase IIaBria-IMTtrade + Checkpoint
Currently in discussions with potential partnersPhase II Bria-IMTtrade plus Additional Combinations (1Q19 4Q22)(eg PD-1 Inhibitor PD-L1 inhibitor anti-CTLA4 anti-GITR anti-OX40)
1Q 2Q 3Q 4Q
2023
Bria-OTStrade Off-The-Shelf Personalized ImmunotherapyMonotherapy and Potential Partnered Combo Therapy
(2H19 Ongoing)
Bria-OTStradeOff-the-Shelf Cell Line cGMP Manufacturing
and BriaDXtrade(1Q18 1Q19)
Registration Studies (1Q20 2H22)Bria-IMTtrade with Checkpoint InhibitorsBria-OTStrade +- Checkpoint Inhibitors
34
Immuno-oncology Deals
Recent deals of small biotechs with big pharma in immuno-oncology
35
Date PartnershipDevelopment stage at the time of the deal Deal size
07122018 Immatics-Genmab Preclinical Up to $28B
04042018 OSE Immunotherapeutics-Boehringer Ingelheim Preclinical Up to euro113B ($139B)
02092018 Pieris Pharmaceuticals-Seattle Genetics Preclinical Up to $123B
2142018 Nektar-BMS Ph III Up to $36B
01222018 Juno-Celgene Ph II $9B (Acquisition)
11142017 Loxo-Bayer Larotrectinib (Ph II) LOXO-195 (Ph III) Up to $155B
1032017 CytomX-Amgen Preclinical Up to $15B
03202017 CytomX--BMS Ph III Up to $36B
6282016 Xencor-Novartis Preclinical Up to $24B
Early Stage Clinical Studies (Comparison)
We compared the interim data of Ph IIIa study of Bria-IMTtrade in advanced breast cancer with thedata in the early stage clinical studies of recently approved breast cancer drugs and one fasttracked product candidate
Apples to apples comparison Early Stage Clinical Studies in oncology are typically done in patientswith no other therapeutic options Thus the patients have very advanced disease and response ratesare typically quite low
The patients in our Ph IIIa study have been heavily pre-treated (median 45 prior regimens)Some recent studies of relevance in breast cancer are noted in the following slides
36
Breast Cancer Market Opportunity
Drug Technology Approved for Market (US)Ibrance (palbociclib) CDK 46 Inhibitor HR+HER2- MBC in combination with
fluvestrant or aromatase inhibitor$933M in 1Q2018 $3126M in 2017
Kisqali (ribociclib) CDK 46 Inhibitor 2017 HR+HER2- MBC in combination with fluvestrant or aromatase inhibitor
Peak sales projected at $25B
Verzenio (abemaciclib) CDK 46 Inhibitor 2017 HR+HER2- MBC in combination with fluvestrant or aromatase inhibitor
balixafortide CXCR4 antagonist Fast track designation in 2018 for HER2- MBC who have failed 2 prior regimens
The market for breast cancer drugs is a multibillion dollar market with new drugs being approvedon an ongoing basis indicating the shortage of safe and effective treatments for this deadly disease
37
Competitors- Phase III Clinical Data Bria-IMTtrade shows superior safety and similar to superior efficacy data compared with those of the multi-billion dollar drugs when they were at a similar early stage of clinical development
Injection site reactions No related SAEs or SUSARs
Tumor vol darr ampor darr circul tumor cellsAll Comers 21(419) 26(519)One or More HLA matches 27(415) 33(515)Two or More HLA matches 50 (24) 75 (34)
Sheet1 (3)
Comp -Slides
Data
HLA (2)
HLA
Data (Ph1-2+4Pt)
Competitors (2018)-Slide
Competitors (2018)
In the Pipeline Protein Kinase C delta (PKCδ) Inhibitors
30 of all human malignancies display activating RAS mutations Another 60 showing over-activity of Ras-signaling pathways
Ras has been termed ldquoundruggablerdquo (no one has been able to make a Ras inhibitor drug)
BriaCellrsquos novel proprietary PKCδ inhibitors have shown activity against multiple RAS transformed tumors Lung cancer Melanoma Breast cancer Neuroendocrine cancer Pancreatic cancer Colorectal cancer
This target has an attractive safety profile based on in vivo studies and knock out mouse studies
PKCδ inhibitors should qualify for an accelerated clinical development plan and regulatory pathway
Could be in clinic within 24 months
Cost-Effective Additional Shot-on-Goal and additional partnership opportunities
Early-Stage Preclinical Program
39
Protein Kinase C delta (PKCδ) Inhibitors
Activated PKCδ inhibits RAS degradation which in turn stimulates tumor growth
Koo et al Oncotarget 621328 2016
30 of all human malignancies display activating RASmutations with another 60 showing over-activity of Ras-signaling pathways
BriaCellrsquos novel proprietary PKCδ inhibitors have shownactivity against multiple RAS transformed tumors
This target has an attractive safety profile based on in vivostudies and knock out mouse studies
PKCδ also has potential activity as an immunotherapeuticby blocking TGFβ signaling
PKCδ inhibitors are applicable to specific niche tumor typeswhich provide an accelerated clinical development plan
Structural aspects of first generation inhibitor rottlerin and staurosporine (pan-PKC activator) were combined to create second generation inhibitor KAM1
Third generation inhibitors such as BJE6-106 have improved potency and selectivity Fourth generation inhibitors under development to optimize drug-like characteristics PKCδ inhibitors lack endothelial cell cytotoxicity amp PKCδ deficient mice develop normally and are fertile Potentially no marked intrinsic toxicity by inhibiting PKCδ
Mukai H Saeki T Shimada K Naito Y Matsubara N Nakanishi T Obaishi H Namiki M Sasaki Y Phase 1 combination study of eribulin mesylate with trastuzumab for advanced or recurrent human epidermal growth factor receptor 2 positive breast cancer Invest New Drugs 2015 Feb33(1)119-27
AstraZeneca
Lynparza (Olaparib) + Cediranib
PARP inhibitor + inhibitor of VEGF receptor tyrosine kinases
HR+ HER2- MBC
BC amp OC
2013
28 (8 BC)
3 for BC
Olaparib (a poly (ADP-ribose) polymerase (PARP) inhibitor) amp Cediranib (Vascular endothelial growth factor receptor (VEGFR) 1 2 and 3 tyrosine kinase inhibitor)3 at dose level (DL) 0 (cediranib 20mg olaparib 100mg) 3 at DL1 (cediranib 20mg olaparib 200mg) 7 at DL2 (cediranib 30mg olaparib 200mg) 6 at DL3 (cediranib 30mg olaparib 400mg)
Liu JF Tolaney SM Birrer M Fleming GF Buss MK Dahlberg SE Lee H Whalen C Tyburski K Winer E Ivy P Matulonis UA A Phase 1 trial of the poly(ADP-ribose) polymerase inhibitor olaparib (AZD2281) in combination with the anti-angiogenic cediranib (AZD2171) in recurrent epithelial ovarian or triple-negative breast cancer Eur J Cancer 2013 Sep49(14)2972-8
Reyon Pharmaceutical
VM206RY
Heterologous prime-boost with a truncated HER2 sequence
HER2+ Stage IIIampIV BC
2015
9
2 chemo
Plasmid DNA (pHM-GM-CSF expressing truncated HER2 amp GM-CSF) amp adenoviral vector (Ad-HM containing modified HER2) (2 4 and 8 mgpatientvisit) of pHM-GM-CSF 3x IM weeks 0 2 and 4 Ad-HM 3 times 109 virus particles at week 6
11 PR
4 pts showed 7 minor AEs
Unclear
Kim SB Ahn JH Kim J Jung KH A phase 1 study of a heterologous prime-boost vaccination involving a truncated HER2 sequence in patients with HER2-expressing breast cancer Mol Ther Methods Clin Dev 2015 Sep 30215031 doi 101038mtm201531 eCollection 2015
Rodon J Peacuterez-Fidalgo A Krop IE Burris H Guerrero-Zotano A Britten CD Becerra C Schellens J Richards DA Schuler M Abu-Khalaf M Johnson FM Ranson M Edenfield J Silva AP Hackl W Quadt C Demanse D Duval V Baselga J Phase 11b dose escalation and expansion study of BEZ235 a dual PI3KmTOR inhibitor in patients with advanced solid tumors including patients with advanced breast cancer Cancer Chemother Pharmacol 2018 Jun 7 doi 101007s00280-018-3610-z [Epub ahead of print]
Celgene (Abraxane)
Gemcitabine + Abraxane (nab-paclitaxel)
Chemo + Chemo
OC BC NSCLC amp Panc cancer + Lung OC BC Kaposi sarcoma
MBC
2016
9
Adjuvant chemo (100)chemo post-adjuvant (33)
Gem (nucleoside metabolic inhibitor 1250 mgm2) on days 1 and 8 nab-Pac (microtubule inhibitor) starting dose of 180 mgm2 (cohort 1) 220 mgm2 (cohort 2) and 260 mgm2 (cohort 3) on day 1 of the 21-day cycle using a 3 + 3 design
0
MTD not reached29 Gr3 Neutropenia59 Gr1 Peripheralneuropathy
Yoshitomi S Taira N Doihara H Mizoo T Nogami T Iwamoto T Motoki T Shien T Ogasawara Y Matsuoka J Tsuji H Mitsuhashi T A phase 1 dose-finding and pharmacokinetic study of gemcitabine with nab-paclitaxel in patients with metastatic breast cancer Cancer Chemother Pharmacol 2016 Aug78(2)289-94
Eli Lilly
Erbituxreg (cetuximab) + Taxane
EGFR inhibitor antineoplastic agent + Chemo
Headamp Neck Colorectal Cancer
TNBC
2007-2010
18
1 chemo
Cetuximab (epidermal growth factor receptor (EGFR) antagonist ) an initial loading dose of cetuximab 400 mgm2 followed by a weekly dose of 250 mgm2Paclitaxel (microtubule inhibitor) 80 mgm2 or Docetaxel at an initial dose of 30 mgm2 was administered weekly
56 CR 22 PR
83 Dermatologic toxicity11 Grade3+
Nechushtan H Vainer G Stainberg H Salmon AY Hamburger T Peretz T A phase 12 of a combination of cetuximab and taxane for triple negative breast cancer patients Breast 2014 Aug23(4)435-8
Polyphor
Balixafortide (POL6326) + eribulin
CXCR4 antagonist + tubulin-based antimitotic
Heavily pretreated Relapsed MBC
2014-2016
56
3rd line 3 chemo
3+3 dose escalation The highest dose was established as eribulin 14 mgmsup2 on days 2 and 9 and balixafortide 55 mgkg on days 1minus3 and 8minus10 of the 21-day cycle
30 PR
41 Gr34 Neutropenia11 Gr34 Leucopenia11 Gr34 Febrileneutropenia2 Related mortalities
Apr 2018 Fast Track for HER2-MBC who have failed 2prior regimens
Pernas S Martin M Kaufman PA Gil-Martin M Gomez Pardo P Lopez-Tarruella S Manso L Ciruelos E Perez-Fidalgo JA Hernando C Ademuyiwa FO Weilbaecher K Mayer I Pluard TJ Martinez Garcia M Vahdat L Perez-Garcia J Wach A Barker D Fung S Romagnoli B Cortes J Balixafortide plus eribulin in HER2-negative metastatic breast cancer a phase 1 single-arm dose-escalation trial Lancet Oncol 2018 Jun19(6)812-824
11 PRndashbut only + letrozole (No Resp on monotherapy)
61 Gr34 Neutropenia39 Gr34 Leucopenia
$933M in 1Q2018 $31B in 2017
Tamura K Mukai H Naito Y Yonemori K Kodaira M Tanabe Y Yamamoto N Osera S Sasaki M Mori Y Hashigaki S Nagasawa T Umeyama Y Yoshino T Phase I study of palbociclib a cyclin-dependent kinase 46 inhibitor in Japanese patients Cancer Sci 2016 Jun107(6)755-63 doi 101111cas12932 Epub 2016 May 11
Pfizer
Ibrancereg (palbociclib)
CDK 46 Inhibitor
HR+ HER2- MBC
Heavily pretreated Relapsed Metastatic Cancer
2004-2008
41 (5 BC)
chemo naiumlve (17) 1-2 (51)3 (29) 3+ (2)
Palbociclib 25-150 mg dose ranging
0
20 Gr34 Neutropenia23 Gr34 Leucopenia
$933M in 1Q2018 $31B in 2017
Flaherty KT Lorusso PM Demichele A Abramson VG Courtney R Randolph SS Shaik MN Wilner KD ODwyer PJ Schwartz GK Phase I dose-escalation trial of the oral cyclin-dependent kinase 46 inhibitor PD 0332991 administered using a 21-day schedule in patients with advanced cancer Clin Cancer Res 2012 Jan 1518(2)568-76 doi 1011581078-0432CCR-11-0509 Epub 2011 Nov 16
Novartis
Kisqalireg (ribociclib)
CDK 46 Inhibitors
Premenopausal HR+ HER2- MBC
Heavily pretreated Relapsed Metastatic Cancer
2016
132 (20 BC)
0-1 (25) 2-3 (42) 4+ (32)
Ribociclib 50 mg ranging up to 1200 mg dose escalation
23 PRndashincluded 1 in BC (5 of BC pts)
27 Gr34 Neutropenia17 Gr34 Leucopenia
Peak sales projected at $25B
Infante JR Cassier PA Gerecitano JF Witteveen PO Chugh R Ribrag V Chakraborty A Matano A Dobson JR Crystal AS Parasuraman S Shapiro GI A Phase I Study of the Cyclin-Dependent Kinase 46 Inhibitor Ribociclib (LEE011) in Patients with Advanced Solid Tumors and Lymphomas Clin Cancer Res 2016 Dec 122(23)5696-5705 Epub 2016 Aug 19
Eli Lilly
Verzenioreg (abemaciclib)
CDK 46 Inhibitors
HR+HER2minusMBC
Heavily pretreated Relapsed Metastatic Cancer
2016
12 (1 BC)
1 (312) 2 (212) 3+ (7)
Abemaciclib 100 mg ranging up to 200 mg dose escalation
17 PR (included 1 in BC)
17 Gr34 Neutropenia33 Gr34 Leucopenia
Peak sales projected at $2B
Fujiwara Y Tamura K Kondo S Tanabe Y Iwasa S Shimomura A Kitano S Ogasawara K Turner PK Mori J Asou H Chan EM Yamamoto N Phase 1 study of abemaciclib an inhibitor of CDK 4 and 6 as a single agent for Japanese patients with advanced cancer Cancer Chemother Pharmacol 2016 Aug78(2)281-8 doi 101007s00280-016-3085-8 Epub 2016 Jun 16
Mukai H Saeki T Shimada K Naito Y Matsubara N Nakanishi T Obaishi H Namiki M Sasaki Y Phase 1 combination study of eribulin mesylate with trastuzumab for advanced or recurrent human epidermal growth factor receptor 2 positive breast cancer Invest New Drugs 2015 Feb33(1)119-27
AstraZeneca
Lynparza (Olaparib)+ Cediranib
PARP inhibitor+ inhibitor of VEGF RTK
HR+ HER2- MBC
BC amp OC
13
28 (8 BC)
3 for BC
Olaparib (a poly (ADP-ribose) polymerase (PARP) inhibitor) amp Cediranib (Vascular endothelial growth factor receptor (VEGFR) 1 2 and 3 tyrosine kinase inhibitor)3 at dose level (DL) 0 (cediranib 20mg olaparib 100mg) 3 at DL1 (cediranib 20mg olaparib 200mg) 7 at DL2 (cediranib 30mg olaparib 200mg) 6 at DL3 (cediranib 30mg olaparib 400mg)
Liu JF Tolaney SM Birrer M Fleming GF Buss MK Dahlberg SE Lee H Whalen C Tyburski K Winer E Ivy P Matulonis UA A Phase 1 trial of the poly(ADP-ribose) polymerase inhibitor olaparib (AZD2281) in combination with the anti-angiogenic cediranib (AZD2171) in recurrent epithelial ovarian or triple-negative breast cancer Eur J Cancer 2013 Sep49(14)2972-8
ReyonPharma
VM206RY
Heterologous prime-boost with a truncated HER2 sequence
HER2+ Stg IIIampIV BC
15
9
2 chemo
Plasmid DNA (pHM-GM-CSF expressing truncated HER2 amp GM-CSF) amp adenoviral vector (Ad-HM containing modified HER2) (2 4 and 8 mgpatientvisit) of pHM-GM-CSF 3x IM weeks 0 2 and 4 Ad-HM 3 times 109 virus particles at week 6
11 PR
4 pts 7 minor AEs
Unclear
Kim SB Ahn JH Kim J Jung KH A phase 1 study of a heterologous prime-boost vaccination involving a truncated HER2 sequence in patients with HER2-expressing breast cancer Mol Ther Methods Clin Dev 2015 Sep 30215031 doi 101038mtm201531 eCollection 2015
Rodon J Peacuterez-Fidalgo A Krop IE Burris H Guerrero-Zotano A Britten CD Becerra C Schellens J Richards DA Schuler M Abu-Khalaf M Johnson FM Ranson M Edenfield J Silva AP Hackl W Quadt C Demanse D Duval V Baselga J Phase 11b dose escalation and expansion study of BEZ235 a dual PI3KmTOR inhibitor in patients with advanced solid tumors including patients with advanced breast cancer Cancer Chemother Pharmacol 2018 Jun 7 doi 101007s00280-018-3610-z [Epub ahead of print]
Celgene(Abraxane)
Gemcitabine + Abraxane (nab-paclitaxel)
Chemo+ Chemo
OC BC NSCLC PC + LC OC BC KS
MBC
16
9
Adjuv chemo (100)chemo post-adjuv (33)
Gem (nucleoside metabolic inhibitor 1250 mgm2) on days 1 and 8 nab-Pac (microtubule inhibitor) starting dose of 180 mgm2 (cohort 1) 220 mgm2 (cohort 2) and 260 mgm2 (cohort 3) on day 1 of the 21-day cycle using a 3 + 3 design
0
MTD not reached29 Gr3 Neutropenia59 Gr1 Peripheralneuropathy
Yoshitomi S Taira N Doihara H Mizoo T Nogami T Iwamoto T Motoki T Shien T Ogasawara Y Matsuoka J Tsuji H Mitsuhashi T A phase 1 dose-finding and pharmacokinetic study of gemcitabine with nab-paclitaxel in patients with metastatic breast cancer Cancer Chemother Pharmacol 2016 Aug78(2)289-94
Eli Lilly
Erbituxreg (cetuximab) + Taxane
EGFR inhibitor antineoplastic agent + Chemo
Head amp NeckColorectal
TNBC
07-10
18
1 chemo
Cetuximab (epidermal growth factor receptor (EGFR) antagonist ) an initial loading dose of cetuximab 400 mgm2 followed by a weekly dose of 250 mgm2Paclitaxel (microtubule inhibitor) 80 mgm2 or Docetaxel at an initial dose of 30 mgm2 was administered weekly
56 CR 22 PR
83 Dermatologic toxicity11 Grade3+
Nechushtan H Vainer G Stainberg H Salmon AY Hamburger T Peretz T A phase 12 of a combination of cetuximab and taxane for triple negative breast cancer patients Breast 2014 Aug23(4)435-8
Polyphor
Balixafortide (POL6326) + eribulin
CXCR4 antagonist + tubulin-based antimitotic
Heavily pretreatedRelapsed MBC
14-16
56
3rd line 3 chemo
3+3 dose escalation The highest dose was established as eribulin 14 mgmsup2 on days 2 and 9 and balixafortide 55 mgkg on days 1minus3 and 8minus10 of the 21-day cycle
30 PR
41 Gr34 Neutropenia11 Gr34 Leucopenia11 Gr34 Febrileneutropenia2 Related mortalities
42018 Fast Track (HER2-MBC failed 2 prior regimens)
Pernas S Martin M Kaufman PA Gil-Martin M Gomez Pardo P Lopez-Tarruella S Manso L Ciruelos E Perez-Fidalgo JA Hernando C Ademuyiwa FO Weilbaecher K Mayer I Pluard TJ Martinez Garcia M Vahdat L Perez-Garcia J Wach A Barker D Fung S Romagnoli B Cortes J Balixafortide plus eribulin in HER2-negative metastatic breast cancer a phase 1 single-arm dose-escalation trial Lancet Oncol 2018 Jun19(6)812-824
1 PRndashbut only + letrozoleNo Resp on monotherapy
61 Gr34 Neutropenia39 Gr34 Leucopenia
$933M (1Q18)$31B (2017)
Tamura K Mukai H Naito Y Yonemori K Kodaira M Tanabe Y Yamamoto N Osera S Sasaki M Mori Y Hashigaki S Nagasawa T Umeyama Y Yoshino T Phase I study of palbociclib a cyclin-dependent kinase 46 inhibitor in Japanese patients Cancer Sci 2016 Jun107(6)755-63 doi 101111cas12932 Epub 2016 May 11
Pfizer
Ibrancereg (palbociclib)
CDK 46 Inhibitor
HR+ HER2- MBC
Heavily pretreatedRelapsed Met Cancer
04-08
41 (5 BC)
chemo naiumlve (17)1-2(51) 3(29) 3+(2)
Palbociclib 25-150 mg dose ranging
0
20 Gr34 Neutropenia23 Gr34 Leucopenia
$933M (1Q18)$31B (2017)
Flaherty KT Lorusso PM Demichele A Abramson VG Courtney R Randolph SS Shaik MN Wilner KD ODwyer PJ Schwartz GK Phase I dose-escalation trial of the oral cyclin-dependent kinase 46 inhibitor PD 0332991 administered using a 21-day schedule in patients with advanced cancer Clin Cancer Res 2012 Jan 1518(2)568-76 doi 1011581078-0432CCR-11-0509 Epub 2011 Nov 16
Novartis
Kisqalireg (ribociclib)
CDK 46 Inhibitor
Premenopausal HR+ HER2- MBC
Heavily pretreatedRelapsed Met Cancer
16
132 (20 BC)
0-1 (25) 2-3 (42)4+ (32)
Ribociclib 50 mg ranging up to 1200 mg dose escalation
23 PR-included 1 BC (5 of BC pts)
27 Gr34 Neutropenia17 Gr34 Leucopenia
Peak sales est at $25B
Infante JR Cassier PA Gerecitano JF Witteveen PO Chugh R Ribrag V Chakraborty A Matano A Dobson JR Crystal AS Parasuraman S Shapiro GI A Phase I Study of the Cyclin-Dependent Kinase 46 Inhibitor Ribociclib (LEE011) in Patients with Advanced Solid Tumors and Lymphomas Clin Cancer Res 2016 Dec 122(23)5696-5705 Epub 2016 Aug 19
Eli Lilly
Verzenioreg (abemaciclib)
CDK 46 Inhibitor
HR+HER2minusMBC
Heavily pretreatedRelapsed Met Cancer
16
12 (1 BC)
1 (312) 2 (212) 3+(7)
Abemaciclib 100 mg ranging up to 200 mg dose escalation
17 PR (included 1 BC)
17 Gr34 Neutropenia33 Gr34 Leucopenia
Peak sales est at $2B
Fujiwara Y Tamura K Kondo S Tanabe Y Iwasa S Shimomura A Kitano S Ogasawara K Turner PK Mori J Asou H Chan EM Yamamoto N Phase 1 study of abemaciclib an inhibitor of CDK 4 and 6 as a single agent for Japanese patients with advanced cancer Cancer Chemother Pharmacol 2016 Aug78(2)281-8 doi 101007s00280-016-3085-8 Epub 2016 Jun 16
Mukai H Saeki T Shimada K Naito Y Matsubara N Nakanishi T Obaishi H Namiki M Sasaki Y Phase 1 combination study of eribulin mesylate with trastuzumab for advanced or recurrent human epidermal growth factor receptor 2 positive breast cancer Invest New Drugs 2015 Feb33(1)119-27
AstraZeneca
Lynparza (Olaparib) + Cediranib
PARP inhibitor + inhibitor of VEGF receptor tyrosine kinases
HR+ HER2- MBC
BC amp OC
2013
28 (8 BC)
3 for BC
Olaparib (a poly (ADP-ribose) polymerase (PARP) inhibitor) amp Cediranib (Vascular endothelial growth factor receptor (VEGFR) 1 2 and 3 tyrosine kinase inhibitor)3 at dose level (DL) 0 (cediranib 20mg olaparib 100mg) 3 at DL1 (cediranib 20mg olaparib 200mg) 7 at DL2 (cediranib 30mg olaparib 200mg) 6 at DL3 (cediranib 30mg olaparib 400mg)
Liu JF Tolaney SM Birrer M Fleming GF Buss MK Dahlberg SE Lee H Whalen C Tyburski K Winer E Ivy P Matulonis UA A Phase 1 trial of the poly(ADP-ribose) polymerase inhibitor olaparib (AZD2281) in combination with the anti-angiogenic cediranib (AZD2171) in recurrent epithelial ovarian or triple-negative breast cancer Eur J Cancer 2013 Sep49(14)2972-8
Reyon Pharmaceutical
VM206RY
Heterologous prime-boost with a truncated HER2 sequence
HER2+ Stage IIIampIV BC
2015
9
2 chemo
Plasmid DNA (pHM-GM-CSF expressing truncated HER2 amp GM-CSF) amp adenoviral vector (Ad-HM containing modified HER2) (2 4 and 8 mgpatientvisit) of pHM-GM-CSF 3x IM weeks 0 2 and 4 Ad-HM 3 times 109 virus particles at week 6
11 PR
4 pts showed 7 minor AEs
Unclear
Kim SB Ahn JH Kim J Jung KH A phase 1 study of a heterologous prime-boost vaccination involving a truncated HER2 sequence in patients with HER2-expressing breast cancer Mol Ther Methods Clin Dev 2015 Sep 30215031 doi 101038mtm201531 eCollection 2015
Rodon J Peacuterez-Fidalgo A Krop IE Burris H Guerrero-Zotano A Britten CD Becerra C Schellens J Richards DA Schuler M Abu-Khalaf M Johnson FM Ranson M Edenfield J Silva AP Hackl W Quadt C Demanse D Duval V Baselga J Phase 11b dose escalation and expansion study of BEZ235 a dual PI3KmTOR inhibitor in patients with advanced solid tumors including patients with advanced breast cancer Cancer Chemother Pharmacol 2018 Jun 7 doi 101007s00280-018-3610-z [Epub ahead of print]
Celgene (Abraxane)
Gemcitabine + Abraxane (nab-paclitaxel)
Chemo + Chemo
OC BC NSCLC amp Panc cancer + Lung OC BC Kaposi sarcoma
MBC
2016
9
Adjuvant chemo (100)chemo post-adjuvant (33)
Gem (nucleoside metabolic inhibitor 1250 mgm2) on days 1 and 8 nab-Pac (microtubule inhibitor) starting dose of 180 mgm2 (cohort 1) 220 mgm2 (cohort 2) and 260 mgm2 (cohort 3) on day 1 of the 21-day cycle using a 3 + 3 design
0
MTD not reached29 Gr3 Neutropenia59 Gr1 Peripheralneuropathy
Yoshitomi S Taira N Doihara H Mizoo T Nogami T Iwamoto T Motoki T Shien T Ogasawara Y Matsuoka J Tsuji H Mitsuhashi T A phase 1 dose-finding and pharmacokinetic study of gemcitabine with nab-paclitaxel in patients with metastatic breast cancer Cancer Chemother Pharmacol 2016 Aug78(2)289-94
Eli Lilly
Erbituxreg (cetuximab) + Taxane
EGFR inhibitor antineoplastic agent + Chemo
Headamp Neck Colorectal Cancer
TNBC
2007-2010
18
1 chemo
Cetuximab (epidermal growth factor receptor (EGFR) antagonist ) an initial loading dose of cetuximab 400 mgm2 followed by a weekly dose of 250 mgm2Paclitaxel (microtubule inhibitor) 80 mgm2 or Docetaxel at an initial dose of 30 mgm2 was administered weekly
56 CR 22 PR
83 Dermatologic toxicity11 Grade3+
Nechushtan H Vainer G Stainberg H Salmon AY Hamburger T Peretz T A phase 12 of a combination of cetuximab and taxane for triple negative breast cancer patients Breast 2014 Aug23(4)435-8
Polyphor
Balixafortide (POL6326) + eribulin
CXCR4 antagonist + tubulin-based antimitotic
Heavily pretreated Relapsed MBC
2014-2016
56
3rd line 3 chemo
3+3 dose escalation The highest dose was established as eribulin 14 mgmsup2 on days 2 and 9 and balixafortide 55 mgkg on days 1minus3 and 8minus10 of the 21-day cycle
30 PR
41 Gr34 Neutropenia11 Gr34 Leucopenia11 Gr34 Febrileneutropenia2 Related mortalities
Apr 2018 Fast Track for HER2-MBC who have failed 2prior regimens
Pernas S Martin M Kaufman PA Gil-Martin M Gomez Pardo P Lopez-Tarruella S Manso L Ciruelos E Perez-Fidalgo JA Hernando C Ademuyiwa FO Weilbaecher K Mayer I Pluard TJ Martinez Garcia M Vahdat L Perez-Garcia J Wach A Barker D Fung S Romagnoli B Cortes J Balixafortide plus eribulin in HER2-negative metastatic breast cancer a phase 1 single-arm dose-escalation trial Lancet Oncol 2018 Jun19(6)812-824
11 PRndashbut only + letrozole (No Resp on monotherapy)
61 Gr34 Neutropenia39 Gr34 Leucopenia
$933M in 1Q2018 $31B in 2017
Tamura K Mukai H Naito Y Yonemori K Kodaira M Tanabe Y Yamamoto N Osera S Sasaki M Mori Y Hashigaki S Nagasawa T Umeyama Y Yoshino T Phase I study of palbociclib a cyclin-dependent kinase 46 inhibitor in Japanese patients Cancer Sci 2016 Jun107(6)755-63 doi 101111cas12932 Epub 2016 May 11
Pfizer
Ibrancereg (palbociclib)
CDK 46 Inhibitor
HR+ HER2- MBC
Heavily pretreated Relapsed Metastatic Cancer
2004-2008
41 (5 BC)
chemo naiumlve (17) 1-2 (51)3 (29) 3+ (2)
Palbociclib 25-150 mg dose ranging
0
20 Gr34 Neutropenia23 Gr34 Leucopenia
$933M in 1Q2018 $31B in 2017
Flaherty KT Lorusso PM Demichele A Abramson VG Courtney R Randolph SS Shaik MN Wilner KD ODwyer PJ Schwartz GK Phase I dose-escalation trial of the oral cyclin-dependent kinase 46 inhibitor PD 0332991 administered using a 21-day schedule in patients with advanced cancer Clin Cancer Res 2012 Jan 1518(2)568-76 doi 1011581078-0432CCR-11-0509 Epub 2011 Nov 16
Novartis
Kisqalireg (ribociclib)
CDK 46 Inhibitors
Premenopausal HR+ HER2- MBC
Heavily pretreated Relapsed Metastatic Cancer
2016
132 (20 BC)
0-1 (25) 2-3 (42) 4+ (32)
Ribociclib 50 mg ranging up to 1200 mg dose escalation
23 PRndashincluded 1 in BC (5 of BC pts)
27 Gr34 Neutropenia17 Gr34 Leucopenia
Peak sales projected at $25B
Infante JR Cassier PA Gerecitano JF Witteveen PO Chugh R Ribrag V Chakraborty A Matano A Dobson JR Crystal AS Parasuraman S Shapiro GI A Phase I Study of the Cyclin-Dependent Kinase 46 Inhibitor Ribociclib (LEE011) in Patients with Advanced Solid Tumors and Lymphomas Clin Cancer Res 2016 Dec 122(23)5696-5705 Epub 2016 Aug 19
Eli Lilly
Verzenioreg (abemaciclib)
CDK 46 Inhibitors
HR+HER2minusMBC
Heavily pretreated Relapsed Metastatic Cancer
2016
12 (1 BC)
1 (312) 2 (212) 3+ (7)
Abemaciclib 100 mg ranging up to 200 mg dose escalation
17 PR (included 1 in BC)
17 Gr34 Neutropenia33 Gr34 Leucopenia
Peak sales projected at $2B
Fujiwara Y Tamura K Kondo S Tanabe Y Iwasa S Shimomura A Kitano S Ogasawara K Turner PK Mori J Asou H Chan EM Yamamoto N Phase 1 study of abemaciclib an inhibitor of CDK 4 and 6 as a single agent for Japanese patients with advanced cancer Cancer Chemother Pharmacol 2016 Aug78(2)281-8 doi 101007s00280-016-3085-8 Epub 2016 Jun 16
Mukai H Saeki T Shimada K Naito Y Matsubara N Nakanishi T Obaishi H Namiki M Sasaki Y Phase 1 combination study of eribulin mesylate with trastuzumab for advanced or recurrent human epidermal growth factor receptor 2 positive breast cancer Invest New Drugs 2015 Feb33(1)119-27
AstraZeneca
Lynparza (Olaparib)+ Cediranib
PARP inhibitor+ inhibitor of VEGF RTK
HR+ HER2- MBC
BC amp OC
13
28 (8 BC)
3 for BC
Olaparib (a poly (ADP-ribose) polymerase (PARP) inhibitor) amp Cediranib (Vascular endothelial growth factor receptor (VEGFR) 1 2 and 3 tyrosine kinase inhibitor)3 at dose level (DL) 0 (cediranib 20mg olaparib 100mg) 3 at DL1 (cediranib 20mg olaparib 200mg) 7 at DL2 (cediranib 30mg olaparib 200mg) 6 at DL3 (cediranib 30mg olaparib 400mg)
Liu JF Tolaney SM Birrer M Fleming GF Buss MK Dahlberg SE Lee H Whalen C Tyburski K Winer E Ivy P Matulonis UA A Phase 1 trial of the poly(ADP-ribose) polymerase inhibitor olaparib (AZD2281) in combination with the anti-angiogenic cediranib (AZD2171) in recurrent epithelial ovarian or triple-negative breast cancer Eur J Cancer 2013 Sep49(14)2972-8
ReyonPharma
VM206RY
Heterologous prime-boost with a truncated HER2 sequence
HER2+ Stg IIIampIV BC
15
9
2 chemo
Plasmid DNA (pHM-GM-CSF expressing truncated HER2 amp GM-CSF) amp adenoviral vector (Ad-HM containing modified HER2) (2 4 and 8 mgpatientvisit) of pHM-GM-CSF 3x IM weeks 0 2 and 4 Ad-HM 3 times 109 virus particles at week 6
11 PR
4 pts 7 minor AEs
Unclear
Kim SB Ahn JH Kim J Jung KH A phase 1 study of a heterologous prime-boost vaccination involving a truncated HER2 sequence in patients with HER2-expressing breast cancer Mol Ther Methods Clin Dev 2015 Sep 30215031 doi 101038mtm201531 eCollection 2015
Rodon J Peacuterez-Fidalgo A Krop IE Burris H Guerrero-Zotano A Britten CD Becerra C Schellens J Richards DA Schuler M Abu-Khalaf M Johnson FM Ranson M Edenfield J Silva AP Hackl W Quadt C Demanse D Duval V Baselga J Phase 11b dose escalation and expansion study of BEZ235 a dual PI3KmTOR inhibitor in patients with advanced solid tumors including patients with advanced breast cancer Cancer Chemother Pharmacol 2018 Jun 7 doi 101007s00280-018-3610-z [Epub ahead of print]
Celgene(Abraxane)
Gemcitabine + Abraxane (nab-paclitaxel)
Chemo+ Chemo
OC BC NSCLC PC + LC OC BC KS
MBC
16
9
Adjuv chemo (100)chemo post-adjuv (33)
Gem (nucleoside metabolic inhibitor 1250 mgm2) on days 1 and 8 nab-Pac (microtubule inhibitor) starting dose of 180 mgm2 (cohort 1) 220 mgm2 (cohort 2) and 260 mgm2 (cohort 3) on day 1 of the 21-day cycle using a 3 + 3 design
0
MTD not reached29 Gr3 Neutropenia59 Gr1 Peripheralneuropathy
Yoshitomi S Taira N Doihara H Mizoo T Nogami T Iwamoto T Motoki T Shien T Ogasawara Y Matsuoka J Tsuji H Mitsuhashi T A phase 1 dose-finding and pharmacokinetic study of gemcitabine with nab-paclitaxel in patients with metastatic breast cancer Cancer Chemother Pharmacol 2016 Aug78(2)289-94
Eli Lilly
Erbituxreg (cetuximab) + Taxane
EGFR inhibitor antineoplastic agent + Chemo
Head amp NeckColorectal
TNBC
07-10
18
1 chemo
Cetuximab (epidermal growth factor receptor (EGFR) antagonist ) an initial loading dose of cetuximab 400 mgm2 followed by a weekly dose of 250 mgm2Paclitaxel (microtubule inhibitor) 80 mgm2 or Docetaxel at an initial dose of 30 mgm2 was administered weekly
56 CR 22 PR
83 Dermatologic toxicity11 Grade3+
Nechushtan H Vainer G Stainberg H Salmon AY Hamburger T Peretz T A phase 12 of a combination of cetuximab and taxane for triple negative breast cancer patients Breast 2014 Aug23(4)435-8
Polyphor
Balixafortide (POL6326) + eribulin
CXCR4 antagonist + tubulin-based antimitotic
Heavily pretreatedRelapsed MBC
14-16
56
3rd line 3 chemo
3+3 dose escalation The highest dose was established as eribulin 14 mgmsup2 on days 2 and 9 and balixafortide 55 mgkg on days 1minus3 and 8minus10 of the 21-day cycle
30 PR
41 Gr34 Neutropenia11 Gr34 Leucopenia11 Gr34 Febrileneutropenia2 Related mortalities
42018 Fast Track (HER2-MBC failed 2 prior regimens)
Pernas S Martin M Kaufman PA Gil-Martin M Gomez Pardo P Lopez-Tarruella S Manso L Ciruelos E Perez-Fidalgo JA Hernando C Ademuyiwa FO Weilbaecher K Mayer I Pluard TJ Martinez Garcia M Vahdat L Perez-Garcia J Wach A Barker D Fung S Romagnoli B Cortes J Balixafortide plus eribulin in HER2-negative metastatic breast cancer a phase 1 single-arm dose-escalation trial Lancet Oncol 2018 Jun19(6)812-824
1 PRndashbut only + letrozoleNo Resp on monotherapy
61 Gr34 Neutropenia39 Gr34 Leucopenia
$933M (1Q18)$31B (2017)
Tamura K Mukai H Naito Y Yonemori K Kodaira M Tanabe Y Yamamoto N Osera S Sasaki M Mori Y Hashigaki S Nagasawa T Umeyama Y Yoshino T Phase I study of palbociclib a cyclin-dependent kinase 46 inhibitor in Japanese patients Cancer Sci 2016 Jun107(6)755-63 doi 101111cas12932 Epub 2016 May 11
Pfizer
Ibrancereg (palbociclib)
CDK 46 Inhibitor
HR+ HER2- MBC
Heavily pretreatedRelapsed Met Cancer
04-08
41 (5 BC)
chemo naiumlve (17)1-2(51) 3(29) 3+(2)
Palbociclib 25-150 mg dose ranging
0
20 Gr34 Neutropenia23 Gr34 Leucopenia
$933M (1Q18)$31B (2017)
Flaherty KT Lorusso PM Demichele A Abramson VG Courtney R Randolph SS Shaik MN Wilner KD ODwyer PJ Schwartz GK Phase I dose-escalation trial of the oral cyclin-dependent kinase 46 inhibitor PD 0332991 administered using a 21-day schedule in patients with advanced cancer Clin Cancer Res 2012 Jan 1518(2)568-76 doi 1011581078-0432CCR-11-0509 Epub 2011 Nov 16
Novartis
Kisqalireg (ribociclib)
CDK 46 Inhibitor
Premenopausal HR+ HER2- MBC
Heavily pretreatedRelapsed Met Cancer
16
132 (20 BC)
0-1 (25) 2-3 (42)4+ (32)
Ribociclib 50 mg ranging up to 1200 mg dose escalation
23 PR-included 1 BC (5 of BC pts)
27 Gr34 Neutropenia17 Gr34 Leucopenia
Peak sales est at $25B
Infante JR Cassier PA Gerecitano JF Witteveen PO Chugh R Ribrag V Chakraborty A Matano A Dobson JR Crystal AS Parasuraman S Shapiro GI A Phase I Study of the Cyclin-Dependent Kinase 46 Inhibitor Ribociclib (LEE011) in Patients with Advanced Solid Tumors and Lymphomas Clin Cancer Res 2016 Dec 122(23)5696-5705 Epub 2016 Aug 19
Eli Lilly
Verzenioreg (abemaciclib)
CDK 46 Inhibitor
HR+HER2minusMBC
Heavily pretreatedRelapsed Met Cancer
16
12 (1 BC)
1 (312) 2 (212) 3+(7)
Abemaciclib 100 mg ranging up to 200 mg dose escalation
17 PR (included 1 BC)
17 Gr34 Neutropenia33 Gr34 Leucopenia
Peak sales est at $2B
Fujiwara Y Tamura K Kondo S Tanabe Y Iwasa S Shimomura A Kitano S Ogasawara K Turner PK Mori J Asou H Chan EM Yamamoto N Phase 1 study of abemaciclib an inhibitor of CDK 4 and 6 as a single agent for Japanese patients with advanced cancer Cancer Chemother Pharmacol 2016 Aug78(2)281-8 doi 101007s00280-016-3085-8 Epub 2016 Jun 16
Bria-IMTtrade and Bria-OTStrade shouldsynergize with existing approvedimmunotherapies as well as those stillunder development
This includes immune checkpointinhibitors such as antibodies to PD-1CTLA-4 GITR and CD73 inhibitors whicheliminate tumor immunosuppression Checkpoint Inhibitors were the
subject of the 2018 Nobel Prize inMedicine
In addition immunostimulatoryantibodies to molecules such as OX40should enhance responses to Bria-IMTtradeand Bria-OTStrade
13
Q3 2018 Data on first 20 Patients on Bria-IMTtrade Q3 2018 Initiate Combination Study of Bria-IMTtrade with Keytruda or Yervoy
Q4 2018 Switch to a novel frozen Bria-IMTtrade formulation Q4 2018 Safety Data (6 patients) of the Bria-IMTtrade - Keytrudareg Combination Study (SABC meeting) Q4 2018 Ongoing Corporate PartnershipCollaboration Discussions
Q1 2019 Efficacy Data (6 patients) of the Bria-IMTtrade - Keytrudareg Combination Study Q2 2019 Initiation of Bria-OTStrade GMP manufacturing (KBI BioPharma) Q2 2019 Additional Safety amp Efficacy data Monotherapy and Combination Studies (AACR meeting) Q2 2019 Final data for Monotherapy and Additional Data for the Combination Study (ASCO meeting) H1 2019 Candidate Selection for a PKCδ Inhibitor H1 2019 Initiate additional immunotherapy program H2 2019 Bria-OTStrade Authorization from FDA clearance for dosing H2 2019 Bria-OTStrade First Patient Dosed
Upcoming Milestones amp Catalysts
14
Involved in over 10 drugs brought to the market
Experienced Management Team
Management
William V Williams MD FACP President amp CEO VP Exploratory Development Incyte Corporation VP Experimental Medicine GlaxoSmithKline Head Rheumatology Research University of Pennsylvania Facilitated entry of over 20 compounds into the clinic including ruxolitinib (Jakafi)
baricitinib amp epacadostat NDAs including Jakafi Boniva Bexxar Author of over 120 peer-reviewed publications amp over 20 patents
Gadi Levin CA MBA CFO CFO of Labstyle Innovations Ltd VP of Finance for two Israeli investment houses in the fields of private equity
hedge funds and real estate Financial Consultant various firms Accountant Arthur Andersen
Markus Lacher PhD Senior Director RampD Founder T cell Therapeutics Inc an immuno-oncology company Sr Clinical Scientist Cesca Therapeutics Inc a clinical-stage autologous cell
therapy company Scientist at BioTime Inc and OncoCyte Corporation Editorial advisory board Recent Patents on Anti-Cancer Drug Discovery
Farrah Dean MSc MBA Manager Corp Development Investor relations CytRx Corporation amp CCG Investor Relations Senior Associate Equity Analyst Oppenheimer amp Co Rodman amp Renshaw amp
Brian Metcalf PhD Recently retired as CSO from Global Blood Therapeutics Former Head of Research amp Development Incyte Corporation Former Head of Medicinal Chemistry SmithKline Beecham
Douglas Faller MD PhD Professor of Medicine Pediatrics Biochemistry Microbiology Pathology and
Laboratory Medicine HematologistOncologist former Director of the Cancer Center Boston University School of Medicine
Founder of several successful biotechnology companies
Robert Williams PhD University Distinguished Professor of Chemistry Colorado State University Founder of several successful biotechnology companies including Microcide Xcyte
Therapies HemaQuest Arch Therapeutics and Cetya Therapeutics
Thomas Kieber-Emmons PhD Deputy Director University of Arkansas Cancer Center Expert in targeted cancer immunotherapies structural biology and computational
chemistry
Maria Trojanowska PhD Professor of Medicine Boston University School of Medicine Director The Arthritis Center
16
Veteran Board of Directors
Board of Directors
Saeid Babaei PhD MBA Chairman Entrepreneur 20 yrs of biotech leadership roles Current CEO AbCelex VP Bus Develop Lorus Therap Dir of Corp Develop Northern Therapeutics
Rahoul Sharan CA Director Chairman Potash Ridge Director of the Board Ansell Capital Corp Parallel Resources amp Galaxy Capital
Corporation
Martin Schmieg CPA Director CFO Sirna Therapeutics Inc amp Isolagen Inc CEO Freedom-2 Inc (now PharmaCyte Inc) Advisor Caladrius Biosciences Inc Beckman Coulter Genomics Calimmune
Charles Wiseman MD Co-Founder amp Director Director Immunotherapy Lab St Vincent Medical Center Chief Breast Cancer Basic Research Lab Univ of Texas MD Anderson Hospital amp
Tumour Institute Assist Prof Dept of Molecular Carcinogenesis amp Virology MD Anderson Acting Chief Div of Oncology White Memorial Medical Center LA
William V Williams MD FACP President amp CEO VP Exploratory Development Incyte Corporation VP Experimental Medicine GlaxoSmithKline Head Rheumatology Research University of Pennsylvania
Prior Affiliations
17
Drug Approvals by BriaCell Management Team
Bexxarreg (tositumomab and Iodine I131 tositumomab) Treatment of CD20 antigen-expressing relapsed or refractory low grade follicular or transformed non-Hodgkins lymphoma
Myleranreg (busulfan) for chronic myelogenous leukemia Defense of formulation change sNDA
Hycamtinreg (topotecan) for ovarian cancer Pediatric use sNDA
Navelbinereg (vinorelbine tartrate) for non-small cell lung cancer Pediatric use sNDA
Bonivareg (ibandronate) monthly oral treatment of osteoporosis
Bonivareg (ibandronate) quarterly intraveous treatment of osteoporosis
Zofranreg (ondansetron) for prevention of nausea and vomiting Pediatric use sNDA
Jakafireg (ruxolitinib) for myelofibrosis Jakafireg (ruxolitinib) for polycythemia vera
Olumiantreg (baricitinib) for rheumatoid arthritis Approved in USA Japan and Europe
18
Share Metrics
BCTV BCTXF 19
Data as of 1092018
Ticker TSX BCTV
US Ticker OTCQBBCTXF
Share Price (CAD) as of Oct 9 2018 $012
52-Week Range (CAD) $009-019
Shares Outstanding as of Oct 9 2018 1611M
Market Cap as of Oct 9 2018 (CAD) $193M
Cash and Short Term Investments as of July 31 2018 (CAD) $23M
Total Shareholders Equity as of July 31 2018 (CAD) $12M
Number of Warrants $014-$035 (CAD) as of Oct 9 2018 601M
Number of Compensation Warrants $014-$030 (CAD) as of Oct 9 2018 45M
Number of Options $014- $026 (CAD$) as of Oct 9 2018 93M
Developing Bria-OTStrade the First Off-the-Shelf Personalized Immunotherapy
Targeting Adv Breast Cancer Unmet medical need (42000 death in the US in 2017 ) $1 Bil- $5 Bil market opportunity depending on patient treatment stage
Impressive results in 2 proof-of-concept clinical trials Rapid Response Rate Repeated following re-treatment Excellent Safety Profile
Completed enrollment in Phase IIIa clinical trial of Bria-IMTtrade with outstanding safety amp efficacy data Initiated Phase IIa Combination Study of Bria-IMTtrade with Keytrudareg (Merck amp Co Inc)
Developing Bria-OTStrade along with BriaDXtrade its companion diagnostic test Ability to match and treat ~90 of patient population with Off-the-Shelf personalized immunotherapy
Experienced Management has been involved in over 10 drug approvals
Patient B001 Breast 70 No 1101 - 3501 4001 Negative -
Bria-IMTtradeHuman Proof-of-Concept Trials in Breast Cancer (Patient A002)
24
Proof-of-Concept Results Resulted in BriaCellrsquos Immunotherapy Strategy Use BriaDXtrade diagnostic to select only those patients matching Bria-IMTtrade Use BriaDXtrade diagnostic test to select Bria-OTStrade alleles matching ~90 of all patients
Bria-IMTtradeCurrent Phase IIIa Data Supports HLA Matching Hypothesis Six patients treated in 2017 Bria-IMTtrade was safe and well tolerated
Patient 01-002 73-year-old woman with breast cancer diagnosed in 1995 Developed liver metastases in2010 and lung metastases in 2017 Previously treated with 7 rounds of chemotherapy with 8 differentchemotherapy agents Received 5 cycles of Bria-IMTtrade over 3 months then monthly cycles (6 months total)Evaluated after 3 months and 6 months After 3 months despite the extensive prior therapy her scans notedthat ldquothere has been a clear response in the multiple bilateral pulmonary nodulesrdquo The response wasmaintained after 6 months of Bria-IMTtrade treatment She matches Bria-IMTtrade at 2 HLA alleles
The liver tumors were stable to slightly increased at 3 months and then progressed after 6 months
This supports our hypothesis of heightened anti-tumor activity in patients with a matched HLA types Clear path to develop BriaDXtrade to select the patients using HLA testing
1 RLL 29 Not Detectable Not Detectable2 LUL apical pleural based 34 tiny nodule lt 1mm scar tiny nodule lt 1mm scar3 xxx 39 Not Detectable Not Detectable4 40 Not Detectable Not Detectable5 RLL 45 Not Detectable Not Detectable6 LLL 49 Not Detectable Not Detectable7 xxx 52 Not Detectable Not Detectable8 RLL 52 Not Detectable Not Detectable9 RLL 56 Not Detectable Not Detectable
10 RLL costophrenic recess 56 Not Detectable Not Detectable11 XXX 58 Not Detectable Not Detectable12 LUL 60 Not Detectable Not Detectable13 XXX 67 15 1514 RUL 72 15 1515 LLL 76 Not Detectable Not Detectable16 RUL Noncalcified Nodule 77 Not Detectable Not Detectable17 RLL costophrenic recess 79 10 1018 RUL 82 Not Detectable Not Detectable19 RLL 90 Not Detectable Not Detectable20 RLL 91 lt 01 lt 0121 xxx xxx Not Detectable Not Detectable
27
Clinical Development Update ndash Summary 2018 September 26
Completed enrollment of Adv Breast cancer patients in the Phase IIIa ldquomonotherapyrdquo study of Bria-IMTtrade
We have confirmed our mechanism of action and achieved proof of concept
Initial safety data appears superior to that of the other advanced or approved drugs for breast cancer when they were at a similar clinical stage of development
Initial efficacy data is similar or superior to those of other advanced or approved drugs for breast cancer when they were at a similar clinical stage of development
Initiated Combination Study of Bria-IMTtrade with Keytrudareg or Yervoyreg in Adv breast cancer patients expecting even better response rates than those in the ldquomonotherapyrdquo study Initial safety data is expected in 4Q2018 Initial efficacy data is expected in 1Q2019
Bria-OTStrade the first off-the-shelf personalized treatment for advanced breast cancer is expected to enter the clinic in 2019
28
Bria-IMTtrade Excellent Safety Data - To Date
To date Bria-IMTtrade has been dosed in 24 patients (4 in 2004-2005 20 in 2017-2018)
Interim Data (20 patients)-Ongoing Phase IIIa Study (2017-2018)
Bria-IMTtrade has been very well tolerated (ge60 doses given to date) The majority of adverse events (AEs) were limited to expected minor local irritation at the
injection sites No related grade gt3 or unexpected AEs No related serious AEs No serious unexpected related AEs Most patients who have dropped out did so due to worsening of their underlying disease
Based on the current study Bria-IMTtrade has an excellent safety profile
29
Bria-IMTtrade - Efficacy as Predicted
Interim Data (19 patients)-Ongoing Phase IIIa Study (2017-2018) amp Original Study (2004-2005)
PD-L1 expression on circulating cancer cells amp cancer-associated cells in 100 of patients (to date) Strong rationale for combination with checkpoint inhibitors like Keytruda
30
Bria-IMTtrade appears to be most effective in patients who match with Bria-IMT trade at 2 HLA loci (types) further supporting our ldquoHLA Matching Hypothesisrdquo and the development of Bria-OTS trade to cover 90 of the patient population
Combination with immune checkpoint inhibitors may induce a more potent anti-cancer response leading to our strategy of combination studies of Bria-IMT trade with Keytruda or Yervoy
Patients (n) HLA Match
Tumor Shrinkage
Biological Response
4 ge2 50 7515 ge1 27 334 0 0 0
Biological response includes tumor shrinkage or lower circulating cancer associated cells
The confirmatory Bria-IMTtrade monotherapy Phase IIa trial has completed enrollment Additional Support for the HLA-matching hypothesis has been obtained
Bria-IMTtrade Combination Therapy study with immune checkpoint inhibitors Keytrudareg if PD-L12 positive (ge1) Yervoyreg if PD-L12 negative (lt1) Accepting patients from the monotherapy study who develop progressive disease Also enrolling patients directly into this study to enhance experience with the combination In discussion with other pharmaceutical companies to evaluate additional combinations with other
immunotherapies
Bria-OTStrade Off-the-Shelf Personalized Targeted Immunotherapy Developing Bria-OTStrade to co-express GM-CSF and interferon-α Pre-manufacture additional HLA alleles ndash Total of 15 alleles (8 Class I and 7 Class II) Co-development of BriaDXtrade companion diagnostic for HLA typing Combination therapy clinical trial with immune checkpoint inhibitors for non-responders using
information from the Bria-IMTtrade Combination Therapy Study
33
Development Timeline ndash Breast Cancer
20192018 2020 2021
Phase IIIaBria-IMTtrade
Monotherapy
Currently Enrolling Phase IIaBria-IMTtrade + Checkpoint
Currently in discussions with potential partnersPhase II Bria-IMTtrade plus Additional Combinations (1Q19 4Q22)(eg PD-1 Inhibitor PD-L1 inhibitor anti-CTLA4 anti-GITR anti-OX40)
1Q 2Q 3Q 4Q
2023
Bria-OTStrade Off-The-Shelf Personalized ImmunotherapyMonotherapy and Potential Partnered Combo Therapy
(2H19 Ongoing)
Bria-OTStradeOff-the-Shelf Cell Line cGMP Manufacturing
and BriaDXtrade(1Q18 1Q19)
Registration Studies (1Q20 2H22)Bria-IMTtrade with Checkpoint InhibitorsBria-OTStrade +- Checkpoint Inhibitors
34
Immuno-oncology Deals
Recent deals of small biotechs with big pharma in immuno-oncology
35
Date PartnershipDevelopment stage at the time of the deal Deal size
07122018 Immatics-Genmab Preclinical Up to $28B
04042018 OSE Immunotherapeutics-Boehringer Ingelheim Preclinical Up to euro113B ($139B)
02092018 Pieris Pharmaceuticals-Seattle Genetics Preclinical Up to $123B
2142018 Nektar-BMS Ph III Up to $36B
01222018 Juno-Celgene Ph II $9B (Acquisition)
11142017 Loxo-Bayer Larotrectinib (Ph II) LOXO-195 (Ph III) Up to $155B
1032017 CytomX-Amgen Preclinical Up to $15B
03202017 CytomX--BMS Ph III Up to $36B
6282016 Xencor-Novartis Preclinical Up to $24B
Early Stage Clinical Studies (Comparison)
We compared the interim data of Ph IIIa study of Bria-IMTtrade in advanced breast cancer with thedata in the early stage clinical studies of recently approved breast cancer drugs and one fasttracked product candidate
Apples to apples comparison Early Stage Clinical Studies in oncology are typically done in patientswith no other therapeutic options Thus the patients have very advanced disease and response ratesare typically quite low
The patients in our Ph IIIa study have been heavily pre-treated (median 45 prior regimens)Some recent studies of relevance in breast cancer are noted in the following slides
36
Breast Cancer Market Opportunity
Drug Technology Approved for Market (US)Ibrance (palbociclib) CDK 46 Inhibitor HR+HER2- MBC in combination with
fluvestrant or aromatase inhibitor$933M in 1Q2018 $3126M in 2017
Kisqali (ribociclib) CDK 46 Inhibitor 2017 HR+HER2- MBC in combination with fluvestrant or aromatase inhibitor
Peak sales projected at $25B
Verzenio (abemaciclib) CDK 46 Inhibitor 2017 HR+HER2- MBC in combination with fluvestrant or aromatase inhibitor
balixafortide CXCR4 antagonist Fast track designation in 2018 for HER2- MBC who have failed 2 prior regimens
The market for breast cancer drugs is a multibillion dollar market with new drugs being approvedon an ongoing basis indicating the shortage of safe and effective treatments for this deadly disease
37
Competitors- Phase III Clinical Data Bria-IMTtrade shows superior safety and similar to superior efficacy data compared with those of the multi-billion dollar drugs when they were at a similar early stage of clinical development
Injection site reactions No related SAEs or SUSARs
Tumor vol darr ampor darr circul tumor cellsAll Comers 21(419) 26(519)One or More HLA matches 27(415) 33(515)Two or More HLA matches 50 (24) 75 (34)
Sheet1 (3)
Comp -Slides
Data
HLA (2)
HLA
Data (Ph1-2+4Pt)
Competitors (2018)-Slide
Competitors (2018)
In the Pipeline Protein Kinase C delta (PKCδ) Inhibitors
30 of all human malignancies display activating RAS mutations Another 60 showing over-activity of Ras-signaling pathways
Ras has been termed ldquoundruggablerdquo (no one has been able to make a Ras inhibitor drug)
BriaCellrsquos novel proprietary PKCδ inhibitors have shown activity against multiple RAS transformed tumors Lung cancer Melanoma Breast cancer Neuroendocrine cancer Pancreatic cancer Colorectal cancer
This target has an attractive safety profile based on in vivo studies and knock out mouse studies
PKCδ inhibitors should qualify for an accelerated clinical development plan and regulatory pathway
Could be in clinic within 24 months
Cost-Effective Additional Shot-on-Goal and additional partnership opportunities
Early-Stage Preclinical Program
39
Protein Kinase C delta (PKCδ) Inhibitors
Activated PKCδ inhibits RAS degradation which in turn stimulates tumor growth
Koo et al Oncotarget 621328 2016
30 of all human malignancies display activating RASmutations with another 60 showing over-activity of Ras-signaling pathways
BriaCellrsquos novel proprietary PKCδ inhibitors have shownactivity against multiple RAS transformed tumors
This target has an attractive safety profile based on in vivostudies and knock out mouse studies
PKCδ also has potential activity as an immunotherapeuticby blocking TGFβ signaling
PKCδ inhibitors are applicable to specific niche tumor typeswhich provide an accelerated clinical development plan
Structural aspects of first generation inhibitor rottlerin and staurosporine (pan-PKC activator) were combined to create second generation inhibitor KAM1
Third generation inhibitors such as BJE6-106 have improved potency and selectivity Fourth generation inhibitors under development to optimize drug-like characteristics PKCδ inhibitors lack endothelial cell cytotoxicity amp PKCδ deficient mice develop normally and are fertile Potentially no marked intrinsic toxicity by inhibiting PKCδ
Mukai H Saeki T Shimada K Naito Y Matsubara N Nakanishi T Obaishi H Namiki M Sasaki Y Phase 1 combination study of eribulin mesylate with trastuzumab for advanced or recurrent human epidermal growth factor receptor 2 positive breast cancer Invest New Drugs 2015 Feb33(1)119-27
AstraZeneca
Lynparza (Olaparib) + Cediranib
PARP inhibitor + inhibitor of VEGF receptor tyrosine kinases
HR+ HER2- MBC
BC amp OC
2013
28 (8 BC)
3 for BC
Olaparib (a poly (ADP-ribose) polymerase (PARP) inhibitor) amp Cediranib (Vascular endothelial growth factor receptor (VEGFR) 1 2 and 3 tyrosine kinase inhibitor)3 at dose level (DL) 0 (cediranib 20mg olaparib 100mg) 3 at DL1 (cediranib 20mg olaparib 200mg) 7 at DL2 (cediranib 30mg olaparib 200mg) 6 at DL3 (cediranib 30mg olaparib 400mg)
Liu JF Tolaney SM Birrer M Fleming GF Buss MK Dahlberg SE Lee H Whalen C Tyburski K Winer E Ivy P Matulonis UA A Phase 1 trial of the poly(ADP-ribose) polymerase inhibitor olaparib (AZD2281) in combination with the anti-angiogenic cediranib (AZD2171) in recurrent epithelial ovarian or triple-negative breast cancer Eur J Cancer 2013 Sep49(14)2972-8
Reyon Pharmaceutical
VM206RY
Heterologous prime-boost with a truncated HER2 sequence
HER2+ Stage IIIampIV BC
2015
9
2 chemo
Plasmid DNA (pHM-GM-CSF expressing truncated HER2 amp GM-CSF) amp adenoviral vector (Ad-HM containing modified HER2) (2 4 and 8 mgpatientvisit) of pHM-GM-CSF 3x IM weeks 0 2 and 4 Ad-HM 3 times 109 virus particles at week 6
11 PR
4 pts showed 7 minor AEs
Unclear
Kim SB Ahn JH Kim J Jung KH A phase 1 study of a heterologous prime-boost vaccination involving a truncated HER2 sequence in patients with HER2-expressing breast cancer Mol Ther Methods Clin Dev 2015 Sep 30215031 doi 101038mtm201531 eCollection 2015
Rodon J Peacuterez-Fidalgo A Krop IE Burris H Guerrero-Zotano A Britten CD Becerra C Schellens J Richards DA Schuler M Abu-Khalaf M Johnson FM Ranson M Edenfield J Silva AP Hackl W Quadt C Demanse D Duval V Baselga J Phase 11b dose escalation and expansion study of BEZ235 a dual PI3KmTOR inhibitor in patients with advanced solid tumors including patients with advanced breast cancer Cancer Chemother Pharmacol 2018 Jun 7 doi 101007s00280-018-3610-z [Epub ahead of print]
Celgene (Abraxane)
Gemcitabine + Abraxane (nab-paclitaxel)
Chemo + Chemo
OC BC NSCLC amp Panc cancer + Lung OC BC Kaposi sarcoma
MBC
2016
9
Adjuvant chemo (100)chemo post-adjuvant (33)
Gem (nucleoside metabolic inhibitor 1250 mgm2) on days 1 and 8 nab-Pac (microtubule inhibitor) starting dose of 180 mgm2 (cohort 1) 220 mgm2 (cohort 2) and 260 mgm2 (cohort 3) on day 1 of the 21-day cycle using a 3 + 3 design
0
MTD not reached29 Gr3 Neutropenia59 Gr1 Peripheralneuropathy
Yoshitomi S Taira N Doihara H Mizoo T Nogami T Iwamoto T Motoki T Shien T Ogasawara Y Matsuoka J Tsuji H Mitsuhashi T A phase 1 dose-finding and pharmacokinetic study of gemcitabine with nab-paclitaxel in patients with metastatic breast cancer Cancer Chemother Pharmacol 2016 Aug78(2)289-94
Eli Lilly
Erbituxreg (cetuximab) + Taxane
EGFR inhibitor antineoplastic agent + Chemo
Headamp Neck Colorectal Cancer
TNBC
2007-2010
18
1 chemo
Cetuximab (epidermal growth factor receptor (EGFR) antagonist ) an initial loading dose of cetuximab 400 mgm2 followed by a weekly dose of 250 mgm2Paclitaxel (microtubule inhibitor) 80 mgm2 or Docetaxel at an initial dose of 30 mgm2 was administered weekly
56 CR 22 PR
83 Dermatologic toxicity11 Grade3+
Nechushtan H Vainer G Stainberg H Salmon AY Hamburger T Peretz T A phase 12 of a combination of cetuximab and taxane for triple negative breast cancer patients Breast 2014 Aug23(4)435-8
Polyphor
Balixafortide (POL6326) + eribulin
CXCR4 antagonist + tubulin-based antimitotic
Heavily pretreated Relapsed MBC
2014-2016
56
3rd line 3 chemo
3+3 dose escalation The highest dose was established as eribulin 14 mgmsup2 on days 2 and 9 and balixafortide 55 mgkg on days 1minus3 and 8minus10 of the 21-day cycle
30 PR
41 Gr34 Neutropenia11 Gr34 Leucopenia11 Gr34 Febrileneutropenia2 Related mortalities
Apr 2018 Fast Track for HER2-MBC who have failed 2prior regimens
Pernas S Martin M Kaufman PA Gil-Martin M Gomez Pardo P Lopez-Tarruella S Manso L Ciruelos E Perez-Fidalgo JA Hernando C Ademuyiwa FO Weilbaecher K Mayer I Pluard TJ Martinez Garcia M Vahdat L Perez-Garcia J Wach A Barker D Fung S Romagnoli B Cortes J Balixafortide plus eribulin in HER2-negative metastatic breast cancer a phase 1 single-arm dose-escalation trial Lancet Oncol 2018 Jun19(6)812-824
11 PRndashbut only + letrozole (No Resp on monotherapy)
61 Gr34 Neutropenia39 Gr34 Leucopenia
$933M in 1Q2018 $31B in 2017
Tamura K Mukai H Naito Y Yonemori K Kodaira M Tanabe Y Yamamoto N Osera S Sasaki M Mori Y Hashigaki S Nagasawa T Umeyama Y Yoshino T Phase I study of palbociclib a cyclin-dependent kinase 46 inhibitor in Japanese patients Cancer Sci 2016 Jun107(6)755-63 doi 101111cas12932 Epub 2016 May 11
Pfizer
Ibrancereg (palbociclib)
CDK 46 Inhibitor
HR+ HER2- MBC
Heavily pretreated Relapsed Metastatic Cancer
2004-2008
41 (5 BC)
chemo naiumlve (17) 1-2 (51)3 (29) 3+ (2)
Palbociclib 25-150 mg dose ranging
0
20 Gr34 Neutropenia23 Gr34 Leucopenia
$933M in 1Q2018 $31B in 2017
Flaherty KT Lorusso PM Demichele A Abramson VG Courtney R Randolph SS Shaik MN Wilner KD ODwyer PJ Schwartz GK Phase I dose-escalation trial of the oral cyclin-dependent kinase 46 inhibitor PD 0332991 administered using a 21-day schedule in patients with advanced cancer Clin Cancer Res 2012 Jan 1518(2)568-76 doi 1011581078-0432CCR-11-0509 Epub 2011 Nov 16
Novartis
Kisqalireg (ribociclib)
CDK 46 Inhibitors
Premenopausal HR+ HER2- MBC
Heavily pretreated Relapsed Metastatic Cancer
2016
132 (20 BC)
0-1 (25) 2-3 (42) 4+ (32)
Ribociclib 50 mg ranging up to 1200 mg dose escalation
23 PRndashincluded 1 in BC (5 of BC pts)
27 Gr34 Neutropenia17 Gr34 Leucopenia
Peak sales projected at $25B
Infante JR Cassier PA Gerecitano JF Witteveen PO Chugh R Ribrag V Chakraborty A Matano A Dobson JR Crystal AS Parasuraman S Shapiro GI A Phase I Study of the Cyclin-Dependent Kinase 46 Inhibitor Ribociclib (LEE011) in Patients with Advanced Solid Tumors and Lymphomas Clin Cancer Res 2016 Dec 122(23)5696-5705 Epub 2016 Aug 19
Eli Lilly
Verzenioreg (abemaciclib)
CDK 46 Inhibitors
HR+HER2minusMBC
Heavily pretreated Relapsed Metastatic Cancer
2016
12 (1 BC)
1 (312) 2 (212) 3+ (7)
Abemaciclib 100 mg ranging up to 200 mg dose escalation
17 PR (included 1 in BC)
17 Gr34 Neutropenia33 Gr34 Leucopenia
Peak sales projected at $2B
Fujiwara Y Tamura K Kondo S Tanabe Y Iwasa S Shimomura A Kitano S Ogasawara K Turner PK Mori J Asou H Chan EM Yamamoto N Phase 1 study of abemaciclib an inhibitor of CDK 4 and 6 as a single agent for Japanese patients with advanced cancer Cancer Chemother Pharmacol 2016 Aug78(2)281-8 doi 101007s00280-016-3085-8 Epub 2016 Jun 16
Mukai H Saeki T Shimada K Naito Y Matsubara N Nakanishi T Obaishi H Namiki M Sasaki Y Phase 1 combination study of eribulin mesylate with trastuzumab for advanced or recurrent human epidermal growth factor receptor 2 positive breast cancer Invest New Drugs 2015 Feb33(1)119-27
AstraZeneca
Lynparza (Olaparib)+ Cediranib
PARP inhibitor+ inhibitor of VEGF RTK
HR+ HER2- MBC
BC amp OC
13
28 (8 BC)
3 for BC
Olaparib (a poly (ADP-ribose) polymerase (PARP) inhibitor) amp Cediranib (Vascular endothelial growth factor receptor (VEGFR) 1 2 and 3 tyrosine kinase inhibitor)3 at dose level (DL) 0 (cediranib 20mg olaparib 100mg) 3 at DL1 (cediranib 20mg olaparib 200mg) 7 at DL2 (cediranib 30mg olaparib 200mg) 6 at DL3 (cediranib 30mg olaparib 400mg)
Liu JF Tolaney SM Birrer M Fleming GF Buss MK Dahlberg SE Lee H Whalen C Tyburski K Winer E Ivy P Matulonis UA A Phase 1 trial of the poly(ADP-ribose) polymerase inhibitor olaparib (AZD2281) in combination with the anti-angiogenic cediranib (AZD2171) in recurrent epithelial ovarian or triple-negative breast cancer Eur J Cancer 2013 Sep49(14)2972-8
ReyonPharma
VM206RY
Heterologous prime-boost with a truncated HER2 sequence
HER2+ Stg IIIampIV BC
15
9
2 chemo
Plasmid DNA (pHM-GM-CSF expressing truncated HER2 amp GM-CSF) amp adenoviral vector (Ad-HM containing modified HER2) (2 4 and 8 mgpatientvisit) of pHM-GM-CSF 3x IM weeks 0 2 and 4 Ad-HM 3 times 109 virus particles at week 6
11 PR
4 pts 7 minor AEs
Unclear
Kim SB Ahn JH Kim J Jung KH A phase 1 study of a heterologous prime-boost vaccination involving a truncated HER2 sequence in patients with HER2-expressing breast cancer Mol Ther Methods Clin Dev 2015 Sep 30215031 doi 101038mtm201531 eCollection 2015
Rodon J Peacuterez-Fidalgo A Krop IE Burris H Guerrero-Zotano A Britten CD Becerra C Schellens J Richards DA Schuler M Abu-Khalaf M Johnson FM Ranson M Edenfield J Silva AP Hackl W Quadt C Demanse D Duval V Baselga J Phase 11b dose escalation and expansion study of BEZ235 a dual PI3KmTOR inhibitor in patients with advanced solid tumors including patients with advanced breast cancer Cancer Chemother Pharmacol 2018 Jun 7 doi 101007s00280-018-3610-z [Epub ahead of print]
Celgene(Abraxane)
Gemcitabine + Abraxane (nab-paclitaxel)
Chemo+ Chemo
OC BC NSCLC PC + LC OC BC KS
MBC
16
9
Adjuv chemo (100)chemo post-adjuv (33)
Gem (nucleoside metabolic inhibitor 1250 mgm2) on days 1 and 8 nab-Pac (microtubule inhibitor) starting dose of 180 mgm2 (cohort 1) 220 mgm2 (cohort 2) and 260 mgm2 (cohort 3) on day 1 of the 21-day cycle using a 3 + 3 design
0
MTD not reached29 Gr3 Neutropenia59 Gr1 Peripheralneuropathy
Yoshitomi S Taira N Doihara H Mizoo T Nogami T Iwamoto T Motoki T Shien T Ogasawara Y Matsuoka J Tsuji H Mitsuhashi T A phase 1 dose-finding and pharmacokinetic study of gemcitabine with nab-paclitaxel in patients with metastatic breast cancer Cancer Chemother Pharmacol 2016 Aug78(2)289-94
Eli Lilly
Erbituxreg (cetuximab) + Taxane
EGFR inhibitor antineoplastic agent + Chemo
Head amp NeckColorectal
TNBC
07-10
18
1 chemo
Cetuximab (epidermal growth factor receptor (EGFR) antagonist ) an initial loading dose of cetuximab 400 mgm2 followed by a weekly dose of 250 mgm2Paclitaxel (microtubule inhibitor) 80 mgm2 or Docetaxel at an initial dose of 30 mgm2 was administered weekly
56 CR 22 PR
83 Dermatologic toxicity11 Grade3+
Nechushtan H Vainer G Stainberg H Salmon AY Hamburger T Peretz T A phase 12 of a combination of cetuximab and taxane for triple negative breast cancer patients Breast 2014 Aug23(4)435-8
Polyphor
Balixafortide (POL6326) + eribulin
CXCR4 antagonist + tubulin-based antimitotic
Heavily pretreatedRelapsed MBC
14-16
56
3rd line 3 chemo
3+3 dose escalation The highest dose was established as eribulin 14 mgmsup2 on days 2 and 9 and balixafortide 55 mgkg on days 1minus3 and 8minus10 of the 21-day cycle
30 PR
41 Gr34 Neutropenia11 Gr34 Leucopenia11 Gr34 Febrileneutropenia2 Related mortalities
42018 Fast Track (HER2-MBC failed 2 prior regimens)
Pernas S Martin M Kaufman PA Gil-Martin M Gomez Pardo P Lopez-Tarruella S Manso L Ciruelos E Perez-Fidalgo JA Hernando C Ademuyiwa FO Weilbaecher K Mayer I Pluard TJ Martinez Garcia M Vahdat L Perez-Garcia J Wach A Barker D Fung S Romagnoli B Cortes J Balixafortide plus eribulin in HER2-negative metastatic breast cancer a phase 1 single-arm dose-escalation trial Lancet Oncol 2018 Jun19(6)812-824
1 PRndashbut only + letrozoleNo Resp on monotherapy
61 Gr34 Neutropenia39 Gr34 Leucopenia
$933M (1Q18)$31B (2017)
Tamura K Mukai H Naito Y Yonemori K Kodaira M Tanabe Y Yamamoto N Osera S Sasaki M Mori Y Hashigaki S Nagasawa T Umeyama Y Yoshino T Phase I study of palbociclib a cyclin-dependent kinase 46 inhibitor in Japanese patients Cancer Sci 2016 Jun107(6)755-63 doi 101111cas12932 Epub 2016 May 11
Pfizer
Ibrancereg (palbociclib)
CDK 46 Inhibitor
HR+ HER2- MBC
Heavily pretreatedRelapsed Met Cancer
04-08
41 (5 BC)
chemo naiumlve (17)1-2(51) 3(29) 3+(2)
Palbociclib 25-150 mg dose ranging
0
20 Gr34 Neutropenia23 Gr34 Leucopenia
$933M (1Q18)$31B (2017)
Flaherty KT Lorusso PM Demichele A Abramson VG Courtney R Randolph SS Shaik MN Wilner KD ODwyer PJ Schwartz GK Phase I dose-escalation trial of the oral cyclin-dependent kinase 46 inhibitor PD 0332991 administered using a 21-day schedule in patients with advanced cancer Clin Cancer Res 2012 Jan 1518(2)568-76 doi 1011581078-0432CCR-11-0509 Epub 2011 Nov 16
Novartis
Kisqalireg (ribociclib)
CDK 46 Inhibitor
Premenopausal HR+ HER2- MBC
Heavily pretreatedRelapsed Met Cancer
16
132 (20 BC)
0-1 (25) 2-3 (42)4+ (32)
Ribociclib 50 mg ranging up to 1200 mg dose escalation
23 PR-included 1 BC (5 of BC pts)
27 Gr34 Neutropenia17 Gr34 Leucopenia
Peak sales est at $25B
Infante JR Cassier PA Gerecitano JF Witteveen PO Chugh R Ribrag V Chakraborty A Matano A Dobson JR Crystal AS Parasuraman S Shapiro GI A Phase I Study of the Cyclin-Dependent Kinase 46 Inhibitor Ribociclib (LEE011) in Patients with Advanced Solid Tumors and Lymphomas Clin Cancer Res 2016 Dec 122(23)5696-5705 Epub 2016 Aug 19
Eli Lilly
Verzenioreg (abemaciclib)
CDK 46 Inhibitor
HR+HER2minusMBC
Heavily pretreatedRelapsed Met Cancer
16
12 (1 BC)
1 (312) 2 (212) 3+(7)
Abemaciclib 100 mg ranging up to 200 mg dose escalation
17 PR (included 1 BC)
17 Gr34 Neutropenia33 Gr34 Leucopenia
Peak sales est at $2B
Fujiwara Y Tamura K Kondo S Tanabe Y Iwasa S Shimomura A Kitano S Ogasawara K Turner PK Mori J Asou H Chan EM Yamamoto N Phase 1 study of abemaciclib an inhibitor of CDK 4 and 6 as a single agent for Japanese patients with advanced cancer Cancer Chemother Pharmacol 2016 Aug78(2)281-8 doi 101007s00280-016-3085-8 Epub 2016 Jun 16
Mukai H Saeki T Shimada K Naito Y Matsubara N Nakanishi T Obaishi H Namiki M Sasaki Y Phase 1 combination study of eribulin mesylate with trastuzumab for advanced or recurrent human epidermal growth factor receptor 2 positive breast cancer Invest New Drugs 2015 Feb33(1)119-27
AstraZeneca
Lynparza (Olaparib) + Cediranib
PARP inhibitor + inhibitor of VEGF receptor tyrosine kinases
HR+ HER2- MBC
BC amp OC
2013
28 (8 BC)
3 for BC
Olaparib (a poly (ADP-ribose) polymerase (PARP) inhibitor) amp Cediranib (Vascular endothelial growth factor receptor (VEGFR) 1 2 and 3 tyrosine kinase inhibitor)3 at dose level (DL) 0 (cediranib 20mg olaparib 100mg) 3 at DL1 (cediranib 20mg olaparib 200mg) 7 at DL2 (cediranib 30mg olaparib 200mg) 6 at DL3 (cediranib 30mg olaparib 400mg)
Liu JF Tolaney SM Birrer M Fleming GF Buss MK Dahlberg SE Lee H Whalen C Tyburski K Winer E Ivy P Matulonis UA A Phase 1 trial of the poly(ADP-ribose) polymerase inhibitor olaparib (AZD2281) in combination with the anti-angiogenic cediranib (AZD2171) in recurrent epithelial ovarian or triple-negative breast cancer Eur J Cancer 2013 Sep49(14)2972-8
Reyon Pharmaceutical
VM206RY
Heterologous prime-boost with a truncated HER2 sequence
HER2+ Stage IIIampIV BC
2015
9
2 chemo
Plasmid DNA (pHM-GM-CSF expressing truncated HER2 amp GM-CSF) amp adenoviral vector (Ad-HM containing modified HER2) (2 4 and 8 mgpatientvisit) of pHM-GM-CSF 3x IM weeks 0 2 and 4 Ad-HM 3 times 109 virus particles at week 6
11 PR
4 pts showed 7 minor AEs
Unclear
Kim SB Ahn JH Kim J Jung KH A phase 1 study of a heterologous prime-boost vaccination involving a truncated HER2 sequence in patients with HER2-expressing breast cancer Mol Ther Methods Clin Dev 2015 Sep 30215031 doi 101038mtm201531 eCollection 2015
Rodon J Peacuterez-Fidalgo A Krop IE Burris H Guerrero-Zotano A Britten CD Becerra C Schellens J Richards DA Schuler M Abu-Khalaf M Johnson FM Ranson M Edenfield J Silva AP Hackl W Quadt C Demanse D Duval V Baselga J Phase 11b dose escalation and expansion study of BEZ235 a dual PI3KmTOR inhibitor in patients with advanced solid tumors including patients with advanced breast cancer Cancer Chemother Pharmacol 2018 Jun 7 doi 101007s00280-018-3610-z [Epub ahead of print]
Celgene (Abraxane)
Gemcitabine + Abraxane (nab-paclitaxel)
Chemo + Chemo
OC BC NSCLC amp Panc cancer + Lung OC BC Kaposi sarcoma
MBC
2016
9
Adjuvant chemo (100)chemo post-adjuvant (33)
Gem (nucleoside metabolic inhibitor 1250 mgm2) on days 1 and 8 nab-Pac (microtubule inhibitor) starting dose of 180 mgm2 (cohort 1) 220 mgm2 (cohort 2) and 260 mgm2 (cohort 3) on day 1 of the 21-day cycle using a 3 + 3 design
0
MTD not reached29 Gr3 Neutropenia59 Gr1 Peripheralneuropathy
Yoshitomi S Taira N Doihara H Mizoo T Nogami T Iwamoto T Motoki T Shien T Ogasawara Y Matsuoka J Tsuji H Mitsuhashi T A phase 1 dose-finding and pharmacokinetic study of gemcitabine with nab-paclitaxel in patients with metastatic breast cancer Cancer Chemother Pharmacol 2016 Aug78(2)289-94
Eli Lilly
Erbituxreg (cetuximab) + Taxane
EGFR inhibitor antineoplastic agent + Chemo
Headamp Neck Colorectal Cancer
TNBC
2007-2010
18
1 chemo
Cetuximab (epidermal growth factor receptor (EGFR) antagonist ) an initial loading dose of cetuximab 400 mgm2 followed by a weekly dose of 250 mgm2Paclitaxel (microtubule inhibitor) 80 mgm2 or Docetaxel at an initial dose of 30 mgm2 was administered weekly
56 CR 22 PR
83 Dermatologic toxicity11 Grade3+
Nechushtan H Vainer G Stainberg H Salmon AY Hamburger T Peretz T A phase 12 of a combination of cetuximab and taxane for triple negative breast cancer patients Breast 2014 Aug23(4)435-8
Polyphor
Balixafortide (POL6326) + eribulin
CXCR4 antagonist + tubulin-based antimitotic
Heavily pretreated Relapsed MBC
2014-2016
56
3rd line 3 chemo
3+3 dose escalation The highest dose was established as eribulin 14 mgmsup2 on days 2 and 9 and balixafortide 55 mgkg on days 1minus3 and 8minus10 of the 21-day cycle
30 PR
41 Gr34 Neutropenia11 Gr34 Leucopenia11 Gr34 Febrileneutropenia2 Related mortalities
Apr 2018 Fast Track for HER2-MBC who have failed 2prior regimens
Pernas S Martin M Kaufman PA Gil-Martin M Gomez Pardo P Lopez-Tarruella S Manso L Ciruelos E Perez-Fidalgo JA Hernando C Ademuyiwa FO Weilbaecher K Mayer I Pluard TJ Martinez Garcia M Vahdat L Perez-Garcia J Wach A Barker D Fung S Romagnoli B Cortes J Balixafortide plus eribulin in HER2-negative metastatic breast cancer a phase 1 single-arm dose-escalation trial Lancet Oncol 2018 Jun19(6)812-824
11 PRndashbut only + letrozole (No Resp on monotherapy)
61 Gr34 Neutropenia39 Gr34 Leucopenia
$933M in 1Q2018 $31B in 2017
Tamura K Mukai H Naito Y Yonemori K Kodaira M Tanabe Y Yamamoto N Osera S Sasaki M Mori Y Hashigaki S Nagasawa T Umeyama Y Yoshino T Phase I study of palbociclib a cyclin-dependent kinase 46 inhibitor in Japanese patients Cancer Sci 2016 Jun107(6)755-63 doi 101111cas12932 Epub 2016 May 11
Pfizer
Ibrancereg (palbociclib)
CDK 46 Inhibitor
HR+ HER2- MBC
Heavily pretreated Relapsed Metastatic Cancer
2004-2008
41 (5 BC)
chemo naiumlve (17) 1-2 (51)3 (29) 3+ (2)
Palbociclib 25-150 mg dose ranging
0
20 Gr34 Neutropenia23 Gr34 Leucopenia
$933M in 1Q2018 $31B in 2017
Flaherty KT Lorusso PM Demichele A Abramson VG Courtney R Randolph SS Shaik MN Wilner KD ODwyer PJ Schwartz GK Phase I dose-escalation trial of the oral cyclin-dependent kinase 46 inhibitor PD 0332991 administered using a 21-day schedule in patients with advanced cancer Clin Cancer Res 2012 Jan 1518(2)568-76 doi 1011581078-0432CCR-11-0509 Epub 2011 Nov 16
Novartis
Kisqalireg (ribociclib)
CDK 46 Inhibitors
Premenopausal HR+ HER2- MBC
Heavily pretreated Relapsed Metastatic Cancer
2016
132 (20 BC)
0-1 (25) 2-3 (42) 4+ (32)
Ribociclib 50 mg ranging up to 1200 mg dose escalation
23 PRndashincluded 1 in BC (5 of BC pts)
27 Gr34 Neutropenia17 Gr34 Leucopenia
Peak sales projected at $25B
Infante JR Cassier PA Gerecitano JF Witteveen PO Chugh R Ribrag V Chakraborty A Matano A Dobson JR Crystal AS Parasuraman S Shapiro GI A Phase I Study of the Cyclin-Dependent Kinase 46 Inhibitor Ribociclib (LEE011) in Patients with Advanced Solid Tumors and Lymphomas Clin Cancer Res 2016 Dec 122(23)5696-5705 Epub 2016 Aug 19
Eli Lilly
Verzenioreg (abemaciclib)
CDK 46 Inhibitors
HR+HER2minusMBC
Heavily pretreated Relapsed Metastatic Cancer
2016
12 (1 BC)
1 (312) 2 (212) 3+ (7)
Abemaciclib 100 mg ranging up to 200 mg dose escalation
17 PR (included 1 in BC)
17 Gr34 Neutropenia33 Gr34 Leucopenia
Peak sales projected at $2B
Fujiwara Y Tamura K Kondo S Tanabe Y Iwasa S Shimomura A Kitano S Ogasawara K Turner PK Mori J Asou H Chan EM Yamamoto N Phase 1 study of abemaciclib an inhibitor of CDK 4 and 6 as a single agent for Japanese patients with advanced cancer Cancer Chemother Pharmacol 2016 Aug78(2)281-8 doi 101007s00280-016-3085-8 Epub 2016 Jun 16
Mukai H Saeki T Shimada K Naito Y Matsubara N Nakanishi T Obaishi H Namiki M Sasaki Y Phase 1 combination study of eribulin mesylate with trastuzumab for advanced or recurrent human epidermal growth factor receptor 2 positive breast cancer Invest New Drugs 2015 Feb33(1)119-27
AstraZeneca
Lynparza (Olaparib)+ Cediranib
PARP inhibitor+ inhibitor of VEGF RTK
HR+ HER2- MBC
BC amp OC
13
28 (8 BC)
3 for BC
Olaparib (a poly (ADP-ribose) polymerase (PARP) inhibitor) amp Cediranib (Vascular endothelial growth factor receptor (VEGFR) 1 2 and 3 tyrosine kinase inhibitor)3 at dose level (DL) 0 (cediranib 20mg olaparib 100mg) 3 at DL1 (cediranib 20mg olaparib 200mg) 7 at DL2 (cediranib 30mg olaparib 200mg) 6 at DL3 (cediranib 30mg olaparib 400mg)
Liu JF Tolaney SM Birrer M Fleming GF Buss MK Dahlberg SE Lee H Whalen C Tyburski K Winer E Ivy P Matulonis UA A Phase 1 trial of the poly(ADP-ribose) polymerase inhibitor olaparib (AZD2281) in combination with the anti-angiogenic cediranib (AZD2171) in recurrent epithelial ovarian or triple-negative breast cancer Eur J Cancer 2013 Sep49(14)2972-8
ReyonPharma
VM206RY
Heterologous prime-boost with a truncated HER2 sequence
HER2+ Stg IIIampIV BC
15
9
2 chemo
Plasmid DNA (pHM-GM-CSF expressing truncated HER2 amp GM-CSF) amp adenoviral vector (Ad-HM containing modified HER2) (2 4 and 8 mgpatientvisit) of pHM-GM-CSF 3x IM weeks 0 2 and 4 Ad-HM 3 times 109 virus particles at week 6
11 PR
4 pts 7 minor AEs
Unclear
Kim SB Ahn JH Kim J Jung KH A phase 1 study of a heterologous prime-boost vaccination involving a truncated HER2 sequence in patients with HER2-expressing breast cancer Mol Ther Methods Clin Dev 2015 Sep 30215031 doi 101038mtm201531 eCollection 2015
Rodon J Peacuterez-Fidalgo A Krop IE Burris H Guerrero-Zotano A Britten CD Becerra C Schellens J Richards DA Schuler M Abu-Khalaf M Johnson FM Ranson M Edenfield J Silva AP Hackl W Quadt C Demanse D Duval V Baselga J Phase 11b dose escalation and expansion study of BEZ235 a dual PI3KmTOR inhibitor in patients with advanced solid tumors including patients with advanced breast cancer Cancer Chemother Pharmacol 2018 Jun 7 doi 101007s00280-018-3610-z [Epub ahead of print]
Celgene(Abraxane)
Gemcitabine + Abraxane (nab-paclitaxel)
Chemo+ Chemo
OC BC NSCLC PC + LC OC BC KS
MBC
16
9
Adjuv chemo (100)chemo post-adjuv (33)
Gem (nucleoside metabolic inhibitor 1250 mgm2) on days 1 and 8 nab-Pac (microtubule inhibitor) starting dose of 180 mgm2 (cohort 1) 220 mgm2 (cohort 2) and 260 mgm2 (cohort 3) on day 1 of the 21-day cycle using a 3 + 3 design
0
MTD not reached29 Gr3 Neutropenia59 Gr1 Peripheralneuropathy
Yoshitomi S Taira N Doihara H Mizoo T Nogami T Iwamoto T Motoki T Shien T Ogasawara Y Matsuoka J Tsuji H Mitsuhashi T A phase 1 dose-finding and pharmacokinetic study of gemcitabine with nab-paclitaxel in patients with metastatic breast cancer Cancer Chemother Pharmacol 2016 Aug78(2)289-94
Eli Lilly
Erbituxreg (cetuximab) + Taxane
EGFR inhibitor antineoplastic agent + Chemo
Head amp NeckColorectal
TNBC
07-10
18
1 chemo
Cetuximab (epidermal growth factor receptor (EGFR) antagonist ) an initial loading dose of cetuximab 400 mgm2 followed by a weekly dose of 250 mgm2Paclitaxel (microtubule inhibitor) 80 mgm2 or Docetaxel at an initial dose of 30 mgm2 was administered weekly
56 CR 22 PR
83 Dermatologic toxicity11 Grade3+
Nechushtan H Vainer G Stainberg H Salmon AY Hamburger T Peretz T A phase 12 of a combination of cetuximab and taxane for triple negative breast cancer patients Breast 2014 Aug23(4)435-8
Polyphor
Balixafortide (POL6326) + eribulin
CXCR4 antagonist + tubulin-based antimitotic
Heavily pretreatedRelapsed MBC
14-16
56
3rd line 3 chemo
3+3 dose escalation The highest dose was established as eribulin 14 mgmsup2 on days 2 and 9 and balixafortide 55 mgkg on days 1minus3 and 8minus10 of the 21-day cycle
30 PR
41 Gr34 Neutropenia11 Gr34 Leucopenia11 Gr34 Febrileneutropenia2 Related mortalities
42018 Fast Track (HER2-MBC failed 2 prior regimens)
Pernas S Martin M Kaufman PA Gil-Martin M Gomez Pardo P Lopez-Tarruella S Manso L Ciruelos E Perez-Fidalgo JA Hernando C Ademuyiwa FO Weilbaecher K Mayer I Pluard TJ Martinez Garcia M Vahdat L Perez-Garcia J Wach A Barker D Fung S Romagnoli B Cortes J Balixafortide plus eribulin in HER2-negative metastatic breast cancer a phase 1 single-arm dose-escalation trial Lancet Oncol 2018 Jun19(6)812-824
1 PRndashbut only + letrozoleNo Resp on monotherapy
61 Gr34 Neutropenia39 Gr34 Leucopenia
$933M (1Q18)$31B (2017)
Tamura K Mukai H Naito Y Yonemori K Kodaira M Tanabe Y Yamamoto N Osera S Sasaki M Mori Y Hashigaki S Nagasawa T Umeyama Y Yoshino T Phase I study of palbociclib a cyclin-dependent kinase 46 inhibitor in Japanese patients Cancer Sci 2016 Jun107(6)755-63 doi 101111cas12932 Epub 2016 May 11
Pfizer
Ibrancereg (palbociclib)
CDK 46 Inhibitor
HR+ HER2- MBC
Heavily pretreatedRelapsed Met Cancer
04-08
41 (5 BC)
chemo naiumlve (17)1-2(51) 3(29) 3+(2)
Palbociclib 25-150 mg dose ranging
0
20 Gr34 Neutropenia23 Gr34 Leucopenia
$933M (1Q18)$31B (2017)
Flaherty KT Lorusso PM Demichele A Abramson VG Courtney R Randolph SS Shaik MN Wilner KD ODwyer PJ Schwartz GK Phase I dose-escalation trial of the oral cyclin-dependent kinase 46 inhibitor PD 0332991 administered using a 21-day schedule in patients with advanced cancer Clin Cancer Res 2012 Jan 1518(2)568-76 doi 1011581078-0432CCR-11-0509 Epub 2011 Nov 16
Novartis
Kisqalireg (ribociclib)
CDK 46 Inhibitor
Premenopausal HR+ HER2- MBC
Heavily pretreatedRelapsed Met Cancer
16
132 (20 BC)
0-1 (25) 2-3 (42)4+ (32)
Ribociclib 50 mg ranging up to 1200 mg dose escalation
23 PR-included 1 BC (5 of BC pts)
27 Gr34 Neutropenia17 Gr34 Leucopenia
Peak sales est at $25B
Infante JR Cassier PA Gerecitano JF Witteveen PO Chugh R Ribrag V Chakraborty A Matano A Dobson JR Crystal AS Parasuraman S Shapiro GI A Phase I Study of the Cyclin-Dependent Kinase 46 Inhibitor Ribociclib (LEE011) in Patients with Advanced Solid Tumors and Lymphomas Clin Cancer Res 2016 Dec 122(23)5696-5705 Epub 2016 Aug 19
Eli Lilly
Verzenioreg (abemaciclib)
CDK 46 Inhibitor
HR+HER2minusMBC
Heavily pretreatedRelapsed Met Cancer
16
12 (1 BC)
1 (312) 2 (212) 3+(7)
Abemaciclib 100 mg ranging up to 200 mg dose escalation
17 PR (included 1 BC)
17 Gr34 Neutropenia33 Gr34 Leucopenia
Peak sales est at $2B
Fujiwara Y Tamura K Kondo S Tanabe Y Iwasa S Shimomura A Kitano S Ogasawara K Turner PK Mori J Asou H Chan EM Yamamoto N Phase 1 study of abemaciclib an inhibitor of CDK 4 and 6 as a single agent for Japanese patients with advanced cancer Cancer Chemother Pharmacol 2016 Aug78(2)281-8 doi 101007s00280-016-3085-8 Epub 2016 Jun 16
Bria-IMTtrade and Bria-OTStrade shouldsynergize with existing approvedimmunotherapies as well as those stillunder development
This includes immune checkpointinhibitors such as antibodies to PD-1CTLA-4 GITR and CD73 inhibitors whicheliminate tumor immunosuppression Checkpoint Inhibitors were the
subject of the 2018 Nobel Prize inMedicine
In addition immunostimulatoryantibodies to molecules such as OX40should enhance responses to Bria-IMTtradeand Bria-OTStrade
13
Q3 2018 Data on first 20 Patients on Bria-IMTtrade Q3 2018 Initiate Combination Study of Bria-IMTtrade with Keytruda or Yervoy
Q4 2018 Switch to a novel frozen Bria-IMTtrade formulation Q4 2018 Safety Data (6 patients) of the Bria-IMTtrade - Keytrudareg Combination Study (SABC meeting) Q4 2018 Ongoing Corporate PartnershipCollaboration Discussions
Q1 2019 Efficacy Data (6 patients) of the Bria-IMTtrade - Keytrudareg Combination Study Q2 2019 Initiation of Bria-OTStrade GMP manufacturing (KBI BioPharma) Q2 2019 Additional Safety amp Efficacy data Monotherapy and Combination Studies (AACR meeting) Q2 2019 Final data for Monotherapy and Additional Data for the Combination Study (ASCO meeting) H1 2019 Candidate Selection for a PKCδ Inhibitor H1 2019 Initiate additional immunotherapy program H2 2019 Bria-OTStrade Authorization from FDA clearance for dosing H2 2019 Bria-OTStrade First Patient Dosed
Upcoming Milestones amp Catalysts
14
Involved in over 10 drugs brought to the market
Experienced Management Team
Management
William V Williams MD FACP President amp CEO VP Exploratory Development Incyte Corporation VP Experimental Medicine GlaxoSmithKline Head Rheumatology Research University of Pennsylvania Facilitated entry of over 20 compounds into the clinic including ruxolitinib (Jakafi)
baricitinib amp epacadostat NDAs including Jakafi Boniva Bexxar Author of over 120 peer-reviewed publications amp over 20 patents
Gadi Levin CA MBA CFO CFO of Labstyle Innovations Ltd VP of Finance for two Israeli investment houses in the fields of private equity
hedge funds and real estate Financial Consultant various firms Accountant Arthur Andersen
Markus Lacher PhD Senior Director RampD Founder T cell Therapeutics Inc an immuno-oncology company Sr Clinical Scientist Cesca Therapeutics Inc a clinical-stage autologous cell
therapy company Scientist at BioTime Inc and OncoCyte Corporation Editorial advisory board Recent Patents on Anti-Cancer Drug Discovery
Farrah Dean MSc MBA Manager Corp Development Investor relations CytRx Corporation amp CCG Investor Relations Senior Associate Equity Analyst Oppenheimer amp Co Rodman amp Renshaw amp
Brian Metcalf PhD Recently retired as CSO from Global Blood Therapeutics Former Head of Research amp Development Incyte Corporation Former Head of Medicinal Chemistry SmithKline Beecham
Douglas Faller MD PhD Professor of Medicine Pediatrics Biochemistry Microbiology Pathology and
Laboratory Medicine HematologistOncologist former Director of the Cancer Center Boston University School of Medicine
Founder of several successful biotechnology companies
Robert Williams PhD University Distinguished Professor of Chemistry Colorado State University Founder of several successful biotechnology companies including Microcide Xcyte
Therapies HemaQuest Arch Therapeutics and Cetya Therapeutics
Thomas Kieber-Emmons PhD Deputy Director University of Arkansas Cancer Center Expert in targeted cancer immunotherapies structural biology and computational
chemistry
Maria Trojanowska PhD Professor of Medicine Boston University School of Medicine Director The Arthritis Center
16
Veteran Board of Directors
Board of Directors
Saeid Babaei PhD MBA Chairman Entrepreneur 20 yrs of biotech leadership roles Current CEO AbCelex VP Bus Develop Lorus Therap Dir of Corp Develop Northern Therapeutics
Rahoul Sharan CA Director Chairman Potash Ridge Director of the Board Ansell Capital Corp Parallel Resources amp Galaxy Capital
Corporation
Martin Schmieg CPA Director CFO Sirna Therapeutics Inc amp Isolagen Inc CEO Freedom-2 Inc (now PharmaCyte Inc) Advisor Caladrius Biosciences Inc Beckman Coulter Genomics Calimmune
Charles Wiseman MD Co-Founder amp Director Director Immunotherapy Lab St Vincent Medical Center Chief Breast Cancer Basic Research Lab Univ of Texas MD Anderson Hospital amp
Tumour Institute Assist Prof Dept of Molecular Carcinogenesis amp Virology MD Anderson Acting Chief Div of Oncology White Memorial Medical Center LA
William V Williams MD FACP President amp CEO VP Exploratory Development Incyte Corporation VP Experimental Medicine GlaxoSmithKline Head Rheumatology Research University of Pennsylvania
Prior Affiliations
17
Drug Approvals by BriaCell Management Team
Bexxarreg (tositumomab and Iodine I131 tositumomab) Treatment of CD20 antigen-expressing relapsed or refractory low grade follicular or transformed non-Hodgkins lymphoma
Myleranreg (busulfan) for chronic myelogenous leukemia Defense of formulation change sNDA
Hycamtinreg (topotecan) for ovarian cancer Pediatric use sNDA
Navelbinereg (vinorelbine tartrate) for non-small cell lung cancer Pediatric use sNDA
Bonivareg (ibandronate) monthly oral treatment of osteoporosis
Bonivareg (ibandronate) quarterly intraveous treatment of osteoporosis
Zofranreg (ondansetron) for prevention of nausea and vomiting Pediatric use sNDA
Jakafireg (ruxolitinib) for myelofibrosis Jakafireg (ruxolitinib) for polycythemia vera
Olumiantreg (baricitinib) for rheumatoid arthritis Approved in USA Japan and Europe
18
Share Metrics
BCTV BCTXF 19
Data as of 1092018
Ticker TSX BCTV
US Ticker OTCQBBCTXF
Share Price (CAD) as of Oct 9 2018 $012
52-Week Range (CAD) $009-019
Shares Outstanding as of Oct 9 2018 1611M
Market Cap as of Oct 9 2018 (CAD) $193M
Cash and Short Term Investments as of July 31 2018 (CAD) $23M
Total Shareholders Equity as of July 31 2018 (CAD) $12M
Number of Warrants $014-$035 (CAD) as of Oct 9 2018 601M
Number of Compensation Warrants $014-$030 (CAD) as of Oct 9 2018 45M
Number of Options $014- $026 (CAD$) as of Oct 9 2018 93M
Developing Bria-OTStrade the First Off-the-Shelf Personalized Immunotherapy
Targeting Adv Breast Cancer Unmet medical need (42000 death in the US in 2017 ) $1 Bil- $5 Bil market opportunity depending on patient treatment stage
Impressive results in 2 proof-of-concept clinical trials Rapid Response Rate Repeated following re-treatment Excellent Safety Profile
Completed enrollment in Phase IIIa clinical trial of Bria-IMTtrade with outstanding safety amp efficacy data Initiated Phase IIa Combination Study of Bria-IMTtrade with Keytrudareg (Merck amp Co Inc)
Developing Bria-OTStrade along with BriaDXtrade its companion diagnostic test Ability to match and treat ~90 of patient population with Off-the-Shelf personalized immunotherapy
Experienced Management has been involved in over 10 drug approvals
Patient B001 Breast 70 No 1101 - 3501 4001 Negative -
Bria-IMTtradeHuman Proof-of-Concept Trials in Breast Cancer (Patient A002)
24
Proof-of-Concept Results Resulted in BriaCellrsquos Immunotherapy Strategy Use BriaDXtrade diagnostic to select only those patients matching Bria-IMTtrade Use BriaDXtrade diagnostic test to select Bria-OTStrade alleles matching ~90 of all patients
Bria-IMTtradeCurrent Phase IIIa Data Supports HLA Matching Hypothesis Six patients treated in 2017 Bria-IMTtrade was safe and well tolerated
Patient 01-002 73-year-old woman with breast cancer diagnosed in 1995 Developed liver metastases in2010 and lung metastases in 2017 Previously treated with 7 rounds of chemotherapy with 8 differentchemotherapy agents Received 5 cycles of Bria-IMTtrade over 3 months then monthly cycles (6 months total)Evaluated after 3 months and 6 months After 3 months despite the extensive prior therapy her scans notedthat ldquothere has been a clear response in the multiple bilateral pulmonary nodulesrdquo The response wasmaintained after 6 months of Bria-IMTtrade treatment She matches Bria-IMTtrade at 2 HLA alleles
The liver tumors were stable to slightly increased at 3 months and then progressed after 6 months
This supports our hypothesis of heightened anti-tumor activity in patients with a matched HLA types Clear path to develop BriaDXtrade to select the patients using HLA testing
1 RLL 29 Not Detectable Not Detectable2 LUL apical pleural based 34 tiny nodule lt 1mm scar tiny nodule lt 1mm scar3 xxx 39 Not Detectable Not Detectable4 40 Not Detectable Not Detectable5 RLL 45 Not Detectable Not Detectable6 LLL 49 Not Detectable Not Detectable7 xxx 52 Not Detectable Not Detectable8 RLL 52 Not Detectable Not Detectable9 RLL 56 Not Detectable Not Detectable
10 RLL costophrenic recess 56 Not Detectable Not Detectable11 XXX 58 Not Detectable Not Detectable12 LUL 60 Not Detectable Not Detectable13 XXX 67 15 1514 RUL 72 15 1515 LLL 76 Not Detectable Not Detectable16 RUL Noncalcified Nodule 77 Not Detectable Not Detectable17 RLL costophrenic recess 79 10 1018 RUL 82 Not Detectable Not Detectable19 RLL 90 Not Detectable Not Detectable20 RLL 91 lt 01 lt 0121 xxx xxx Not Detectable Not Detectable
27
Clinical Development Update ndash Summary 2018 September 26
Completed enrollment of Adv Breast cancer patients in the Phase IIIa ldquomonotherapyrdquo study of Bria-IMTtrade
We have confirmed our mechanism of action and achieved proof of concept
Initial safety data appears superior to that of the other advanced or approved drugs for breast cancer when they were at a similar clinical stage of development
Initial efficacy data is similar or superior to those of other advanced or approved drugs for breast cancer when they were at a similar clinical stage of development
Initiated Combination Study of Bria-IMTtrade with Keytrudareg or Yervoyreg in Adv breast cancer patients expecting even better response rates than those in the ldquomonotherapyrdquo study Initial safety data is expected in 4Q2018 Initial efficacy data is expected in 1Q2019
Bria-OTStrade the first off-the-shelf personalized treatment for advanced breast cancer is expected to enter the clinic in 2019
28
Bria-IMTtrade Excellent Safety Data - To Date
To date Bria-IMTtrade has been dosed in 24 patients (4 in 2004-2005 20 in 2017-2018)
Interim Data (20 patients)-Ongoing Phase IIIa Study (2017-2018)
Bria-IMTtrade has been very well tolerated (ge60 doses given to date) The majority of adverse events (AEs) were limited to expected minor local irritation at the
injection sites No related grade gt3 or unexpected AEs No related serious AEs No serious unexpected related AEs Most patients who have dropped out did so due to worsening of their underlying disease
Based on the current study Bria-IMTtrade has an excellent safety profile
29
Bria-IMTtrade - Efficacy as Predicted
Interim Data (19 patients)-Ongoing Phase IIIa Study (2017-2018) amp Original Study (2004-2005)
PD-L1 expression on circulating cancer cells amp cancer-associated cells in 100 of patients (to date) Strong rationale for combination with checkpoint inhibitors like Keytruda
30
Bria-IMTtrade appears to be most effective in patients who match with Bria-IMT trade at 2 HLA loci (types) further supporting our ldquoHLA Matching Hypothesisrdquo and the development of Bria-OTS trade to cover 90 of the patient population
Combination with immune checkpoint inhibitors may induce a more potent anti-cancer response leading to our strategy of combination studies of Bria-IMT trade with Keytruda or Yervoy
Patients (n) HLA Match
Tumor Shrinkage
Biological Response
4 ge2 50 7515 ge1 27 334 0 0 0
Biological response includes tumor shrinkage or lower circulating cancer associated cells
The confirmatory Bria-IMTtrade monotherapy Phase IIa trial has completed enrollment Additional Support for the HLA-matching hypothesis has been obtained
Bria-IMTtrade Combination Therapy study with immune checkpoint inhibitors Keytrudareg if PD-L12 positive (ge1) Yervoyreg if PD-L12 negative (lt1) Accepting patients from the monotherapy study who develop progressive disease Also enrolling patients directly into this study to enhance experience with the combination In discussion with other pharmaceutical companies to evaluate additional combinations with other
immunotherapies
Bria-OTStrade Off-the-Shelf Personalized Targeted Immunotherapy Developing Bria-OTStrade to co-express GM-CSF and interferon-α Pre-manufacture additional HLA alleles ndash Total of 15 alleles (8 Class I and 7 Class II) Co-development of BriaDXtrade companion diagnostic for HLA typing Combination therapy clinical trial with immune checkpoint inhibitors for non-responders using
information from the Bria-IMTtrade Combination Therapy Study
33
Development Timeline ndash Breast Cancer
20192018 2020 2021
Phase IIIaBria-IMTtrade
Monotherapy
Currently Enrolling Phase IIaBria-IMTtrade + Checkpoint
Currently in discussions with potential partnersPhase II Bria-IMTtrade plus Additional Combinations (1Q19 4Q22)(eg PD-1 Inhibitor PD-L1 inhibitor anti-CTLA4 anti-GITR anti-OX40)
1Q 2Q 3Q 4Q
2023
Bria-OTStrade Off-The-Shelf Personalized ImmunotherapyMonotherapy and Potential Partnered Combo Therapy
(2H19 Ongoing)
Bria-OTStradeOff-the-Shelf Cell Line cGMP Manufacturing
and BriaDXtrade(1Q18 1Q19)
Registration Studies (1Q20 2H22)Bria-IMTtrade with Checkpoint InhibitorsBria-OTStrade +- Checkpoint Inhibitors
34
Immuno-oncology Deals
Recent deals of small biotechs with big pharma in immuno-oncology
35
Date PartnershipDevelopment stage at the time of the deal Deal size
07122018 Immatics-Genmab Preclinical Up to $28B
04042018 OSE Immunotherapeutics-Boehringer Ingelheim Preclinical Up to euro113B ($139B)
02092018 Pieris Pharmaceuticals-Seattle Genetics Preclinical Up to $123B
2142018 Nektar-BMS Ph III Up to $36B
01222018 Juno-Celgene Ph II $9B (Acquisition)
11142017 Loxo-Bayer Larotrectinib (Ph II) LOXO-195 (Ph III) Up to $155B
1032017 CytomX-Amgen Preclinical Up to $15B
03202017 CytomX--BMS Ph III Up to $36B
6282016 Xencor-Novartis Preclinical Up to $24B
Early Stage Clinical Studies (Comparison)
We compared the interim data of Ph IIIa study of Bria-IMTtrade in advanced breast cancer with thedata in the early stage clinical studies of recently approved breast cancer drugs and one fasttracked product candidate
Apples to apples comparison Early Stage Clinical Studies in oncology are typically done in patientswith no other therapeutic options Thus the patients have very advanced disease and response ratesare typically quite low
The patients in our Ph IIIa study have been heavily pre-treated (median 45 prior regimens)Some recent studies of relevance in breast cancer are noted in the following slides
36
Breast Cancer Market Opportunity
Drug Technology Approved for Market (US)Ibrance (palbociclib) CDK 46 Inhibitor HR+HER2- MBC in combination with
fluvestrant or aromatase inhibitor$933M in 1Q2018 $3126M in 2017
Kisqali (ribociclib) CDK 46 Inhibitor 2017 HR+HER2- MBC in combination with fluvestrant or aromatase inhibitor
Peak sales projected at $25B
Verzenio (abemaciclib) CDK 46 Inhibitor 2017 HR+HER2- MBC in combination with fluvestrant or aromatase inhibitor
balixafortide CXCR4 antagonist Fast track designation in 2018 for HER2- MBC who have failed 2 prior regimens
The market for breast cancer drugs is a multibillion dollar market with new drugs being approvedon an ongoing basis indicating the shortage of safe and effective treatments for this deadly disease
37
Competitors- Phase III Clinical Data Bria-IMTtrade shows superior safety and similar to superior efficacy data compared with those of the multi-billion dollar drugs when they were at a similar early stage of clinical development
Injection site reactions No related SAEs or SUSARs
Tumor vol darr ampor darr circul tumor cellsAll Comers 21(419) 26(519)One or More HLA matches 27(415) 33(515)Two or More HLA matches 50 (24) 75 (34)
Sheet1 (3)
Comp -Slides
Data
HLA (2)
HLA
Data (Ph1-2+4Pt)
Competitors (2018)-Slide
Competitors (2018)
In the Pipeline Protein Kinase C delta (PKCδ) Inhibitors
30 of all human malignancies display activating RAS mutations Another 60 showing over-activity of Ras-signaling pathways
Ras has been termed ldquoundruggablerdquo (no one has been able to make a Ras inhibitor drug)
BriaCellrsquos novel proprietary PKCδ inhibitors have shown activity against multiple RAS transformed tumors Lung cancer Melanoma Breast cancer Neuroendocrine cancer Pancreatic cancer Colorectal cancer
This target has an attractive safety profile based on in vivo studies and knock out mouse studies
PKCδ inhibitors should qualify for an accelerated clinical development plan and regulatory pathway
Could be in clinic within 24 months
Cost-Effective Additional Shot-on-Goal and additional partnership opportunities
Early-Stage Preclinical Program
39
Protein Kinase C delta (PKCδ) Inhibitors
Activated PKCδ inhibits RAS degradation which in turn stimulates tumor growth
Koo et al Oncotarget 621328 2016
30 of all human malignancies display activating RASmutations with another 60 showing over-activity of Ras-signaling pathways
BriaCellrsquos novel proprietary PKCδ inhibitors have shownactivity against multiple RAS transformed tumors
This target has an attractive safety profile based on in vivostudies and knock out mouse studies
PKCδ also has potential activity as an immunotherapeuticby blocking TGFβ signaling
PKCδ inhibitors are applicable to specific niche tumor typeswhich provide an accelerated clinical development plan
Structural aspects of first generation inhibitor rottlerin and staurosporine (pan-PKC activator) were combined to create second generation inhibitor KAM1
Third generation inhibitors such as BJE6-106 have improved potency and selectivity Fourth generation inhibitors under development to optimize drug-like characteristics PKCδ inhibitors lack endothelial cell cytotoxicity amp PKCδ deficient mice develop normally and are fertile Potentially no marked intrinsic toxicity by inhibiting PKCδ
Mukai H Saeki T Shimada K Naito Y Matsubara N Nakanishi T Obaishi H Namiki M Sasaki Y Phase 1 combination study of eribulin mesylate with trastuzumab for advanced or recurrent human epidermal growth factor receptor 2 positive breast cancer Invest New Drugs 2015 Feb33(1)119-27
AstraZeneca
Lynparza (Olaparib) + Cediranib
PARP inhibitor + inhibitor of VEGF receptor tyrosine kinases
HR+ HER2- MBC
BC amp OC
2013
28 (8 BC)
3 for BC
Olaparib (a poly (ADP-ribose) polymerase (PARP) inhibitor) amp Cediranib (Vascular endothelial growth factor receptor (VEGFR) 1 2 and 3 tyrosine kinase inhibitor)3 at dose level (DL) 0 (cediranib 20mg olaparib 100mg) 3 at DL1 (cediranib 20mg olaparib 200mg) 7 at DL2 (cediranib 30mg olaparib 200mg) 6 at DL3 (cediranib 30mg olaparib 400mg)
Liu JF Tolaney SM Birrer M Fleming GF Buss MK Dahlberg SE Lee H Whalen C Tyburski K Winer E Ivy P Matulonis UA A Phase 1 trial of the poly(ADP-ribose) polymerase inhibitor olaparib (AZD2281) in combination with the anti-angiogenic cediranib (AZD2171) in recurrent epithelial ovarian or triple-negative breast cancer Eur J Cancer 2013 Sep49(14)2972-8
Reyon Pharmaceutical
VM206RY
Heterologous prime-boost with a truncated HER2 sequence
HER2+ Stage IIIampIV BC
2015
9
2 chemo
Plasmid DNA (pHM-GM-CSF expressing truncated HER2 amp GM-CSF) amp adenoviral vector (Ad-HM containing modified HER2) (2 4 and 8 mgpatientvisit) of pHM-GM-CSF 3x IM weeks 0 2 and 4 Ad-HM 3 times 109 virus particles at week 6
11 PR
4 pts showed 7 minor AEs
Unclear
Kim SB Ahn JH Kim J Jung KH A phase 1 study of a heterologous prime-boost vaccination involving a truncated HER2 sequence in patients with HER2-expressing breast cancer Mol Ther Methods Clin Dev 2015 Sep 30215031 doi 101038mtm201531 eCollection 2015
Rodon J Peacuterez-Fidalgo A Krop IE Burris H Guerrero-Zotano A Britten CD Becerra C Schellens J Richards DA Schuler M Abu-Khalaf M Johnson FM Ranson M Edenfield J Silva AP Hackl W Quadt C Demanse D Duval V Baselga J Phase 11b dose escalation and expansion study of BEZ235 a dual PI3KmTOR inhibitor in patients with advanced solid tumors including patients with advanced breast cancer Cancer Chemother Pharmacol 2018 Jun 7 doi 101007s00280-018-3610-z [Epub ahead of print]
Celgene (Abraxane)
Gemcitabine + Abraxane (nab-paclitaxel)
Chemo + Chemo
OC BC NSCLC amp Panc cancer + Lung OC BC Kaposi sarcoma
MBC
2016
9
Adjuvant chemo (100)chemo post-adjuvant (33)
Gem (nucleoside metabolic inhibitor 1250 mgm2) on days 1 and 8 nab-Pac (microtubule inhibitor) starting dose of 180 mgm2 (cohort 1) 220 mgm2 (cohort 2) and 260 mgm2 (cohort 3) on day 1 of the 21-day cycle using a 3 + 3 design
0
MTD not reached29 Gr3 Neutropenia59 Gr1 Peripheralneuropathy
Yoshitomi S Taira N Doihara H Mizoo T Nogami T Iwamoto T Motoki T Shien T Ogasawara Y Matsuoka J Tsuji H Mitsuhashi T A phase 1 dose-finding and pharmacokinetic study of gemcitabine with nab-paclitaxel in patients with metastatic breast cancer Cancer Chemother Pharmacol 2016 Aug78(2)289-94
Eli Lilly
Erbituxreg (cetuximab) + Taxane
EGFR inhibitor antineoplastic agent + Chemo
Headamp Neck Colorectal Cancer
TNBC
2007-2010
18
1 chemo
Cetuximab (epidermal growth factor receptor (EGFR) antagonist ) an initial loading dose of cetuximab 400 mgm2 followed by a weekly dose of 250 mgm2Paclitaxel (microtubule inhibitor) 80 mgm2 or Docetaxel at an initial dose of 30 mgm2 was administered weekly
56 CR 22 PR
83 Dermatologic toxicity11 Grade3+
Nechushtan H Vainer G Stainberg H Salmon AY Hamburger T Peretz T A phase 12 of a combination of cetuximab and taxane for triple negative breast cancer patients Breast 2014 Aug23(4)435-8
Polyphor
Balixafortide (POL6326) + eribulin
CXCR4 antagonist + tubulin-based antimitotic
Heavily pretreated Relapsed MBC
2014-2016
56
3rd line 3 chemo
3+3 dose escalation The highest dose was established as eribulin 14 mgmsup2 on days 2 and 9 and balixafortide 55 mgkg on days 1minus3 and 8minus10 of the 21-day cycle
30 PR
41 Gr34 Neutropenia11 Gr34 Leucopenia11 Gr34 Febrileneutropenia2 Related mortalities
Apr 2018 Fast Track for HER2-MBC who have failed 2prior regimens
Pernas S Martin M Kaufman PA Gil-Martin M Gomez Pardo P Lopez-Tarruella S Manso L Ciruelos E Perez-Fidalgo JA Hernando C Ademuyiwa FO Weilbaecher K Mayer I Pluard TJ Martinez Garcia M Vahdat L Perez-Garcia J Wach A Barker D Fung S Romagnoli B Cortes J Balixafortide plus eribulin in HER2-negative metastatic breast cancer a phase 1 single-arm dose-escalation trial Lancet Oncol 2018 Jun19(6)812-824
11 PRndashbut only + letrozole (No Resp on monotherapy)
61 Gr34 Neutropenia39 Gr34 Leucopenia
$933M in 1Q2018 $31B in 2017
Tamura K Mukai H Naito Y Yonemori K Kodaira M Tanabe Y Yamamoto N Osera S Sasaki M Mori Y Hashigaki S Nagasawa T Umeyama Y Yoshino T Phase I study of palbociclib a cyclin-dependent kinase 46 inhibitor in Japanese patients Cancer Sci 2016 Jun107(6)755-63 doi 101111cas12932 Epub 2016 May 11
Pfizer
Ibrancereg (palbociclib)
CDK 46 Inhibitor
HR+ HER2- MBC
Heavily pretreated Relapsed Metastatic Cancer
2004-2008
41 (5 BC)
chemo naiumlve (17) 1-2 (51)3 (29) 3+ (2)
Palbociclib 25-150 mg dose ranging
0
20 Gr34 Neutropenia23 Gr34 Leucopenia
$933M in 1Q2018 $31B in 2017
Flaherty KT Lorusso PM Demichele A Abramson VG Courtney R Randolph SS Shaik MN Wilner KD ODwyer PJ Schwartz GK Phase I dose-escalation trial of the oral cyclin-dependent kinase 46 inhibitor PD 0332991 administered using a 21-day schedule in patients with advanced cancer Clin Cancer Res 2012 Jan 1518(2)568-76 doi 1011581078-0432CCR-11-0509 Epub 2011 Nov 16
Novartis
Kisqalireg (ribociclib)
CDK 46 Inhibitors
Premenopausal HR+ HER2- MBC
Heavily pretreated Relapsed Metastatic Cancer
2016
132 (20 BC)
0-1 (25) 2-3 (42) 4+ (32)
Ribociclib 50 mg ranging up to 1200 mg dose escalation
23 PRndashincluded 1 in BC (5 of BC pts)
27 Gr34 Neutropenia17 Gr34 Leucopenia
Peak sales projected at $25B
Infante JR Cassier PA Gerecitano JF Witteveen PO Chugh R Ribrag V Chakraborty A Matano A Dobson JR Crystal AS Parasuraman S Shapiro GI A Phase I Study of the Cyclin-Dependent Kinase 46 Inhibitor Ribociclib (LEE011) in Patients with Advanced Solid Tumors and Lymphomas Clin Cancer Res 2016 Dec 122(23)5696-5705 Epub 2016 Aug 19
Eli Lilly
Verzenioreg (abemaciclib)
CDK 46 Inhibitors
HR+HER2minusMBC
Heavily pretreated Relapsed Metastatic Cancer
2016
12 (1 BC)
1 (312) 2 (212) 3+ (7)
Abemaciclib 100 mg ranging up to 200 mg dose escalation
17 PR (included 1 in BC)
17 Gr34 Neutropenia33 Gr34 Leucopenia
Peak sales projected at $2B
Fujiwara Y Tamura K Kondo S Tanabe Y Iwasa S Shimomura A Kitano S Ogasawara K Turner PK Mori J Asou H Chan EM Yamamoto N Phase 1 study of abemaciclib an inhibitor of CDK 4 and 6 as a single agent for Japanese patients with advanced cancer Cancer Chemother Pharmacol 2016 Aug78(2)281-8 doi 101007s00280-016-3085-8 Epub 2016 Jun 16
Mukai H Saeki T Shimada K Naito Y Matsubara N Nakanishi T Obaishi H Namiki M Sasaki Y Phase 1 combination study of eribulin mesylate with trastuzumab for advanced or recurrent human epidermal growth factor receptor 2 positive breast cancer Invest New Drugs 2015 Feb33(1)119-27
AstraZeneca
Lynparza (Olaparib)+ Cediranib
PARP inhibitor+ inhibitor of VEGF RTK
HR+ HER2- MBC
BC amp OC
13
28 (8 BC)
3 for BC
Olaparib (a poly (ADP-ribose) polymerase (PARP) inhibitor) amp Cediranib (Vascular endothelial growth factor receptor (VEGFR) 1 2 and 3 tyrosine kinase inhibitor)3 at dose level (DL) 0 (cediranib 20mg olaparib 100mg) 3 at DL1 (cediranib 20mg olaparib 200mg) 7 at DL2 (cediranib 30mg olaparib 200mg) 6 at DL3 (cediranib 30mg olaparib 400mg)
Liu JF Tolaney SM Birrer M Fleming GF Buss MK Dahlberg SE Lee H Whalen C Tyburski K Winer E Ivy P Matulonis UA A Phase 1 trial of the poly(ADP-ribose) polymerase inhibitor olaparib (AZD2281) in combination with the anti-angiogenic cediranib (AZD2171) in recurrent epithelial ovarian or triple-negative breast cancer Eur J Cancer 2013 Sep49(14)2972-8
ReyonPharma
VM206RY
Heterologous prime-boost with a truncated HER2 sequence
HER2+ Stg IIIampIV BC
15
9
2 chemo
Plasmid DNA (pHM-GM-CSF expressing truncated HER2 amp GM-CSF) amp adenoviral vector (Ad-HM containing modified HER2) (2 4 and 8 mgpatientvisit) of pHM-GM-CSF 3x IM weeks 0 2 and 4 Ad-HM 3 times 109 virus particles at week 6
11 PR
4 pts 7 minor AEs
Unclear
Kim SB Ahn JH Kim J Jung KH A phase 1 study of a heterologous prime-boost vaccination involving a truncated HER2 sequence in patients with HER2-expressing breast cancer Mol Ther Methods Clin Dev 2015 Sep 30215031 doi 101038mtm201531 eCollection 2015
Rodon J Peacuterez-Fidalgo A Krop IE Burris H Guerrero-Zotano A Britten CD Becerra C Schellens J Richards DA Schuler M Abu-Khalaf M Johnson FM Ranson M Edenfield J Silva AP Hackl W Quadt C Demanse D Duval V Baselga J Phase 11b dose escalation and expansion study of BEZ235 a dual PI3KmTOR inhibitor in patients with advanced solid tumors including patients with advanced breast cancer Cancer Chemother Pharmacol 2018 Jun 7 doi 101007s00280-018-3610-z [Epub ahead of print]
Celgene(Abraxane)
Gemcitabine + Abraxane (nab-paclitaxel)
Chemo+ Chemo
OC BC NSCLC PC + LC OC BC KS
MBC
16
9
Adjuv chemo (100)chemo post-adjuv (33)
Gem (nucleoside metabolic inhibitor 1250 mgm2) on days 1 and 8 nab-Pac (microtubule inhibitor) starting dose of 180 mgm2 (cohort 1) 220 mgm2 (cohort 2) and 260 mgm2 (cohort 3) on day 1 of the 21-day cycle using a 3 + 3 design
0
MTD not reached29 Gr3 Neutropenia59 Gr1 Peripheralneuropathy
Yoshitomi S Taira N Doihara H Mizoo T Nogami T Iwamoto T Motoki T Shien T Ogasawara Y Matsuoka J Tsuji H Mitsuhashi T A phase 1 dose-finding and pharmacokinetic study of gemcitabine with nab-paclitaxel in patients with metastatic breast cancer Cancer Chemother Pharmacol 2016 Aug78(2)289-94
Eli Lilly
Erbituxreg (cetuximab) + Taxane
EGFR inhibitor antineoplastic agent + Chemo
Head amp NeckColorectal
TNBC
07-10
18
1 chemo
Cetuximab (epidermal growth factor receptor (EGFR) antagonist ) an initial loading dose of cetuximab 400 mgm2 followed by a weekly dose of 250 mgm2Paclitaxel (microtubule inhibitor) 80 mgm2 or Docetaxel at an initial dose of 30 mgm2 was administered weekly
56 CR 22 PR
83 Dermatologic toxicity11 Grade3+
Nechushtan H Vainer G Stainberg H Salmon AY Hamburger T Peretz T A phase 12 of a combination of cetuximab and taxane for triple negative breast cancer patients Breast 2014 Aug23(4)435-8
Polyphor
Balixafortide (POL6326) + eribulin
CXCR4 antagonist + tubulin-based antimitotic
Heavily pretreatedRelapsed MBC
14-16
56
3rd line 3 chemo
3+3 dose escalation The highest dose was established as eribulin 14 mgmsup2 on days 2 and 9 and balixafortide 55 mgkg on days 1minus3 and 8minus10 of the 21-day cycle
30 PR
41 Gr34 Neutropenia11 Gr34 Leucopenia11 Gr34 Febrileneutropenia2 Related mortalities
42018 Fast Track (HER2-MBC failed 2 prior regimens)
Pernas S Martin M Kaufman PA Gil-Martin M Gomez Pardo P Lopez-Tarruella S Manso L Ciruelos E Perez-Fidalgo JA Hernando C Ademuyiwa FO Weilbaecher K Mayer I Pluard TJ Martinez Garcia M Vahdat L Perez-Garcia J Wach A Barker D Fung S Romagnoli B Cortes J Balixafortide plus eribulin in HER2-negative metastatic breast cancer a phase 1 single-arm dose-escalation trial Lancet Oncol 2018 Jun19(6)812-824
1 PRndashbut only + letrozoleNo Resp on monotherapy
61 Gr34 Neutropenia39 Gr34 Leucopenia
$933M (1Q18)$31B (2017)
Tamura K Mukai H Naito Y Yonemori K Kodaira M Tanabe Y Yamamoto N Osera S Sasaki M Mori Y Hashigaki S Nagasawa T Umeyama Y Yoshino T Phase I study of palbociclib a cyclin-dependent kinase 46 inhibitor in Japanese patients Cancer Sci 2016 Jun107(6)755-63 doi 101111cas12932 Epub 2016 May 11
Pfizer
Ibrancereg (palbociclib)
CDK 46 Inhibitor
HR+ HER2- MBC
Heavily pretreatedRelapsed Met Cancer
04-08
41 (5 BC)
chemo naiumlve (17)1-2(51) 3(29) 3+(2)
Palbociclib 25-150 mg dose ranging
0
20 Gr34 Neutropenia23 Gr34 Leucopenia
$933M (1Q18)$31B (2017)
Flaherty KT Lorusso PM Demichele A Abramson VG Courtney R Randolph SS Shaik MN Wilner KD ODwyer PJ Schwartz GK Phase I dose-escalation trial of the oral cyclin-dependent kinase 46 inhibitor PD 0332991 administered using a 21-day schedule in patients with advanced cancer Clin Cancer Res 2012 Jan 1518(2)568-76 doi 1011581078-0432CCR-11-0509 Epub 2011 Nov 16
Novartis
Kisqalireg (ribociclib)
CDK 46 Inhibitor
Premenopausal HR+ HER2- MBC
Heavily pretreatedRelapsed Met Cancer
16
132 (20 BC)
0-1 (25) 2-3 (42)4+ (32)
Ribociclib 50 mg ranging up to 1200 mg dose escalation
23 PR-included 1 BC (5 of BC pts)
27 Gr34 Neutropenia17 Gr34 Leucopenia
Peak sales est at $25B
Infante JR Cassier PA Gerecitano JF Witteveen PO Chugh R Ribrag V Chakraborty A Matano A Dobson JR Crystal AS Parasuraman S Shapiro GI A Phase I Study of the Cyclin-Dependent Kinase 46 Inhibitor Ribociclib (LEE011) in Patients with Advanced Solid Tumors and Lymphomas Clin Cancer Res 2016 Dec 122(23)5696-5705 Epub 2016 Aug 19
Eli Lilly
Verzenioreg (abemaciclib)
CDK 46 Inhibitor
HR+HER2minusMBC
Heavily pretreatedRelapsed Met Cancer
16
12 (1 BC)
1 (312) 2 (212) 3+(7)
Abemaciclib 100 mg ranging up to 200 mg dose escalation
17 PR (included 1 BC)
17 Gr34 Neutropenia33 Gr34 Leucopenia
Peak sales est at $2B
Fujiwara Y Tamura K Kondo S Tanabe Y Iwasa S Shimomura A Kitano S Ogasawara K Turner PK Mori J Asou H Chan EM Yamamoto N Phase 1 study of abemaciclib an inhibitor of CDK 4 and 6 as a single agent for Japanese patients with advanced cancer Cancer Chemother Pharmacol 2016 Aug78(2)281-8 doi 101007s00280-016-3085-8 Epub 2016 Jun 16
Mukai H Saeki T Shimada K Naito Y Matsubara N Nakanishi T Obaishi H Namiki M Sasaki Y Phase 1 combination study of eribulin mesylate with trastuzumab for advanced or recurrent human epidermal growth factor receptor 2 positive breast cancer Invest New Drugs 2015 Feb33(1)119-27
AstraZeneca
Lynparza (Olaparib) + Cediranib
PARP inhibitor + inhibitor of VEGF receptor tyrosine kinases
HR+ HER2- MBC
BC amp OC
2013
28 (8 BC)
3 for BC
Olaparib (a poly (ADP-ribose) polymerase (PARP) inhibitor) amp Cediranib (Vascular endothelial growth factor receptor (VEGFR) 1 2 and 3 tyrosine kinase inhibitor)3 at dose level (DL) 0 (cediranib 20mg olaparib 100mg) 3 at DL1 (cediranib 20mg olaparib 200mg) 7 at DL2 (cediranib 30mg olaparib 200mg) 6 at DL3 (cediranib 30mg olaparib 400mg)
Liu JF Tolaney SM Birrer M Fleming GF Buss MK Dahlberg SE Lee H Whalen C Tyburski K Winer E Ivy P Matulonis UA A Phase 1 trial of the poly(ADP-ribose) polymerase inhibitor olaparib (AZD2281) in combination with the anti-angiogenic cediranib (AZD2171) in recurrent epithelial ovarian or triple-negative breast cancer Eur J Cancer 2013 Sep49(14)2972-8
Reyon Pharmaceutical
VM206RY
Heterologous prime-boost with a truncated HER2 sequence
HER2+ Stage IIIampIV BC
2015
9
2 chemo
Plasmid DNA (pHM-GM-CSF expressing truncated HER2 amp GM-CSF) amp adenoviral vector (Ad-HM containing modified HER2) (2 4 and 8 mgpatientvisit) of pHM-GM-CSF 3x IM weeks 0 2 and 4 Ad-HM 3 times 109 virus particles at week 6
11 PR
4 pts showed 7 minor AEs
Unclear
Kim SB Ahn JH Kim J Jung KH A phase 1 study of a heterologous prime-boost vaccination involving a truncated HER2 sequence in patients with HER2-expressing breast cancer Mol Ther Methods Clin Dev 2015 Sep 30215031 doi 101038mtm201531 eCollection 2015
Rodon J Peacuterez-Fidalgo A Krop IE Burris H Guerrero-Zotano A Britten CD Becerra C Schellens J Richards DA Schuler M Abu-Khalaf M Johnson FM Ranson M Edenfield J Silva AP Hackl W Quadt C Demanse D Duval V Baselga J Phase 11b dose escalation and expansion study of BEZ235 a dual PI3KmTOR inhibitor in patients with advanced solid tumors including patients with advanced breast cancer Cancer Chemother Pharmacol 2018 Jun 7 doi 101007s00280-018-3610-z [Epub ahead of print]
Celgene (Abraxane)
Gemcitabine + Abraxane (nab-paclitaxel)
Chemo + Chemo
OC BC NSCLC amp Panc cancer + Lung OC BC Kaposi sarcoma
MBC
2016
9
Adjuvant chemo (100)chemo post-adjuvant (33)
Gem (nucleoside metabolic inhibitor 1250 mgm2) on days 1 and 8 nab-Pac (microtubule inhibitor) starting dose of 180 mgm2 (cohort 1) 220 mgm2 (cohort 2) and 260 mgm2 (cohort 3) on day 1 of the 21-day cycle using a 3 + 3 design
0
MTD not reached29 Gr3 Neutropenia59 Gr1 Peripheralneuropathy
Yoshitomi S Taira N Doihara H Mizoo T Nogami T Iwamoto T Motoki T Shien T Ogasawara Y Matsuoka J Tsuji H Mitsuhashi T A phase 1 dose-finding and pharmacokinetic study of gemcitabine with nab-paclitaxel in patients with metastatic breast cancer Cancer Chemother Pharmacol 2016 Aug78(2)289-94
Eli Lilly
Erbituxreg (cetuximab) + Taxane
EGFR inhibitor antineoplastic agent + Chemo
Headamp Neck Colorectal Cancer
TNBC
2007-2010
18
1 chemo
Cetuximab (epidermal growth factor receptor (EGFR) antagonist ) an initial loading dose of cetuximab 400 mgm2 followed by a weekly dose of 250 mgm2Paclitaxel (microtubule inhibitor) 80 mgm2 or Docetaxel at an initial dose of 30 mgm2 was administered weekly
56 CR 22 PR
83 Dermatologic toxicity11 Grade3+
Nechushtan H Vainer G Stainberg H Salmon AY Hamburger T Peretz T A phase 12 of a combination of cetuximab and taxane for triple negative breast cancer patients Breast 2014 Aug23(4)435-8
Polyphor
Balixafortide (POL6326) + eribulin
CXCR4 antagonist + tubulin-based antimitotic
Heavily pretreated Relapsed MBC
2014-2016
56
3rd line 3 chemo
3+3 dose escalation The highest dose was established as eribulin 14 mgmsup2 on days 2 and 9 and balixafortide 55 mgkg on days 1minus3 and 8minus10 of the 21-day cycle
30 PR
41 Gr34 Neutropenia11 Gr34 Leucopenia11 Gr34 Febrileneutropenia2 Related mortalities
Apr 2018 Fast Track for HER2-MBC who have failed 2prior regimens
Pernas S Martin M Kaufman PA Gil-Martin M Gomez Pardo P Lopez-Tarruella S Manso L Ciruelos E Perez-Fidalgo JA Hernando C Ademuyiwa FO Weilbaecher K Mayer I Pluard TJ Martinez Garcia M Vahdat L Perez-Garcia J Wach A Barker D Fung S Romagnoli B Cortes J Balixafortide plus eribulin in HER2-negative metastatic breast cancer a phase 1 single-arm dose-escalation trial Lancet Oncol 2018 Jun19(6)812-824
11 PRndashbut only + letrozole (No Resp on monotherapy)
61 Gr34 Neutropenia39 Gr34 Leucopenia
$933M in 1Q2018 $31B in 2017
Tamura K Mukai H Naito Y Yonemori K Kodaira M Tanabe Y Yamamoto N Osera S Sasaki M Mori Y Hashigaki S Nagasawa T Umeyama Y Yoshino T Phase I study of palbociclib a cyclin-dependent kinase 46 inhibitor in Japanese patients Cancer Sci 2016 Jun107(6)755-63 doi 101111cas12932 Epub 2016 May 11
Pfizer
Ibrancereg (palbociclib)
CDK 46 Inhibitor
HR+ HER2- MBC
Heavily pretreated Relapsed Metastatic Cancer
2004-2008
41 (5 BC)
chemo naiumlve (17) 1-2 (51)3 (29) 3+ (2)
Palbociclib 25-150 mg dose ranging
0
20 Gr34 Neutropenia23 Gr34 Leucopenia
$933M in 1Q2018 $31B in 2017
Flaherty KT Lorusso PM Demichele A Abramson VG Courtney R Randolph SS Shaik MN Wilner KD ODwyer PJ Schwartz GK Phase I dose-escalation trial of the oral cyclin-dependent kinase 46 inhibitor PD 0332991 administered using a 21-day schedule in patients with advanced cancer Clin Cancer Res 2012 Jan 1518(2)568-76 doi 1011581078-0432CCR-11-0509 Epub 2011 Nov 16
Novartis
Kisqalireg (ribociclib)
CDK 46 Inhibitors
Premenopausal HR+ HER2- MBC
Heavily pretreated Relapsed Metastatic Cancer
2016
132 (20 BC)
0-1 (25) 2-3 (42) 4+ (32)
Ribociclib 50 mg ranging up to 1200 mg dose escalation
23 PRndashincluded 1 in BC (5 of BC pts)
27 Gr34 Neutropenia17 Gr34 Leucopenia
Peak sales projected at $25B
Infante JR Cassier PA Gerecitano JF Witteveen PO Chugh R Ribrag V Chakraborty A Matano A Dobson JR Crystal AS Parasuraman S Shapiro GI A Phase I Study of the Cyclin-Dependent Kinase 46 Inhibitor Ribociclib (LEE011) in Patients with Advanced Solid Tumors and Lymphomas Clin Cancer Res 2016 Dec 122(23)5696-5705 Epub 2016 Aug 19
Eli Lilly
Verzenioreg (abemaciclib)
CDK 46 Inhibitors
HR+HER2minusMBC
Heavily pretreated Relapsed Metastatic Cancer
2016
12 (1 BC)
1 (312) 2 (212) 3+ (7)
Abemaciclib 100 mg ranging up to 200 mg dose escalation
17 PR (included 1 in BC)
17 Gr34 Neutropenia33 Gr34 Leucopenia
Peak sales projected at $2B
Fujiwara Y Tamura K Kondo S Tanabe Y Iwasa S Shimomura A Kitano S Ogasawara K Turner PK Mori J Asou H Chan EM Yamamoto N Phase 1 study of abemaciclib an inhibitor of CDK 4 and 6 as a single agent for Japanese patients with advanced cancer Cancer Chemother Pharmacol 2016 Aug78(2)281-8 doi 101007s00280-016-3085-8 Epub 2016 Jun 16
Mukai H Saeki T Shimada K Naito Y Matsubara N Nakanishi T Obaishi H Namiki M Sasaki Y Phase 1 combination study of eribulin mesylate with trastuzumab for advanced or recurrent human epidermal growth factor receptor 2 positive breast cancer Invest New Drugs 2015 Feb33(1)119-27
AstraZeneca
Lynparza (Olaparib)+ Cediranib
PARP inhibitor+ inhibitor of VEGF RTK
HR+ HER2- MBC
BC amp OC
13
28 (8 BC)
3 for BC
Olaparib (a poly (ADP-ribose) polymerase (PARP) inhibitor) amp Cediranib (Vascular endothelial growth factor receptor (VEGFR) 1 2 and 3 tyrosine kinase inhibitor)3 at dose level (DL) 0 (cediranib 20mg olaparib 100mg) 3 at DL1 (cediranib 20mg olaparib 200mg) 7 at DL2 (cediranib 30mg olaparib 200mg) 6 at DL3 (cediranib 30mg olaparib 400mg)
Liu JF Tolaney SM Birrer M Fleming GF Buss MK Dahlberg SE Lee H Whalen C Tyburski K Winer E Ivy P Matulonis UA A Phase 1 trial of the poly(ADP-ribose) polymerase inhibitor olaparib (AZD2281) in combination with the anti-angiogenic cediranib (AZD2171) in recurrent epithelial ovarian or triple-negative breast cancer Eur J Cancer 2013 Sep49(14)2972-8
ReyonPharma
VM206RY
Heterologous prime-boost with a truncated HER2 sequence
HER2+ Stg IIIampIV BC
15
9
2 chemo
Plasmid DNA (pHM-GM-CSF expressing truncated HER2 amp GM-CSF) amp adenoviral vector (Ad-HM containing modified HER2) (2 4 and 8 mgpatientvisit) of pHM-GM-CSF 3x IM weeks 0 2 and 4 Ad-HM 3 times 109 virus particles at week 6
11 PR
4 pts 7 minor AEs
Unclear
Kim SB Ahn JH Kim J Jung KH A phase 1 study of a heterologous prime-boost vaccination involving a truncated HER2 sequence in patients with HER2-expressing breast cancer Mol Ther Methods Clin Dev 2015 Sep 30215031 doi 101038mtm201531 eCollection 2015
Rodon J Peacuterez-Fidalgo A Krop IE Burris H Guerrero-Zotano A Britten CD Becerra C Schellens J Richards DA Schuler M Abu-Khalaf M Johnson FM Ranson M Edenfield J Silva AP Hackl W Quadt C Demanse D Duval V Baselga J Phase 11b dose escalation and expansion study of BEZ235 a dual PI3KmTOR inhibitor in patients with advanced solid tumors including patients with advanced breast cancer Cancer Chemother Pharmacol 2018 Jun 7 doi 101007s00280-018-3610-z [Epub ahead of print]
Celgene(Abraxane)
Gemcitabine + Abraxane (nab-paclitaxel)
Chemo+ Chemo
OC BC NSCLC PC + LC OC BC KS
MBC
16
9
Adjuv chemo (100)chemo post-adjuv (33)
Gem (nucleoside metabolic inhibitor 1250 mgm2) on days 1 and 8 nab-Pac (microtubule inhibitor) starting dose of 180 mgm2 (cohort 1) 220 mgm2 (cohort 2) and 260 mgm2 (cohort 3) on day 1 of the 21-day cycle using a 3 + 3 design
0
MTD not reached29 Gr3 Neutropenia59 Gr1 Peripheralneuropathy
Yoshitomi S Taira N Doihara H Mizoo T Nogami T Iwamoto T Motoki T Shien T Ogasawara Y Matsuoka J Tsuji H Mitsuhashi T A phase 1 dose-finding and pharmacokinetic study of gemcitabine with nab-paclitaxel in patients with metastatic breast cancer Cancer Chemother Pharmacol 2016 Aug78(2)289-94
Eli Lilly
Erbituxreg (cetuximab) + Taxane
EGFR inhibitor antineoplastic agent + Chemo
Head amp NeckColorectal
TNBC
07-10
18
1 chemo
Cetuximab (epidermal growth factor receptor (EGFR) antagonist ) an initial loading dose of cetuximab 400 mgm2 followed by a weekly dose of 250 mgm2Paclitaxel (microtubule inhibitor) 80 mgm2 or Docetaxel at an initial dose of 30 mgm2 was administered weekly
56 CR 22 PR
83 Dermatologic toxicity11 Grade3+
Nechushtan H Vainer G Stainberg H Salmon AY Hamburger T Peretz T A phase 12 of a combination of cetuximab and taxane for triple negative breast cancer patients Breast 2014 Aug23(4)435-8
Polyphor
Balixafortide (POL6326) + eribulin
CXCR4 antagonist + tubulin-based antimitotic
Heavily pretreatedRelapsed MBC
14-16
56
3rd line 3 chemo
3+3 dose escalation The highest dose was established as eribulin 14 mgmsup2 on days 2 and 9 and balixafortide 55 mgkg on days 1minus3 and 8minus10 of the 21-day cycle
30 PR
41 Gr34 Neutropenia11 Gr34 Leucopenia11 Gr34 Febrileneutropenia2 Related mortalities
42018 Fast Track (HER2-MBC failed 2 prior regimens)
Pernas S Martin M Kaufman PA Gil-Martin M Gomez Pardo P Lopez-Tarruella S Manso L Ciruelos E Perez-Fidalgo JA Hernando C Ademuyiwa FO Weilbaecher K Mayer I Pluard TJ Martinez Garcia M Vahdat L Perez-Garcia J Wach A Barker D Fung S Romagnoli B Cortes J Balixafortide plus eribulin in HER2-negative metastatic breast cancer a phase 1 single-arm dose-escalation trial Lancet Oncol 2018 Jun19(6)812-824
1 PRndashbut only + letrozoleNo Resp on monotherapy
61 Gr34 Neutropenia39 Gr34 Leucopenia
$933M (1Q18)$31B (2017)
Tamura K Mukai H Naito Y Yonemori K Kodaira M Tanabe Y Yamamoto N Osera S Sasaki M Mori Y Hashigaki S Nagasawa T Umeyama Y Yoshino T Phase I study of palbociclib a cyclin-dependent kinase 46 inhibitor in Japanese patients Cancer Sci 2016 Jun107(6)755-63 doi 101111cas12932 Epub 2016 May 11
Pfizer
Ibrancereg (palbociclib)
CDK 46 Inhibitor
HR+ HER2- MBC
Heavily pretreatedRelapsed Met Cancer
04-08
41 (5 BC)
chemo naiumlve (17)1-2(51) 3(29) 3+(2)
Palbociclib 25-150 mg dose ranging
0
20 Gr34 Neutropenia23 Gr34 Leucopenia
$933M (1Q18)$31B (2017)
Flaherty KT Lorusso PM Demichele A Abramson VG Courtney R Randolph SS Shaik MN Wilner KD ODwyer PJ Schwartz GK Phase I dose-escalation trial of the oral cyclin-dependent kinase 46 inhibitor PD 0332991 administered using a 21-day schedule in patients with advanced cancer Clin Cancer Res 2012 Jan 1518(2)568-76 doi 1011581078-0432CCR-11-0509 Epub 2011 Nov 16
Novartis
Kisqalireg (ribociclib)
CDK 46 Inhibitor
Premenopausal HR+ HER2- MBC
Heavily pretreatedRelapsed Met Cancer
16
132 (20 BC)
0-1 (25) 2-3 (42)4+ (32)
Ribociclib 50 mg ranging up to 1200 mg dose escalation
23 PR-included 1 BC (5 of BC pts)
27 Gr34 Neutropenia17 Gr34 Leucopenia
Peak sales est at $25B
Infante JR Cassier PA Gerecitano JF Witteveen PO Chugh R Ribrag V Chakraborty A Matano A Dobson JR Crystal AS Parasuraman S Shapiro GI A Phase I Study of the Cyclin-Dependent Kinase 46 Inhibitor Ribociclib (LEE011) in Patients with Advanced Solid Tumors and Lymphomas Clin Cancer Res 2016 Dec 122(23)5696-5705 Epub 2016 Aug 19
Eli Lilly
Verzenioreg (abemaciclib)
CDK 46 Inhibitor
HR+HER2minusMBC
Heavily pretreatedRelapsed Met Cancer
16
12 (1 BC)
1 (312) 2 (212) 3+(7)
Abemaciclib 100 mg ranging up to 200 mg dose escalation
17 PR (included 1 BC)
17 Gr34 Neutropenia33 Gr34 Leucopenia
Peak sales est at $2B
Fujiwara Y Tamura K Kondo S Tanabe Y Iwasa S Shimomura A Kitano S Ogasawara K Turner PK Mori J Asou H Chan EM Yamamoto N Phase 1 study of abemaciclib an inhibitor of CDK 4 and 6 as a single agent for Japanese patients with advanced cancer Cancer Chemother Pharmacol 2016 Aug78(2)281-8 doi 101007s00280-016-3085-8 Epub 2016 Jun 16
Bria-IMTtrade and Bria-OTStrade shouldsynergize with existing approvedimmunotherapies as well as those stillunder development
This includes immune checkpointinhibitors such as antibodies to PD-1CTLA-4 GITR and CD73 inhibitors whicheliminate tumor immunosuppression Checkpoint Inhibitors were the
subject of the 2018 Nobel Prize inMedicine
In addition immunostimulatoryantibodies to molecules such as OX40should enhance responses to Bria-IMTtradeand Bria-OTStrade
13
Q3 2018 Data on first 20 Patients on Bria-IMTtrade Q3 2018 Initiate Combination Study of Bria-IMTtrade with Keytruda or Yervoy
Q4 2018 Switch to a novel frozen Bria-IMTtrade formulation Q4 2018 Safety Data (6 patients) of the Bria-IMTtrade - Keytrudareg Combination Study (SABC meeting) Q4 2018 Ongoing Corporate PartnershipCollaboration Discussions
Q1 2019 Efficacy Data (6 patients) of the Bria-IMTtrade - Keytrudareg Combination Study Q2 2019 Initiation of Bria-OTStrade GMP manufacturing (KBI BioPharma) Q2 2019 Additional Safety amp Efficacy data Monotherapy and Combination Studies (AACR meeting) Q2 2019 Final data for Monotherapy and Additional Data for the Combination Study (ASCO meeting) H1 2019 Candidate Selection for a PKCδ Inhibitor H1 2019 Initiate additional immunotherapy program H2 2019 Bria-OTStrade Authorization from FDA clearance for dosing H2 2019 Bria-OTStrade First Patient Dosed
Upcoming Milestones amp Catalysts
14
Involved in over 10 drugs brought to the market
Experienced Management Team
Management
William V Williams MD FACP President amp CEO VP Exploratory Development Incyte Corporation VP Experimental Medicine GlaxoSmithKline Head Rheumatology Research University of Pennsylvania Facilitated entry of over 20 compounds into the clinic including ruxolitinib (Jakafi)
baricitinib amp epacadostat NDAs including Jakafi Boniva Bexxar Author of over 120 peer-reviewed publications amp over 20 patents
Gadi Levin CA MBA CFO CFO of Labstyle Innovations Ltd VP of Finance for two Israeli investment houses in the fields of private equity
hedge funds and real estate Financial Consultant various firms Accountant Arthur Andersen
Markus Lacher PhD Senior Director RampD Founder T cell Therapeutics Inc an immuno-oncology company Sr Clinical Scientist Cesca Therapeutics Inc a clinical-stage autologous cell
therapy company Scientist at BioTime Inc and OncoCyte Corporation Editorial advisory board Recent Patents on Anti-Cancer Drug Discovery
Farrah Dean MSc MBA Manager Corp Development Investor relations CytRx Corporation amp CCG Investor Relations Senior Associate Equity Analyst Oppenheimer amp Co Rodman amp Renshaw amp
Brian Metcalf PhD Recently retired as CSO from Global Blood Therapeutics Former Head of Research amp Development Incyte Corporation Former Head of Medicinal Chemistry SmithKline Beecham
Douglas Faller MD PhD Professor of Medicine Pediatrics Biochemistry Microbiology Pathology and
Laboratory Medicine HematologistOncologist former Director of the Cancer Center Boston University School of Medicine
Founder of several successful biotechnology companies
Robert Williams PhD University Distinguished Professor of Chemistry Colorado State University Founder of several successful biotechnology companies including Microcide Xcyte
Therapies HemaQuest Arch Therapeutics and Cetya Therapeutics
Thomas Kieber-Emmons PhD Deputy Director University of Arkansas Cancer Center Expert in targeted cancer immunotherapies structural biology and computational
chemistry
Maria Trojanowska PhD Professor of Medicine Boston University School of Medicine Director The Arthritis Center
16
Veteran Board of Directors
Board of Directors
Saeid Babaei PhD MBA Chairman Entrepreneur 20 yrs of biotech leadership roles Current CEO AbCelex VP Bus Develop Lorus Therap Dir of Corp Develop Northern Therapeutics
Rahoul Sharan CA Director Chairman Potash Ridge Director of the Board Ansell Capital Corp Parallel Resources amp Galaxy Capital
Corporation
Martin Schmieg CPA Director CFO Sirna Therapeutics Inc amp Isolagen Inc CEO Freedom-2 Inc (now PharmaCyte Inc) Advisor Caladrius Biosciences Inc Beckman Coulter Genomics Calimmune
Charles Wiseman MD Co-Founder amp Director Director Immunotherapy Lab St Vincent Medical Center Chief Breast Cancer Basic Research Lab Univ of Texas MD Anderson Hospital amp
Tumour Institute Assist Prof Dept of Molecular Carcinogenesis amp Virology MD Anderson Acting Chief Div of Oncology White Memorial Medical Center LA
William V Williams MD FACP President amp CEO VP Exploratory Development Incyte Corporation VP Experimental Medicine GlaxoSmithKline Head Rheumatology Research University of Pennsylvania
Prior Affiliations
17
Drug Approvals by BriaCell Management Team
Bexxarreg (tositumomab and Iodine I131 tositumomab) Treatment of CD20 antigen-expressing relapsed or refractory low grade follicular or transformed non-Hodgkins lymphoma
Myleranreg (busulfan) for chronic myelogenous leukemia Defense of formulation change sNDA
Hycamtinreg (topotecan) for ovarian cancer Pediatric use sNDA
Navelbinereg (vinorelbine tartrate) for non-small cell lung cancer Pediatric use sNDA
Bonivareg (ibandronate) monthly oral treatment of osteoporosis
Bonivareg (ibandronate) quarterly intraveous treatment of osteoporosis
Zofranreg (ondansetron) for prevention of nausea and vomiting Pediatric use sNDA
Jakafireg (ruxolitinib) for myelofibrosis Jakafireg (ruxolitinib) for polycythemia vera
Olumiantreg (baricitinib) for rheumatoid arthritis Approved in USA Japan and Europe
18
Share Metrics
BCTV BCTXF 19
Data as of 1092018
Ticker TSX BCTV
US Ticker OTCQBBCTXF
Share Price (CAD) as of Oct 9 2018 $012
52-Week Range (CAD) $009-019
Shares Outstanding as of Oct 9 2018 1611M
Market Cap as of Oct 9 2018 (CAD) $193M
Cash and Short Term Investments as of July 31 2018 (CAD) $23M
Total Shareholders Equity as of July 31 2018 (CAD) $12M
Number of Warrants $014-$035 (CAD) as of Oct 9 2018 601M
Number of Compensation Warrants $014-$030 (CAD) as of Oct 9 2018 45M
Number of Options $014- $026 (CAD$) as of Oct 9 2018 93M
Developing Bria-OTStrade the First Off-the-Shelf Personalized Immunotherapy
Targeting Adv Breast Cancer Unmet medical need (42000 death in the US in 2017 ) $1 Bil- $5 Bil market opportunity depending on patient treatment stage
Impressive results in 2 proof-of-concept clinical trials Rapid Response Rate Repeated following re-treatment Excellent Safety Profile
Completed enrollment in Phase IIIa clinical trial of Bria-IMTtrade with outstanding safety amp efficacy data Initiated Phase IIa Combination Study of Bria-IMTtrade with Keytrudareg (Merck amp Co Inc)
Developing Bria-OTStrade along with BriaDXtrade its companion diagnostic test Ability to match and treat ~90 of patient population with Off-the-Shelf personalized immunotherapy
Experienced Management has been involved in over 10 drug approvals
Patient B001 Breast 70 No 1101 - 3501 4001 Negative -
Bria-IMTtradeHuman Proof-of-Concept Trials in Breast Cancer (Patient A002)
24
Proof-of-Concept Results Resulted in BriaCellrsquos Immunotherapy Strategy Use BriaDXtrade diagnostic to select only those patients matching Bria-IMTtrade Use BriaDXtrade diagnostic test to select Bria-OTStrade alleles matching ~90 of all patients
Bria-IMTtradeCurrent Phase IIIa Data Supports HLA Matching Hypothesis Six patients treated in 2017 Bria-IMTtrade was safe and well tolerated
Patient 01-002 73-year-old woman with breast cancer diagnosed in 1995 Developed liver metastases in2010 and lung metastases in 2017 Previously treated with 7 rounds of chemotherapy with 8 differentchemotherapy agents Received 5 cycles of Bria-IMTtrade over 3 months then monthly cycles (6 months total)Evaluated after 3 months and 6 months After 3 months despite the extensive prior therapy her scans notedthat ldquothere has been a clear response in the multiple bilateral pulmonary nodulesrdquo The response wasmaintained after 6 months of Bria-IMTtrade treatment She matches Bria-IMTtrade at 2 HLA alleles
The liver tumors were stable to slightly increased at 3 months and then progressed after 6 months
This supports our hypothesis of heightened anti-tumor activity in patients with a matched HLA types Clear path to develop BriaDXtrade to select the patients using HLA testing
1 RLL 29 Not Detectable Not Detectable2 LUL apical pleural based 34 tiny nodule lt 1mm scar tiny nodule lt 1mm scar3 xxx 39 Not Detectable Not Detectable4 40 Not Detectable Not Detectable5 RLL 45 Not Detectable Not Detectable6 LLL 49 Not Detectable Not Detectable7 xxx 52 Not Detectable Not Detectable8 RLL 52 Not Detectable Not Detectable9 RLL 56 Not Detectable Not Detectable
10 RLL costophrenic recess 56 Not Detectable Not Detectable11 XXX 58 Not Detectable Not Detectable12 LUL 60 Not Detectable Not Detectable13 XXX 67 15 1514 RUL 72 15 1515 LLL 76 Not Detectable Not Detectable16 RUL Noncalcified Nodule 77 Not Detectable Not Detectable17 RLL costophrenic recess 79 10 1018 RUL 82 Not Detectable Not Detectable19 RLL 90 Not Detectable Not Detectable20 RLL 91 lt 01 lt 0121 xxx xxx Not Detectable Not Detectable
27
Clinical Development Update ndash Summary 2018 September 26
Completed enrollment of Adv Breast cancer patients in the Phase IIIa ldquomonotherapyrdquo study of Bria-IMTtrade
We have confirmed our mechanism of action and achieved proof of concept
Initial safety data appears superior to that of the other advanced or approved drugs for breast cancer when they were at a similar clinical stage of development
Initial efficacy data is similar or superior to those of other advanced or approved drugs for breast cancer when they were at a similar clinical stage of development
Initiated Combination Study of Bria-IMTtrade with Keytrudareg or Yervoyreg in Adv breast cancer patients expecting even better response rates than those in the ldquomonotherapyrdquo study Initial safety data is expected in 4Q2018 Initial efficacy data is expected in 1Q2019
Bria-OTStrade the first off-the-shelf personalized treatment for advanced breast cancer is expected to enter the clinic in 2019
28
Bria-IMTtrade Excellent Safety Data - To Date
To date Bria-IMTtrade has been dosed in 24 patients (4 in 2004-2005 20 in 2017-2018)
Interim Data (20 patients)-Ongoing Phase IIIa Study (2017-2018)
Bria-IMTtrade has been very well tolerated (ge60 doses given to date) The majority of adverse events (AEs) were limited to expected minor local irritation at the
injection sites No related grade gt3 or unexpected AEs No related serious AEs No serious unexpected related AEs Most patients who have dropped out did so due to worsening of their underlying disease
Based on the current study Bria-IMTtrade has an excellent safety profile
29
Bria-IMTtrade - Efficacy as Predicted
Interim Data (19 patients)-Ongoing Phase IIIa Study (2017-2018) amp Original Study (2004-2005)
PD-L1 expression on circulating cancer cells amp cancer-associated cells in 100 of patients (to date) Strong rationale for combination with checkpoint inhibitors like Keytruda
30
Bria-IMTtrade appears to be most effective in patients who match with Bria-IMT trade at 2 HLA loci (types) further supporting our ldquoHLA Matching Hypothesisrdquo and the development of Bria-OTS trade to cover 90 of the patient population
Combination with immune checkpoint inhibitors may induce a more potent anti-cancer response leading to our strategy of combination studies of Bria-IMT trade with Keytruda or Yervoy
Patients (n) HLA Match
Tumor Shrinkage
Biological Response
4 ge2 50 7515 ge1 27 334 0 0 0
Biological response includes tumor shrinkage or lower circulating cancer associated cells
The confirmatory Bria-IMTtrade monotherapy Phase IIa trial has completed enrollment Additional Support for the HLA-matching hypothesis has been obtained
Bria-IMTtrade Combination Therapy study with immune checkpoint inhibitors Keytrudareg if PD-L12 positive (ge1) Yervoyreg if PD-L12 negative (lt1) Accepting patients from the monotherapy study who develop progressive disease Also enrolling patients directly into this study to enhance experience with the combination In discussion with other pharmaceutical companies to evaluate additional combinations with other
immunotherapies
Bria-OTStrade Off-the-Shelf Personalized Targeted Immunotherapy Developing Bria-OTStrade to co-express GM-CSF and interferon-α Pre-manufacture additional HLA alleles ndash Total of 15 alleles (8 Class I and 7 Class II) Co-development of BriaDXtrade companion diagnostic for HLA typing Combination therapy clinical trial with immune checkpoint inhibitors for non-responders using
information from the Bria-IMTtrade Combination Therapy Study
33
Development Timeline ndash Breast Cancer
20192018 2020 2021
Phase IIIaBria-IMTtrade
Monotherapy
Currently Enrolling Phase IIaBria-IMTtrade + Checkpoint
Currently in discussions with potential partnersPhase II Bria-IMTtrade plus Additional Combinations (1Q19 4Q22)(eg PD-1 Inhibitor PD-L1 inhibitor anti-CTLA4 anti-GITR anti-OX40)
1Q 2Q 3Q 4Q
2023
Bria-OTStrade Off-The-Shelf Personalized ImmunotherapyMonotherapy and Potential Partnered Combo Therapy
(2H19 Ongoing)
Bria-OTStradeOff-the-Shelf Cell Line cGMP Manufacturing
and BriaDXtrade(1Q18 1Q19)
Registration Studies (1Q20 2H22)Bria-IMTtrade with Checkpoint InhibitorsBria-OTStrade +- Checkpoint Inhibitors
34
Immuno-oncology Deals
Recent deals of small biotechs with big pharma in immuno-oncology
35
Date PartnershipDevelopment stage at the time of the deal Deal size
07122018 Immatics-Genmab Preclinical Up to $28B
04042018 OSE Immunotherapeutics-Boehringer Ingelheim Preclinical Up to euro113B ($139B)
02092018 Pieris Pharmaceuticals-Seattle Genetics Preclinical Up to $123B
2142018 Nektar-BMS Ph III Up to $36B
01222018 Juno-Celgene Ph II $9B (Acquisition)
11142017 Loxo-Bayer Larotrectinib (Ph II) LOXO-195 (Ph III) Up to $155B
1032017 CytomX-Amgen Preclinical Up to $15B
03202017 CytomX--BMS Ph III Up to $36B
6282016 Xencor-Novartis Preclinical Up to $24B
Early Stage Clinical Studies (Comparison)
We compared the interim data of Ph IIIa study of Bria-IMTtrade in advanced breast cancer with thedata in the early stage clinical studies of recently approved breast cancer drugs and one fasttracked product candidate
Apples to apples comparison Early Stage Clinical Studies in oncology are typically done in patientswith no other therapeutic options Thus the patients have very advanced disease and response ratesare typically quite low
The patients in our Ph IIIa study have been heavily pre-treated (median 45 prior regimens)Some recent studies of relevance in breast cancer are noted in the following slides
36
Breast Cancer Market Opportunity
Drug Technology Approved for Market (US)Ibrance (palbociclib) CDK 46 Inhibitor HR+HER2- MBC in combination with
fluvestrant or aromatase inhibitor$933M in 1Q2018 $3126M in 2017
Kisqali (ribociclib) CDK 46 Inhibitor 2017 HR+HER2- MBC in combination with fluvestrant or aromatase inhibitor
Peak sales projected at $25B
Verzenio (abemaciclib) CDK 46 Inhibitor 2017 HR+HER2- MBC in combination with fluvestrant or aromatase inhibitor
balixafortide CXCR4 antagonist Fast track designation in 2018 for HER2- MBC who have failed 2 prior regimens
The market for breast cancer drugs is a multibillion dollar market with new drugs being approvedon an ongoing basis indicating the shortage of safe and effective treatments for this deadly disease
37
Competitors- Phase III Clinical Data Bria-IMTtrade shows superior safety and similar to superior efficacy data compared with those of the multi-billion dollar drugs when they were at a similar early stage of clinical development
Injection site reactions No related SAEs or SUSARs
Tumor vol darr ampor darr circul tumor cellsAll Comers 21(419) 26(519)One or More HLA matches 27(415) 33(515)Two or More HLA matches 50 (24) 75 (34)
Sheet1 (3)
Comp -Slides
Data
HLA (2)
HLA
Data (Ph1-2+4Pt)
Competitors (2018)-Slide
Competitors (2018)
In the Pipeline Protein Kinase C delta (PKCδ) Inhibitors
30 of all human malignancies display activating RAS mutations Another 60 showing over-activity of Ras-signaling pathways
Ras has been termed ldquoundruggablerdquo (no one has been able to make a Ras inhibitor drug)
BriaCellrsquos novel proprietary PKCδ inhibitors have shown activity against multiple RAS transformed tumors Lung cancer Melanoma Breast cancer Neuroendocrine cancer Pancreatic cancer Colorectal cancer
This target has an attractive safety profile based on in vivo studies and knock out mouse studies
PKCδ inhibitors should qualify for an accelerated clinical development plan and regulatory pathway
Could be in clinic within 24 months
Cost-Effective Additional Shot-on-Goal and additional partnership opportunities
Early-Stage Preclinical Program
39
Protein Kinase C delta (PKCδ) Inhibitors
Activated PKCδ inhibits RAS degradation which in turn stimulates tumor growth
Koo et al Oncotarget 621328 2016
30 of all human malignancies display activating RASmutations with another 60 showing over-activity of Ras-signaling pathways
BriaCellrsquos novel proprietary PKCδ inhibitors have shownactivity against multiple RAS transformed tumors
This target has an attractive safety profile based on in vivostudies and knock out mouse studies
PKCδ also has potential activity as an immunotherapeuticby blocking TGFβ signaling
PKCδ inhibitors are applicable to specific niche tumor typeswhich provide an accelerated clinical development plan
Structural aspects of first generation inhibitor rottlerin and staurosporine (pan-PKC activator) were combined to create second generation inhibitor KAM1
Third generation inhibitors such as BJE6-106 have improved potency and selectivity Fourth generation inhibitors under development to optimize drug-like characteristics PKCδ inhibitors lack endothelial cell cytotoxicity amp PKCδ deficient mice develop normally and are fertile Potentially no marked intrinsic toxicity by inhibiting PKCδ
Mukai H Saeki T Shimada K Naito Y Matsubara N Nakanishi T Obaishi H Namiki M Sasaki Y Phase 1 combination study of eribulin mesylate with trastuzumab for advanced or recurrent human epidermal growth factor receptor 2 positive breast cancer Invest New Drugs 2015 Feb33(1)119-27
AstraZeneca
Lynparza (Olaparib) + Cediranib
PARP inhibitor + inhibitor of VEGF receptor tyrosine kinases
HR+ HER2- MBC
BC amp OC
2013
28 (8 BC)
3 for BC
Olaparib (a poly (ADP-ribose) polymerase (PARP) inhibitor) amp Cediranib (Vascular endothelial growth factor receptor (VEGFR) 1 2 and 3 tyrosine kinase inhibitor)3 at dose level (DL) 0 (cediranib 20mg olaparib 100mg) 3 at DL1 (cediranib 20mg olaparib 200mg) 7 at DL2 (cediranib 30mg olaparib 200mg) 6 at DL3 (cediranib 30mg olaparib 400mg)
Liu JF Tolaney SM Birrer M Fleming GF Buss MK Dahlberg SE Lee H Whalen C Tyburski K Winer E Ivy P Matulonis UA A Phase 1 trial of the poly(ADP-ribose) polymerase inhibitor olaparib (AZD2281) in combination with the anti-angiogenic cediranib (AZD2171) in recurrent epithelial ovarian or triple-negative breast cancer Eur J Cancer 2013 Sep49(14)2972-8
Reyon Pharmaceutical
VM206RY
Heterologous prime-boost with a truncated HER2 sequence
HER2+ Stage IIIampIV BC
2015
9
2 chemo
Plasmid DNA (pHM-GM-CSF expressing truncated HER2 amp GM-CSF) amp adenoviral vector (Ad-HM containing modified HER2) (2 4 and 8 mgpatientvisit) of pHM-GM-CSF 3x IM weeks 0 2 and 4 Ad-HM 3 times 109 virus particles at week 6
11 PR
4 pts showed 7 minor AEs
Unclear
Kim SB Ahn JH Kim J Jung KH A phase 1 study of a heterologous prime-boost vaccination involving a truncated HER2 sequence in patients with HER2-expressing breast cancer Mol Ther Methods Clin Dev 2015 Sep 30215031 doi 101038mtm201531 eCollection 2015
Rodon J Peacuterez-Fidalgo A Krop IE Burris H Guerrero-Zotano A Britten CD Becerra C Schellens J Richards DA Schuler M Abu-Khalaf M Johnson FM Ranson M Edenfield J Silva AP Hackl W Quadt C Demanse D Duval V Baselga J Phase 11b dose escalation and expansion study of BEZ235 a dual PI3KmTOR inhibitor in patients with advanced solid tumors including patients with advanced breast cancer Cancer Chemother Pharmacol 2018 Jun 7 doi 101007s00280-018-3610-z [Epub ahead of print]
Celgene (Abraxane)
Gemcitabine + Abraxane (nab-paclitaxel)
Chemo + Chemo
OC BC NSCLC amp Panc cancer + Lung OC BC Kaposi sarcoma
MBC
2016
9
Adjuvant chemo (100)chemo post-adjuvant (33)
Gem (nucleoside metabolic inhibitor 1250 mgm2) on days 1 and 8 nab-Pac (microtubule inhibitor) starting dose of 180 mgm2 (cohort 1) 220 mgm2 (cohort 2) and 260 mgm2 (cohort 3) on day 1 of the 21-day cycle using a 3 + 3 design
0
MTD not reached29 Gr3 Neutropenia59 Gr1 Peripheralneuropathy
Yoshitomi S Taira N Doihara H Mizoo T Nogami T Iwamoto T Motoki T Shien T Ogasawara Y Matsuoka J Tsuji H Mitsuhashi T A phase 1 dose-finding and pharmacokinetic study of gemcitabine with nab-paclitaxel in patients with metastatic breast cancer Cancer Chemother Pharmacol 2016 Aug78(2)289-94
Eli Lilly
Erbituxreg (cetuximab) + Taxane
EGFR inhibitor antineoplastic agent + Chemo
Headamp Neck Colorectal Cancer
TNBC
2007-2010
18
1 chemo
Cetuximab (epidermal growth factor receptor (EGFR) antagonist ) an initial loading dose of cetuximab 400 mgm2 followed by a weekly dose of 250 mgm2Paclitaxel (microtubule inhibitor) 80 mgm2 or Docetaxel at an initial dose of 30 mgm2 was administered weekly
56 CR 22 PR
83 Dermatologic toxicity11 Grade3+
Nechushtan H Vainer G Stainberg H Salmon AY Hamburger T Peretz T A phase 12 of a combination of cetuximab and taxane for triple negative breast cancer patients Breast 2014 Aug23(4)435-8
Polyphor
Balixafortide (POL6326) + eribulin
CXCR4 antagonist + tubulin-based antimitotic
Heavily pretreated Relapsed MBC
2014-2016
56
3rd line 3 chemo
3+3 dose escalation The highest dose was established as eribulin 14 mgmsup2 on days 2 and 9 and balixafortide 55 mgkg on days 1minus3 and 8minus10 of the 21-day cycle
30 PR
41 Gr34 Neutropenia11 Gr34 Leucopenia11 Gr34 Febrileneutropenia2 Related mortalities
Apr 2018 Fast Track for HER2-MBC who have failed 2prior regimens
Pernas S Martin M Kaufman PA Gil-Martin M Gomez Pardo P Lopez-Tarruella S Manso L Ciruelos E Perez-Fidalgo JA Hernando C Ademuyiwa FO Weilbaecher K Mayer I Pluard TJ Martinez Garcia M Vahdat L Perez-Garcia J Wach A Barker D Fung S Romagnoli B Cortes J Balixafortide plus eribulin in HER2-negative metastatic breast cancer a phase 1 single-arm dose-escalation trial Lancet Oncol 2018 Jun19(6)812-824
11 PRndashbut only + letrozole (No Resp on monotherapy)
61 Gr34 Neutropenia39 Gr34 Leucopenia
$933M in 1Q2018 $31B in 2017
Tamura K Mukai H Naito Y Yonemori K Kodaira M Tanabe Y Yamamoto N Osera S Sasaki M Mori Y Hashigaki S Nagasawa T Umeyama Y Yoshino T Phase I study of palbociclib a cyclin-dependent kinase 46 inhibitor in Japanese patients Cancer Sci 2016 Jun107(6)755-63 doi 101111cas12932 Epub 2016 May 11
Pfizer
Ibrancereg (palbociclib)
CDK 46 Inhibitor
HR+ HER2- MBC
Heavily pretreated Relapsed Metastatic Cancer
2004-2008
41 (5 BC)
chemo naiumlve (17) 1-2 (51)3 (29) 3+ (2)
Palbociclib 25-150 mg dose ranging
0
20 Gr34 Neutropenia23 Gr34 Leucopenia
$933M in 1Q2018 $31B in 2017
Flaherty KT Lorusso PM Demichele A Abramson VG Courtney R Randolph SS Shaik MN Wilner KD ODwyer PJ Schwartz GK Phase I dose-escalation trial of the oral cyclin-dependent kinase 46 inhibitor PD 0332991 administered using a 21-day schedule in patients with advanced cancer Clin Cancer Res 2012 Jan 1518(2)568-76 doi 1011581078-0432CCR-11-0509 Epub 2011 Nov 16
Novartis
Kisqalireg (ribociclib)
CDK 46 Inhibitors
Premenopausal HR+ HER2- MBC
Heavily pretreated Relapsed Metastatic Cancer
2016
132 (20 BC)
0-1 (25) 2-3 (42) 4+ (32)
Ribociclib 50 mg ranging up to 1200 mg dose escalation
23 PRndashincluded 1 in BC (5 of BC pts)
27 Gr34 Neutropenia17 Gr34 Leucopenia
Peak sales projected at $25B
Infante JR Cassier PA Gerecitano JF Witteveen PO Chugh R Ribrag V Chakraborty A Matano A Dobson JR Crystal AS Parasuraman S Shapiro GI A Phase I Study of the Cyclin-Dependent Kinase 46 Inhibitor Ribociclib (LEE011) in Patients with Advanced Solid Tumors and Lymphomas Clin Cancer Res 2016 Dec 122(23)5696-5705 Epub 2016 Aug 19
Eli Lilly
Verzenioreg (abemaciclib)
CDK 46 Inhibitors
HR+HER2minusMBC
Heavily pretreated Relapsed Metastatic Cancer
2016
12 (1 BC)
1 (312) 2 (212) 3+ (7)
Abemaciclib 100 mg ranging up to 200 mg dose escalation
17 PR (included 1 in BC)
17 Gr34 Neutropenia33 Gr34 Leucopenia
Peak sales projected at $2B
Fujiwara Y Tamura K Kondo S Tanabe Y Iwasa S Shimomura A Kitano S Ogasawara K Turner PK Mori J Asou H Chan EM Yamamoto N Phase 1 study of abemaciclib an inhibitor of CDK 4 and 6 as a single agent for Japanese patients with advanced cancer Cancer Chemother Pharmacol 2016 Aug78(2)281-8 doi 101007s00280-016-3085-8 Epub 2016 Jun 16
Mukai H Saeki T Shimada K Naito Y Matsubara N Nakanishi T Obaishi H Namiki M Sasaki Y Phase 1 combination study of eribulin mesylate with trastuzumab for advanced or recurrent human epidermal growth factor receptor 2 positive breast cancer Invest New Drugs 2015 Feb33(1)119-27
AstraZeneca
Lynparza (Olaparib)+ Cediranib
PARP inhibitor+ inhibitor of VEGF RTK
HR+ HER2- MBC
BC amp OC
13
28 (8 BC)
3 for BC
Olaparib (a poly (ADP-ribose) polymerase (PARP) inhibitor) amp Cediranib (Vascular endothelial growth factor receptor (VEGFR) 1 2 and 3 tyrosine kinase inhibitor)3 at dose level (DL) 0 (cediranib 20mg olaparib 100mg) 3 at DL1 (cediranib 20mg olaparib 200mg) 7 at DL2 (cediranib 30mg olaparib 200mg) 6 at DL3 (cediranib 30mg olaparib 400mg)
Liu JF Tolaney SM Birrer M Fleming GF Buss MK Dahlberg SE Lee H Whalen C Tyburski K Winer E Ivy P Matulonis UA A Phase 1 trial of the poly(ADP-ribose) polymerase inhibitor olaparib (AZD2281) in combination with the anti-angiogenic cediranib (AZD2171) in recurrent epithelial ovarian or triple-negative breast cancer Eur J Cancer 2013 Sep49(14)2972-8
ReyonPharma
VM206RY
Heterologous prime-boost with a truncated HER2 sequence
HER2+ Stg IIIampIV BC
15
9
2 chemo
Plasmid DNA (pHM-GM-CSF expressing truncated HER2 amp GM-CSF) amp adenoviral vector (Ad-HM containing modified HER2) (2 4 and 8 mgpatientvisit) of pHM-GM-CSF 3x IM weeks 0 2 and 4 Ad-HM 3 times 109 virus particles at week 6
11 PR
4 pts 7 minor AEs
Unclear
Kim SB Ahn JH Kim J Jung KH A phase 1 study of a heterologous prime-boost vaccination involving a truncated HER2 sequence in patients with HER2-expressing breast cancer Mol Ther Methods Clin Dev 2015 Sep 30215031 doi 101038mtm201531 eCollection 2015
Rodon J Peacuterez-Fidalgo A Krop IE Burris H Guerrero-Zotano A Britten CD Becerra C Schellens J Richards DA Schuler M Abu-Khalaf M Johnson FM Ranson M Edenfield J Silva AP Hackl W Quadt C Demanse D Duval V Baselga J Phase 11b dose escalation and expansion study of BEZ235 a dual PI3KmTOR inhibitor in patients with advanced solid tumors including patients with advanced breast cancer Cancer Chemother Pharmacol 2018 Jun 7 doi 101007s00280-018-3610-z [Epub ahead of print]
Celgene(Abraxane)
Gemcitabine + Abraxane (nab-paclitaxel)
Chemo+ Chemo
OC BC NSCLC PC + LC OC BC KS
MBC
16
9
Adjuv chemo (100)chemo post-adjuv (33)
Gem (nucleoside metabolic inhibitor 1250 mgm2) on days 1 and 8 nab-Pac (microtubule inhibitor) starting dose of 180 mgm2 (cohort 1) 220 mgm2 (cohort 2) and 260 mgm2 (cohort 3) on day 1 of the 21-day cycle using a 3 + 3 design
0
MTD not reached29 Gr3 Neutropenia59 Gr1 Peripheralneuropathy
Yoshitomi S Taira N Doihara H Mizoo T Nogami T Iwamoto T Motoki T Shien T Ogasawara Y Matsuoka J Tsuji H Mitsuhashi T A phase 1 dose-finding and pharmacokinetic study of gemcitabine with nab-paclitaxel in patients with metastatic breast cancer Cancer Chemother Pharmacol 2016 Aug78(2)289-94
Eli Lilly
Erbituxreg (cetuximab) + Taxane
EGFR inhibitor antineoplastic agent + Chemo
Head amp NeckColorectal
TNBC
07-10
18
1 chemo
Cetuximab (epidermal growth factor receptor (EGFR) antagonist ) an initial loading dose of cetuximab 400 mgm2 followed by a weekly dose of 250 mgm2Paclitaxel (microtubule inhibitor) 80 mgm2 or Docetaxel at an initial dose of 30 mgm2 was administered weekly
56 CR 22 PR
83 Dermatologic toxicity11 Grade3+
Nechushtan H Vainer G Stainberg H Salmon AY Hamburger T Peretz T A phase 12 of a combination of cetuximab and taxane for triple negative breast cancer patients Breast 2014 Aug23(4)435-8
Polyphor
Balixafortide (POL6326) + eribulin
CXCR4 antagonist + tubulin-based antimitotic
Heavily pretreatedRelapsed MBC
14-16
56
3rd line 3 chemo
3+3 dose escalation The highest dose was established as eribulin 14 mgmsup2 on days 2 and 9 and balixafortide 55 mgkg on days 1minus3 and 8minus10 of the 21-day cycle
30 PR
41 Gr34 Neutropenia11 Gr34 Leucopenia11 Gr34 Febrileneutropenia2 Related mortalities
42018 Fast Track (HER2-MBC failed 2 prior regimens)
Pernas S Martin M Kaufman PA Gil-Martin M Gomez Pardo P Lopez-Tarruella S Manso L Ciruelos E Perez-Fidalgo JA Hernando C Ademuyiwa FO Weilbaecher K Mayer I Pluard TJ Martinez Garcia M Vahdat L Perez-Garcia J Wach A Barker D Fung S Romagnoli B Cortes J Balixafortide plus eribulin in HER2-negative metastatic breast cancer a phase 1 single-arm dose-escalation trial Lancet Oncol 2018 Jun19(6)812-824
1 PRndashbut only + letrozoleNo Resp on monotherapy
61 Gr34 Neutropenia39 Gr34 Leucopenia
$933M (1Q18)$31B (2017)
Tamura K Mukai H Naito Y Yonemori K Kodaira M Tanabe Y Yamamoto N Osera S Sasaki M Mori Y Hashigaki S Nagasawa T Umeyama Y Yoshino T Phase I study of palbociclib a cyclin-dependent kinase 46 inhibitor in Japanese patients Cancer Sci 2016 Jun107(6)755-63 doi 101111cas12932 Epub 2016 May 11
Pfizer
Ibrancereg (palbociclib)
CDK 46 Inhibitor
HR+ HER2- MBC
Heavily pretreatedRelapsed Met Cancer
04-08
41 (5 BC)
chemo naiumlve (17)1-2(51) 3(29) 3+(2)
Palbociclib 25-150 mg dose ranging
0
20 Gr34 Neutropenia23 Gr34 Leucopenia
$933M (1Q18)$31B (2017)
Flaherty KT Lorusso PM Demichele A Abramson VG Courtney R Randolph SS Shaik MN Wilner KD ODwyer PJ Schwartz GK Phase I dose-escalation trial of the oral cyclin-dependent kinase 46 inhibitor PD 0332991 administered using a 21-day schedule in patients with advanced cancer Clin Cancer Res 2012 Jan 1518(2)568-76 doi 1011581078-0432CCR-11-0509 Epub 2011 Nov 16
Novartis
Kisqalireg (ribociclib)
CDK 46 Inhibitor
Premenopausal HR+ HER2- MBC
Heavily pretreatedRelapsed Met Cancer
16
132 (20 BC)
0-1 (25) 2-3 (42)4+ (32)
Ribociclib 50 mg ranging up to 1200 mg dose escalation
23 PR-included 1 BC (5 of BC pts)
27 Gr34 Neutropenia17 Gr34 Leucopenia
Peak sales est at $25B
Infante JR Cassier PA Gerecitano JF Witteveen PO Chugh R Ribrag V Chakraborty A Matano A Dobson JR Crystal AS Parasuraman S Shapiro GI A Phase I Study of the Cyclin-Dependent Kinase 46 Inhibitor Ribociclib (LEE011) in Patients with Advanced Solid Tumors and Lymphomas Clin Cancer Res 2016 Dec 122(23)5696-5705 Epub 2016 Aug 19
Eli Lilly
Verzenioreg (abemaciclib)
CDK 46 Inhibitor
HR+HER2minusMBC
Heavily pretreatedRelapsed Met Cancer
16
12 (1 BC)
1 (312) 2 (212) 3+(7)
Abemaciclib 100 mg ranging up to 200 mg dose escalation
17 PR (included 1 BC)
17 Gr34 Neutropenia33 Gr34 Leucopenia
Peak sales est at $2B
Fujiwara Y Tamura K Kondo S Tanabe Y Iwasa S Shimomura A Kitano S Ogasawara K Turner PK Mori J Asou H Chan EM Yamamoto N Phase 1 study of abemaciclib an inhibitor of CDK 4 and 6 as a single agent for Japanese patients with advanced cancer Cancer Chemother Pharmacol 2016 Aug78(2)281-8 doi 101007s00280-016-3085-8 Epub 2016 Jun 16
Mukai H Saeki T Shimada K Naito Y Matsubara N Nakanishi T Obaishi H Namiki M Sasaki Y Phase 1 combination study of eribulin mesylate with trastuzumab for advanced or recurrent human epidermal growth factor receptor 2 positive breast cancer Invest New Drugs 2015 Feb33(1)119-27
AstraZeneca
Lynparza (Olaparib) + Cediranib
PARP inhibitor + inhibitor of VEGF receptor tyrosine kinases
HR+ HER2- MBC
BC amp OC
2013
28 (8 BC)
3 for BC
Olaparib (a poly (ADP-ribose) polymerase (PARP) inhibitor) amp Cediranib (Vascular endothelial growth factor receptor (VEGFR) 1 2 and 3 tyrosine kinase inhibitor)3 at dose level (DL) 0 (cediranib 20mg olaparib 100mg) 3 at DL1 (cediranib 20mg olaparib 200mg) 7 at DL2 (cediranib 30mg olaparib 200mg) 6 at DL3 (cediranib 30mg olaparib 400mg)
Liu JF Tolaney SM Birrer M Fleming GF Buss MK Dahlberg SE Lee H Whalen C Tyburski K Winer E Ivy P Matulonis UA A Phase 1 trial of the poly(ADP-ribose) polymerase inhibitor olaparib (AZD2281) in combination with the anti-angiogenic cediranib (AZD2171) in recurrent epithelial ovarian or triple-negative breast cancer Eur J Cancer 2013 Sep49(14)2972-8
Reyon Pharmaceutical
VM206RY
Heterologous prime-boost with a truncated HER2 sequence
HER2+ Stage IIIampIV BC
2015
9
2 chemo
Plasmid DNA (pHM-GM-CSF expressing truncated HER2 amp GM-CSF) amp adenoviral vector (Ad-HM containing modified HER2) (2 4 and 8 mgpatientvisit) of pHM-GM-CSF 3x IM weeks 0 2 and 4 Ad-HM 3 times 109 virus particles at week 6
11 PR
4 pts showed 7 minor AEs
Unclear
Kim SB Ahn JH Kim J Jung KH A phase 1 study of a heterologous prime-boost vaccination involving a truncated HER2 sequence in patients with HER2-expressing breast cancer Mol Ther Methods Clin Dev 2015 Sep 30215031 doi 101038mtm201531 eCollection 2015
Rodon J Peacuterez-Fidalgo A Krop IE Burris H Guerrero-Zotano A Britten CD Becerra C Schellens J Richards DA Schuler M Abu-Khalaf M Johnson FM Ranson M Edenfield J Silva AP Hackl W Quadt C Demanse D Duval V Baselga J Phase 11b dose escalation and expansion study of BEZ235 a dual PI3KmTOR inhibitor in patients with advanced solid tumors including patients with advanced breast cancer Cancer Chemother Pharmacol 2018 Jun 7 doi 101007s00280-018-3610-z [Epub ahead of print]
Celgene (Abraxane)
Gemcitabine + Abraxane (nab-paclitaxel)
Chemo + Chemo
OC BC NSCLC amp Panc cancer + Lung OC BC Kaposi sarcoma
MBC
2016
9
Adjuvant chemo (100)chemo post-adjuvant (33)
Gem (nucleoside metabolic inhibitor 1250 mgm2) on days 1 and 8 nab-Pac (microtubule inhibitor) starting dose of 180 mgm2 (cohort 1) 220 mgm2 (cohort 2) and 260 mgm2 (cohort 3) on day 1 of the 21-day cycle using a 3 + 3 design
0
MTD not reached29 Gr3 Neutropenia59 Gr1 Peripheralneuropathy
Yoshitomi S Taira N Doihara H Mizoo T Nogami T Iwamoto T Motoki T Shien T Ogasawara Y Matsuoka J Tsuji H Mitsuhashi T A phase 1 dose-finding and pharmacokinetic study of gemcitabine with nab-paclitaxel in patients with metastatic breast cancer Cancer Chemother Pharmacol 2016 Aug78(2)289-94
Eli Lilly
Erbituxreg (cetuximab) + Taxane
EGFR inhibitor antineoplastic agent + Chemo
Headamp Neck Colorectal Cancer
TNBC
2007-2010
18
1 chemo
Cetuximab (epidermal growth factor receptor (EGFR) antagonist ) an initial loading dose of cetuximab 400 mgm2 followed by a weekly dose of 250 mgm2Paclitaxel (microtubule inhibitor) 80 mgm2 or Docetaxel at an initial dose of 30 mgm2 was administered weekly
56 CR 22 PR
83 Dermatologic toxicity11 Grade3+
Nechushtan H Vainer G Stainberg H Salmon AY Hamburger T Peretz T A phase 12 of a combination of cetuximab and taxane for triple negative breast cancer patients Breast 2014 Aug23(4)435-8
Polyphor
Balixafortide (POL6326) + eribulin
CXCR4 antagonist + tubulin-based antimitotic
Heavily pretreated Relapsed MBC
2014-2016
56
3rd line 3 chemo
3+3 dose escalation The highest dose was established as eribulin 14 mgmsup2 on days 2 and 9 and balixafortide 55 mgkg on days 1minus3 and 8minus10 of the 21-day cycle
30 PR
41 Gr34 Neutropenia11 Gr34 Leucopenia11 Gr34 Febrileneutropenia2 Related mortalities
Apr 2018 Fast Track for HER2-MBC who have failed 2prior regimens
Pernas S Martin M Kaufman PA Gil-Martin M Gomez Pardo P Lopez-Tarruella S Manso L Ciruelos E Perez-Fidalgo JA Hernando C Ademuyiwa FO Weilbaecher K Mayer I Pluard TJ Martinez Garcia M Vahdat L Perez-Garcia J Wach A Barker D Fung S Romagnoli B Cortes J Balixafortide plus eribulin in HER2-negative metastatic breast cancer a phase 1 single-arm dose-escalation trial Lancet Oncol 2018 Jun19(6)812-824
11 PRndashbut only + letrozole (No Resp on monotherapy)
61 Gr34 Neutropenia39 Gr34 Leucopenia
$933M in 1Q2018 $31B in 2017
Tamura K Mukai H Naito Y Yonemori K Kodaira M Tanabe Y Yamamoto N Osera S Sasaki M Mori Y Hashigaki S Nagasawa T Umeyama Y Yoshino T Phase I study of palbociclib a cyclin-dependent kinase 46 inhibitor in Japanese patients Cancer Sci 2016 Jun107(6)755-63 doi 101111cas12932 Epub 2016 May 11
Pfizer
Ibrancereg (palbociclib)
CDK 46 Inhibitor
HR+ HER2- MBC
Heavily pretreated Relapsed Metastatic Cancer
2004-2008
41 (5 BC)
chemo naiumlve (17) 1-2 (51)3 (29) 3+ (2)
Palbociclib 25-150 mg dose ranging
0
20 Gr34 Neutropenia23 Gr34 Leucopenia
$933M in 1Q2018 $31B in 2017
Flaherty KT Lorusso PM Demichele A Abramson VG Courtney R Randolph SS Shaik MN Wilner KD ODwyer PJ Schwartz GK Phase I dose-escalation trial of the oral cyclin-dependent kinase 46 inhibitor PD 0332991 administered using a 21-day schedule in patients with advanced cancer Clin Cancer Res 2012 Jan 1518(2)568-76 doi 1011581078-0432CCR-11-0509 Epub 2011 Nov 16
Novartis
Kisqalireg (ribociclib)
CDK 46 Inhibitors
Premenopausal HR+ HER2- MBC
Heavily pretreated Relapsed Metastatic Cancer
2016
132 (20 BC)
0-1 (25) 2-3 (42) 4+ (32)
Ribociclib 50 mg ranging up to 1200 mg dose escalation
23 PRndashincluded 1 in BC (5 of BC pts)
27 Gr34 Neutropenia17 Gr34 Leucopenia
Peak sales projected at $25B
Infante JR Cassier PA Gerecitano JF Witteveen PO Chugh R Ribrag V Chakraborty A Matano A Dobson JR Crystal AS Parasuraman S Shapiro GI A Phase I Study of the Cyclin-Dependent Kinase 46 Inhibitor Ribociclib (LEE011) in Patients with Advanced Solid Tumors and Lymphomas Clin Cancer Res 2016 Dec 122(23)5696-5705 Epub 2016 Aug 19
Eli Lilly
Verzenioreg (abemaciclib)
CDK 46 Inhibitors
HR+HER2minusMBC
Heavily pretreated Relapsed Metastatic Cancer
2016
12 (1 BC)
1 (312) 2 (212) 3+ (7)
Abemaciclib 100 mg ranging up to 200 mg dose escalation
17 PR (included 1 in BC)
17 Gr34 Neutropenia33 Gr34 Leucopenia
Peak sales projected at $2B
Fujiwara Y Tamura K Kondo S Tanabe Y Iwasa S Shimomura A Kitano S Ogasawara K Turner PK Mori J Asou H Chan EM Yamamoto N Phase 1 study of abemaciclib an inhibitor of CDK 4 and 6 as a single agent for Japanese patients with advanced cancer Cancer Chemother Pharmacol 2016 Aug78(2)281-8 doi 101007s00280-016-3085-8 Epub 2016 Jun 16
Mukai H Saeki T Shimada K Naito Y Matsubara N Nakanishi T Obaishi H Namiki M Sasaki Y Phase 1 combination study of eribulin mesylate with trastuzumab for advanced or recurrent human epidermal growth factor receptor 2 positive breast cancer Invest New Drugs 2015 Feb33(1)119-27
AstraZeneca
Lynparza (Olaparib)+ Cediranib
PARP inhibitor+ inhibitor of VEGF RTK
HR+ HER2- MBC
BC amp OC
13
28 (8 BC)
3 for BC
Olaparib (a poly (ADP-ribose) polymerase (PARP) inhibitor) amp Cediranib (Vascular endothelial growth factor receptor (VEGFR) 1 2 and 3 tyrosine kinase inhibitor)3 at dose level (DL) 0 (cediranib 20mg olaparib 100mg) 3 at DL1 (cediranib 20mg olaparib 200mg) 7 at DL2 (cediranib 30mg olaparib 200mg) 6 at DL3 (cediranib 30mg olaparib 400mg)
Liu JF Tolaney SM Birrer M Fleming GF Buss MK Dahlberg SE Lee H Whalen C Tyburski K Winer E Ivy P Matulonis UA A Phase 1 trial of the poly(ADP-ribose) polymerase inhibitor olaparib (AZD2281) in combination with the anti-angiogenic cediranib (AZD2171) in recurrent epithelial ovarian or triple-negative breast cancer Eur J Cancer 2013 Sep49(14)2972-8
ReyonPharma
VM206RY
Heterologous prime-boost with a truncated HER2 sequence
HER2+ Stg IIIampIV BC
15
9
2 chemo
Plasmid DNA (pHM-GM-CSF expressing truncated HER2 amp GM-CSF) amp adenoviral vector (Ad-HM containing modified HER2) (2 4 and 8 mgpatientvisit) of pHM-GM-CSF 3x IM weeks 0 2 and 4 Ad-HM 3 times 109 virus particles at week 6
11 PR
4 pts 7 minor AEs
Unclear
Kim SB Ahn JH Kim J Jung KH A phase 1 study of a heterologous prime-boost vaccination involving a truncated HER2 sequence in patients with HER2-expressing breast cancer Mol Ther Methods Clin Dev 2015 Sep 30215031 doi 101038mtm201531 eCollection 2015
Rodon J Peacuterez-Fidalgo A Krop IE Burris H Guerrero-Zotano A Britten CD Becerra C Schellens J Richards DA Schuler M Abu-Khalaf M Johnson FM Ranson M Edenfield J Silva AP Hackl W Quadt C Demanse D Duval V Baselga J Phase 11b dose escalation and expansion study of BEZ235 a dual PI3KmTOR inhibitor in patients with advanced solid tumors including patients with advanced breast cancer Cancer Chemother Pharmacol 2018 Jun 7 doi 101007s00280-018-3610-z [Epub ahead of print]
Celgene(Abraxane)
Gemcitabine + Abraxane (nab-paclitaxel)
Chemo+ Chemo
OC BC NSCLC PC + LC OC BC KS
MBC
16
9
Adjuv chemo (100)chemo post-adjuv (33)
Gem (nucleoside metabolic inhibitor 1250 mgm2) on days 1 and 8 nab-Pac (microtubule inhibitor) starting dose of 180 mgm2 (cohort 1) 220 mgm2 (cohort 2) and 260 mgm2 (cohort 3) on day 1 of the 21-day cycle using a 3 + 3 design
0
MTD not reached29 Gr3 Neutropenia59 Gr1 Peripheralneuropathy
Yoshitomi S Taira N Doihara H Mizoo T Nogami T Iwamoto T Motoki T Shien T Ogasawara Y Matsuoka J Tsuji H Mitsuhashi T A phase 1 dose-finding and pharmacokinetic study of gemcitabine with nab-paclitaxel in patients with metastatic breast cancer Cancer Chemother Pharmacol 2016 Aug78(2)289-94
Eli Lilly
Erbituxreg (cetuximab) + Taxane
EGFR inhibitor antineoplastic agent + Chemo
Head amp NeckColorectal
TNBC
07-10
18
1 chemo
Cetuximab (epidermal growth factor receptor (EGFR) antagonist ) an initial loading dose of cetuximab 400 mgm2 followed by a weekly dose of 250 mgm2Paclitaxel (microtubule inhibitor) 80 mgm2 or Docetaxel at an initial dose of 30 mgm2 was administered weekly
56 CR 22 PR
83 Dermatologic toxicity11 Grade3+
Nechushtan H Vainer G Stainberg H Salmon AY Hamburger T Peretz T A phase 12 of a combination of cetuximab and taxane for triple negative breast cancer patients Breast 2014 Aug23(4)435-8
Polyphor
Balixafortide (POL6326) + eribulin
CXCR4 antagonist + tubulin-based antimitotic
Heavily pretreatedRelapsed MBC
14-16
56
3rd line 3 chemo
3+3 dose escalation The highest dose was established as eribulin 14 mgmsup2 on days 2 and 9 and balixafortide 55 mgkg on days 1minus3 and 8minus10 of the 21-day cycle
30 PR
41 Gr34 Neutropenia11 Gr34 Leucopenia11 Gr34 Febrileneutropenia2 Related mortalities
42018 Fast Track (HER2-MBC failed 2 prior regimens)
Pernas S Martin M Kaufman PA Gil-Martin M Gomez Pardo P Lopez-Tarruella S Manso L Ciruelos E Perez-Fidalgo JA Hernando C Ademuyiwa FO Weilbaecher K Mayer I Pluard TJ Martinez Garcia M Vahdat L Perez-Garcia J Wach A Barker D Fung S Romagnoli B Cortes J Balixafortide plus eribulin in HER2-negative metastatic breast cancer a phase 1 single-arm dose-escalation trial Lancet Oncol 2018 Jun19(6)812-824
1 PRndashbut only + letrozoleNo Resp on monotherapy
61 Gr34 Neutropenia39 Gr34 Leucopenia
$933M (1Q18)$31B (2017)
Tamura K Mukai H Naito Y Yonemori K Kodaira M Tanabe Y Yamamoto N Osera S Sasaki M Mori Y Hashigaki S Nagasawa T Umeyama Y Yoshino T Phase I study of palbociclib a cyclin-dependent kinase 46 inhibitor in Japanese patients Cancer Sci 2016 Jun107(6)755-63 doi 101111cas12932 Epub 2016 May 11
Pfizer
Ibrancereg (palbociclib)
CDK 46 Inhibitor
HR+ HER2- MBC
Heavily pretreatedRelapsed Met Cancer
04-08
41 (5 BC)
chemo naiumlve (17)1-2(51) 3(29) 3+(2)
Palbociclib 25-150 mg dose ranging
0
20 Gr34 Neutropenia23 Gr34 Leucopenia
$933M (1Q18)$31B (2017)
Flaherty KT Lorusso PM Demichele A Abramson VG Courtney R Randolph SS Shaik MN Wilner KD ODwyer PJ Schwartz GK Phase I dose-escalation trial of the oral cyclin-dependent kinase 46 inhibitor PD 0332991 administered using a 21-day schedule in patients with advanced cancer Clin Cancer Res 2012 Jan 1518(2)568-76 doi 1011581078-0432CCR-11-0509 Epub 2011 Nov 16
Novartis
Kisqalireg (ribociclib)
CDK 46 Inhibitor
Premenopausal HR+ HER2- MBC
Heavily pretreatedRelapsed Met Cancer
16
132 (20 BC)
0-1 (25) 2-3 (42)4+ (32)
Ribociclib 50 mg ranging up to 1200 mg dose escalation
23 PR-included 1 BC (5 of BC pts)
27 Gr34 Neutropenia17 Gr34 Leucopenia
Peak sales est at $25B
Infante JR Cassier PA Gerecitano JF Witteveen PO Chugh R Ribrag V Chakraborty A Matano A Dobson JR Crystal AS Parasuraman S Shapiro GI A Phase I Study of the Cyclin-Dependent Kinase 46 Inhibitor Ribociclib (LEE011) in Patients with Advanced Solid Tumors and Lymphomas Clin Cancer Res 2016 Dec 122(23)5696-5705 Epub 2016 Aug 19
Eli Lilly
Verzenioreg (abemaciclib)
CDK 46 Inhibitor
HR+HER2minusMBC
Heavily pretreatedRelapsed Met Cancer
16
12 (1 BC)
1 (312) 2 (212) 3+(7)
Abemaciclib 100 mg ranging up to 200 mg dose escalation
17 PR (included 1 BC)
17 Gr34 Neutropenia33 Gr34 Leucopenia
Peak sales est at $2B
Fujiwara Y Tamura K Kondo S Tanabe Y Iwasa S Shimomura A Kitano S Ogasawara K Turner PK Mori J Asou H Chan EM Yamamoto N Phase 1 study of abemaciclib an inhibitor of CDK 4 and 6 as a single agent for Japanese patients with advanced cancer Cancer Chemother Pharmacol 2016 Aug78(2)281-8 doi 101007s00280-016-3085-8 Epub 2016 Jun 16
41 Gr34 Neutropenia11 Gr34 Leucopenia11 Gr34 Febrileneutropenia2 Related mortalities
30 PRs in combination with Halaven
Bria-IMTTM
20
Injection site reactions No related SAEs or SUSARs
Tumor vol darr ampor darr circul tumor cells)All Comers 21(419) 26(519)One or More HLA matches 27(415) 33(515)Two or More HLA matches 50 (24) 75 (34))
Drug
Technology
Approved for
Market (US)
Ibrance (palbociclib)
CDK 46 Inhibitor
HR+HER2- MBC in combination with fluvestrant or aromatase inhibitor
$933M in 1Q2018 $3126M in 2017
Kisqali (ribociclib)
CDK 46 Inhibitor
2017 HR+HER2- MBC in combination with fluvestrant or aromatase inhibitor
Peak sales projected at $25B
Verzenio (abemaciclib)
CDK 46 Inhibitor
2017 HR+HER2- MBC in combination with fluvestrant or aromatase inhibitor
Peak sales projected at $2B
Lynparza (olaparib)
Poly (ADP-ribose) polymerase (PARP) inhibitor
2017 ovarian amp breast cancer
$997M in 2017
Halaven (eribulin mesylate)
Tubulin-based antimitotic
2H2017 3rd line MBC amp liposarcoma
$181M in 2017
balixafortide
CXCR4 antagonist
Fast track designation in 2018 for HER2- MBC who have failed 2 prior regimens
Q3 2018 Data on first 20 Patients on Bria-IMTtrade Q3 2018 Initiate Combination Study of Bria-IMTtrade with Keytruda or Yervoy
Q4 2018 Switch to a novel frozen Bria-IMTtrade formulation Q4 2018 Safety Data (6 patients) of the Bria-IMTtrade - Keytrudareg Combination Study (SABC meeting) Q4 2018 Ongoing Corporate PartnershipCollaboration Discussions
Q1 2019 Efficacy Data (6 patients) of the Bria-IMTtrade - Keytrudareg Combination Study Q2 2019 Initiation of Bria-OTStrade GMP manufacturing (KBI BioPharma) Q2 2019 Additional Safety amp Efficacy data Monotherapy and Combination Studies (AACR meeting) Q2 2019 Final data for Monotherapy and Additional Data for the Combination Study (ASCO meeting) H1 2019 Candidate Selection for a PKCδ Inhibitor H1 2019 Initiate additional immunotherapy program H2 2019 Bria-OTStrade Authorization from FDA clearance for dosing H2 2019 Bria-OTStrade First Patient Dosed
Upcoming Milestones amp Catalysts
14
Involved in over 10 drugs brought to the market
Experienced Management Team
Management
William V Williams MD FACP President amp CEO VP Exploratory Development Incyte Corporation VP Experimental Medicine GlaxoSmithKline Head Rheumatology Research University of Pennsylvania Facilitated entry of over 20 compounds into the clinic including ruxolitinib (Jakafi)
baricitinib amp epacadostat NDAs including Jakafi Boniva Bexxar Author of over 120 peer-reviewed publications amp over 20 patents
Gadi Levin CA MBA CFO CFO of Labstyle Innovations Ltd VP of Finance for two Israeli investment houses in the fields of private equity
hedge funds and real estate Financial Consultant various firms Accountant Arthur Andersen
Markus Lacher PhD Senior Director RampD Founder T cell Therapeutics Inc an immuno-oncology company Sr Clinical Scientist Cesca Therapeutics Inc a clinical-stage autologous cell
therapy company Scientist at BioTime Inc and OncoCyte Corporation Editorial advisory board Recent Patents on Anti-Cancer Drug Discovery
Farrah Dean MSc MBA Manager Corp Development Investor relations CytRx Corporation amp CCG Investor Relations Senior Associate Equity Analyst Oppenheimer amp Co Rodman amp Renshaw amp
Brian Metcalf PhD Recently retired as CSO from Global Blood Therapeutics Former Head of Research amp Development Incyte Corporation Former Head of Medicinal Chemistry SmithKline Beecham
Douglas Faller MD PhD Professor of Medicine Pediatrics Biochemistry Microbiology Pathology and
Laboratory Medicine HematologistOncologist former Director of the Cancer Center Boston University School of Medicine
Founder of several successful biotechnology companies
Robert Williams PhD University Distinguished Professor of Chemistry Colorado State University Founder of several successful biotechnology companies including Microcide Xcyte
Therapies HemaQuest Arch Therapeutics and Cetya Therapeutics
Thomas Kieber-Emmons PhD Deputy Director University of Arkansas Cancer Center Expert in targeted cancer immunotherapies structural biology and computational
chemistry
Maria Trojanowska PhD Professor of Medicine Boston University School of Medicine Director The Arthritis Center
16
Veteran Board of Directors
Board of Directors
Saeid Babaei PhD MBA Chairman Entrepreneur 20 yrs of biotech leadership roles Current CEO AbCelex VP Bus Develop Lorus Therap Dir of Corp Develop Northern Therapeutics
Rahoul Sharan CA Director Chairman Potash Ridge Director of the Board Ansell Capital Corp Parallel Resources amp Galaxy Capital
Corporation
Martin Schmieg CPA Director CFO Sirna Therapeutics Inc amp Isolagen Inc CEO Freedom-2 Inc (now PharmaCyte Inc) Advisor Caladrius Biosciences Inc Beckman Coulter Genomics Calimmune
Charles Wiseman MD Co-Founder amp Director Director Immunotherapy Lab St Vincent Medical Center Chief Breast Cancer Basic Research Lab Univ of Texas MD Anderson Hospital amp
Tumour Institute Assist Prof Dept of Molecular Carcinogenesis amp Virology MD Anderson Acting Chief Div of Oncology White Memorial Medical Center LA
William V Williams MD FACP President amp CEO VP Exploratory Development Incyte Corporation VP Experimental Medicine GlaxoSmithKline Head Rheumatology Research University of Pennsylvania
Prior Affiliations
17
Drug Approvals by BriaCell Management Team
Bexxarreg (tositumomab and Iodine I131 tositumomab) Treatment of CD20 antigen-expressing relapsed or refractory low grade follicular or transformed non-Hodgkins lymphoma
Myleranreg (busulfan) for chronic myelogenous leukemia Defense of formulation change sNDA
Hycamtinreg (topotecan) for ovarian cancer Pediatric use sNDA
Navelbinereg (vinorelbine tartrate) for non-small cell lung cancer Pediatric use sNDA
Bonivareg (ibandronate) monthly oral treatment of osteoporosis
Bonivareg (ibandronate) quarterly intraveous treatment of osteoporosis
Zofranreg (ondansetron) for prevention of nausea and vomiting Pediatric use sNDA
Jakafireg (ruxolitinib) for myelofibrosis Jakafireg (ruxolitinib) for polycythemia vera
Olumiantreg (baricitinib) for rheumatoid arthritis Approved in USA Japan and Europe
18
Share Metrics
BCTV BCTXF 19
Data as of 1092018
Ticker TSX BCTV
US Ticker OTCQBBCTXF
Share Price (CAD) as of Oct 9 2018 $012
52-Week Range (CAD) $009-019
Shares Outstanding as of Oct 9 2018 1611M
Market Cap as of Oct 9 2018 (CAD) $193M
Cash and Short Term Investments as of July 31 2018 (CAD) $23M
Total Shareholders Equity as of July 31 2018 (CAD) $12M
Number of Warrants $014-$035 (CAD) as of Oct 9 2018 601M
Number of Compensation Warrants $014-$030 (CAD) as of Oct 9 2018 45M
Number of Options $014- $026 (CAD$) as of Oct 9 2018 93M
Developing Bria-OTStrade the First Off-the-Shelf Personalized Immunotherapy
Targeting Adv Breast Cancer Unmet medical need (42000 death in the US in 2017 ) $1 Bil- $5 Bil market opportunity depending on patient treatment stage
Impressive results in 2 proof-of-concept clinical trials Rapid Response Rate Repeated following re-treatment Excellent Safety Profile
Completed enrollment in Phase IIIa clinical trial of Bria-IMTtrade with outstanding safety amp efficacy data Initiated Phase IIa Combination Study of Bria-IMTtrade with Keytrudareg (Merck amp Co Inc)
Developing Bria-OTStrade along with BriaDXtrade its companion diagnostic test Ability to match and treat ~90 of patient population with Off-the-Shelf personalized immunotherapy
Experienced Management has been involved in over 10 drug approvals
Patient B001 Breast 70 No 1101 - 3501 4001 Negative -
Bria-IMTtradeHuman Proof-of-Concept Trials in Breast Cancer (Patient A002)
24
Proof-of-Concept Results Resulted in BriaCellrsquos Immunotherapy Strategy Use BriaDXtrade diagnostic to select only those patients matching Bria-IMTtrade Use BriaDXtrade diagnostic test to select Bria-OTStrade alleles matching ~90 of all patients
Bria-IMTtradeCurrent Phase IIIa Data Supports HLA Matching Hypothesis Six patients treated in 2017 Bria-IMTtrade was safe and well tolerated
Patient 01-002 73-year-old woman with breast cancer diagnosed in 1995 Developed liver metastases in2010 and lung metastases in 2017 Previously treated with 7 rounds of chemotherapy with 8 differentchemotherapy agents Received 5 cycles of Bria-IMTtrade over 3 months then monthly cycles (6 months total)Evaluated after 3 months and 6 months After 3 months despite the extensive prior therapy her scans notedthat ldquothere has been a clear response in the multiple bilateral pulmonary nodulesrdquo The response wasmaintained after 6 months of Bria-IMTtrade treatment She matches Bria-IMTtrade at 2 HLA alleles
The liver tumors were stable to slightly increased at 3 months and then progressed after 6 months
This supports our hypothesis of heightened anti-tumor activity in patients with a matched HLA types Clear path to develop BriaDXtrade to select the patients using HLA testing
1 RLL 29 Not Detectable Not Detectable2 LUL apical pleural based 34 tiny nodule lt 1mm scar tiny nodule lt 1mm scar3 xxx 39 Not Detectable Not Detectable4 40 Not Detectable Not Detectable5 RLL 45 Not Detectable Not Detectable6 LLL 49 Not Detectable Not Detectable7 xxx 52 Not Detectable Not Detectable8 RLL 52 Not Detectable Not Detectable9 RLL 56 Not Detectable Not Detectable
10 RLL costophrenic recess 56 Not Detectable Not Detectable11 XXX 58 Not Detectable Not Detectable12 LUL 60 Not Detectable Not Detectable13 XXX 67 15 1514 RUL 72 15 1515 LLL 76 Not Detectable Not Detectable16 RUL Noncalcified Nodule 77 Not Detectable Not Detectable17 RLL costophrenic recess 79 10 1018 RUL 82 Not Detectable Not Detectable19 RLL 90 Not Detectable Not Detectable20 RLL 91 lt 01 lt 0121 xxx xxx Not Detectable Not Detectable
27
Clinical Development Update ndash Summary 2018 September 26
Completed enrollment of Adv Breast cancer patients in the Phase IIIa ldquomonotherapyrdquo study of Bria-IMTtrade
We have confirmed our mechanism of action and achieved proof of concept
Initial safety data appears superior to that of the other advanced or approved drugs for breast cancer when they were at a similar clinical stage of development
Initial efficacy data is similar or superior to those of other advanced or approved drugs for breast cancer when they were at a similar clinical stage of development
Initiated Combination Study of Bria-IMTtrade with Keytrudareg or Yervoyreg in Adv breast cancer patients expecting even better response rates than those in the ldquomonotherapyrdquo study Initial safety data is expected in 4Q2018 Initial efficacy data is expected in 1Q2019
Bria-OTStrade the first off-the-shelf personalized treatment for advanced breast cancer is expected to enter the clinic in 2019
28
Bria-IMTtrade Excellent Safety Data - To Date
To date Bria-IMTtrade has been dosed in 24 patients (4 in 2004-2005 20 in 2017-2018)
Interim Data (20 patients)-Ongoing Phase IIIa Study (2017-2018)
Bria-IMTtrade has been very well tolerated (ge60 doses given to date) The majority of adverse events (AEs) were limited to expected minor local irritation at the
injection sites No related grade gt3 or unexpected AEs No related serious AEs No serious unexpected related AEs Most patients who have dropped out did so due to worsening of their underlying disease
Based on the current study Bria-IMTtrade has an excellent safety profile
29
Bria-IMTtrade - Efficacy as Predicted
Interim Data (19 patients)-Ongoing Phase IIIa Study (2017-2018) amp Original Study (2004-2005)
PD-L1 expression on circulating cancer cells amp cancer-associated cells in 100 of patients (to date) Strong rationale for combination with checkpoint inhibitors like Keytruda
30
Bria-IMTtrade appears to be most effective in patients who match with Bria-IMT trade at 2 HLA loci (types) further supporting our ldquoHLA Matching Hypothesisrdquo and the development of Bria-OTS trade to cover 90 of the patient population
Combination with immune checkpoint inhibitors may induce a more potent anti-cancer response leading to our strategy of combination studies of Bria-IMT trade with Keytruda or Yervoy
Patients (n) HLA Match
Tumor Shrinkage
Biological Response
4 ge2 50 7515 ge1 27 334 0 0 0
Biological response includes tumor shrinkage or lower circulating cancer associated cells
The confirmatory Bria-IMTtrade monotherapy Phase IIa trial has completed enrollment Additional Support for the HLA-matching hypothesis has been obtained
Bria-IMTtrade Combination Therapy study with immune checkpoint inhibitors Keytrudareg if PD-L12 positive (ge1) Yervoyreg if PD-L12 negative (lt1) Accepting patients from the monotherapy study who develop progressive disease Also enrolling patients directly into this study to enhance experience with the combination In discussion with other pharmaceutical companies to evaluate additional combinations with other
immunotherapies
Bria-OTStrade Off-the-Shelf Personalized Targeted Immunotherapy Developing Bria-OTStrade to co-express GM-CSF and interferon-α Pre-manufacture additional HLA alleles ndash Total of 15 alleles (8 Class I and 7 Class II) Co-development of BriaDXtrade companion diagnostic for HLA typing Combination therapy clinical trial with immune checkpoint inhibitors for non-responders using
information from the Bria-IMTtrade Combination Therapy Study
33
Development Timeline ndash Breast Cancer
20192018 2020 2021
Phase IIIaBria-IMTtrade
Monotherapy
Currently Enrolling Phase IIaBria-IMTtrade + Checkpoint
Currently in discussions with potential partnersPhase II Bria-IMTtrade plus Additional Combinations (1Q19 4Q22)(eg PD-1 Inhibitor PD-L1 inhibitor anti-CTLA4 anti-GITR anti-OX40)
1Q 2Q 3Q 4Q
2023
Bria-OTStrade Off-The-Shelf Personalized ImmunotherapyMonotherapy and Potential Partnered Combo Therapy
(2H19 Ongoing)
Bria-OTStradeOff-the-Shelf Cell Line cGMP Manufacturing
and BriaDXtrade(1Q18 1Q19)
Registration Studies (1Q20 2H22)Bria-IMTtrade with Checkpoint InhibitorsBria-OTStrade +- Checkpoint Inhibitors
34
Immuno-oncology Deals
Recent deals of small biotechs with big pharma in immuno-oncology
35
Date PartnershipDevelopment stage at the time of the deal Deal size
07122018 Immatics-Genmab Preclinical Up to $28B
04042018 OSE Immunotherapeutics-Boehringer Ingelheim Preclinical Up to euro113B ($139B)
02092018 Pieris Pharmaceuticals-Seattle Genetics Preclinical Up to $123B
2142018 Nektar-BMS Ph III Up to $36B
01222018 Juno-Celgene Ph II $9B (Acquisition)
11142017 Loxo-Bayer Larotrectinib (Ph II) LOXO-195 (Ph III) Up to $155B
1032017 CytomX-Amgen Preclinical Up to $15B
03202017 CytomX--BMS Ph III Up to $36B
6282016 Xencor-Novartis Preclinical Up to $24B
Early Stage Clinical Studies (Comparison)
We compared the interim data of Ph IIIa study of Bria-IMTtrade in advanced breast cancer with thedata in the early stage clinical studies of recently approved breast cancer drugs and one fasttracked product candidate
Apples to apples comparison Early Stage Clinical Studies in oncology are typically done in patientswith no other therapeutic options Thus the patients have very advanced disease and response ratesare typically quite low
The patients in our Ph IIIa study have been heavily pre-treated (median 45 prior regimens)Some recent studies of relevance in breast cancer are noted in the following slides
36
Breast Cancer Market Opportunity
Drug Technology Approved for Market (US)Ibrance (palbociclib) CDK 46 Inhibitor HR+HER2- MBC in combination with
fluvestrant or aromatase inhibitor$933M in 1Q2018 $3126M in 2017
Kisqali (ribociclib) CDK 46 Inhibitor 2017 HR+HER2- MBC in combination with fluvestrant or aromatase inhibitor
Peak sales projected at $25B
Verzenio (abemaciclib) CDK 46 Inhibitor 2017 HR+HER2- MBC in combination with fluvestrant or aromatase inhibitor
balixafortide CXCR4 antagonist Fast track designation in 2018 for HER2- MBC who have failed 2 prior regimens
The market for breast cancer drugs is a multibillion dollar market with new drugs being approvedon an ongoing basis indicating the shortage of safe and effective treatments for this deadly disease
37
Competitors- Phase III Clinical Data Bria-IMTtrade shows superior safety and similar to superior efficacy data compared with those of the multi-billion dollar drugs when they were at a similar early stage of clinical development
Injection site reactions No related SAEs or SUSARs
Tumor vol darr ampor darr circul tumor cellsAll Comers 21(419) 26(519)One or More HLA matches 27(415) 33(515)Two or More HLA matches 50 (24) 75 (34)
Sheet1 (3)
Comp -Slides
Data
HLA (2)
HLA
Data (Ph1-2+4Pt)
Competitors (2018)-Slide
Competitors (2018)
In the Pipeline Protein Kinase C delta (PKCδ) Inhibitors
30 of all human malignancies display activating RAS mutations Another 60 showing over-activity of Ras-signaling pathways
Ras has been termed ldquoundruggablerdquo (no one has been able to make a Ras inhibitor drug)
BriaCellrsquos novel proprietary PKCδ inhibitors have shown activity against multiple RAS transformed tumors Lung cancer Melanoma Breast cancer Neuroendocrine cancer Pancreatic cancer Colorectal cancer
This target has an attractive safety profile based on in vivo studies and knock out mouse studies
PKCδ inhibitors should qualify for an accelerated clinical development plan and regulatory pathway
Could be in clinic within 24 months
Cost-Effective Additional Shot-on-Goal and additional partnership opportunities
Early-Stage Preclinical Program
39
Protein Kinase C delta (PKCδ) Inhibitors
Activated PKCδ inhibits RAS degradation which in turn stimulates tumor growth
Koo et al Oncotarget 621328 2016
30 of all human malignancies display activating RASmutations with another 60 showing over-activity of Ras-signaling pathways
BriaCellrsquos novel proprietary PKCδ inhibitors have shownactivity against multiple RAS transformed tumors
This target has an attractive safety profile based on in vivostudies and knock out mouse studies
PKCδ also has potential activity as an immunotherapeuticby blocking TGFβ signaling
PKCδ inhibitors are applicable to specific niche tumor typeswhich provide an accelerated clinical development plan
Structural aspects of first generation inhibitor rottlerin and staurosporine (pan-PKC activator) were combined to create second generation inhibitor KAM1
Third generation inhibitors such as BJE6-106 have improved potency and selectivity Fourth generation inhibitors under development to optimize drug-like characteristics PKCδ inhibitors lack endothelial cell cytotoxicity amp PKCδ deficient mice develop normally and are fertile Potentially no marked intrinsic toxicity by inhibiting PKCδ
Mukai H Saeki T Shimada K Naito Y Matsubara N Nakanishi T Obaishi H Namiki M Sasaki Y Phase 1 combination study of eribulin mesylate with trastuzumab for advanced or recurrent human epidermal growth factor receptor 2 positive breast cancer Invest New Drugs 2015 Feb33(1)119-27
AstraZeneca
Lynparza (Olaparib) + Cediranib
PARP inhibitor + inhibitor of VEGF receptor tyrosine kinases
HR+ HER2- MBC
BC amp OC
2013
28 (8 BC)
3 for BC
Olaparib (a poly (ADP-ribose) polymerase (PARP) inhibitor) amp Cediranib (Vascular endothelial growth factor receptor (VEGFR) 1 2 and 3 tyrosine kinase inhibitor)3 at dose level (DL) 0 (cediranib 20mg olaparib 100mg) 3 at DL1 (cediranib 20mg olaparib 200mg) 7 at DL2 (cediranib 30mg olaparib 200mg) 6 at DL3 (cediranib 30mg olaparib 400mg)
Liu JF Tolaney SM Birrer M Fleming GF Buss MK Dahlberg SE Lee H Whalen C Tyburski K Winer E Ivy P Matulonis UA A Phase 1 trial of the poly(ADP-ribose) polymerase inhibitor olaparib (AZD2281) in combination with the anti-angiogenic cediranib (AZD2171) in recurrent epithelial ovarian or triple-negative breast cancer Eur J Cancer 2013 Sep49(14)2972-8
Reyon Pharmaceutical
VM206RY
Heterologous prime-boost with a truncated HER2 sequence
HER2+ Stage IIIampIV BC
2015
9
2 chemo
Plasmid DNA (pHM-GM-CSF expressing truncated HER2 amp GM-CSF) amp adenoviral vector (Ad-HM containing modified HER2) (2 4 and 8 mgpatientvisit) of pHM-GM-CSF 3x IM weeks 0 2 and 4 Ad-HM 3 times 109 virus particles at week 6
11 PR
4 pts showed 7 minor AEs
Unclear
Kim SB Ahn JH Kim J Jung KH A phase 1 study of a heterologous prime-boost vaccination involving a truncated HER2 sequence in patients with HER2-expressing breast cancer Mol Ther Methods Clin Dev 2015 Sep 30215031 doi 101038mtm201531 eCollection 2015
Rodon J Peacuterez-Fidalgo A Krop IE Burris H Guerrero-Zotano A Britten CD Becerra C Schellens J Richards DA Schuler M Abu-Khalaf M Johnson FM Ranson M Edenfield J Silva AP Hackl W Quadt C Demanse D Duval V Baselga J Phase 11b dose escalation and expansion study of BEZ235 a dual PI3KmTOR inhibitor in patients with advanced solid tumors including patients with advanced breast cancer Cancer Chemother Pharmacol 2018 Jun 7 doi 101007s00280-018-3610-z [Epub ahead of print]
Celgene (Abraxane)
Gemcitabine + Abraxane (nab-paclitaxel)
Chemo + Chemo
OC BC NSCLC amp Panc cancer + Lung OC BC Kaposi sarcoma
MBC
2016
9
Adjuvant chemo (100)chemo post-adjuvant (33)
Gem (nucleoside metabolic inhibitor 1250 mgm2) on days 1 and 8 nab-Pac (microtubule inhibitor) starting dose of 180 mgm2 (cohort 1) 220 mgm2 (cohort 2) and 260 mgm2 (cohort 3) on day 1 of the 21-day cycle using a 3 + 3 design
0
MTD not reached29 Gr3 Neutropenia59 Gr1 Peripheralneuropathy
Yoshitomi S Taira N Doihara H Mizoo T Nogami T Iwamoto T Motoki T Shien T Ogasawara Y Matsuoka J Tsuji H Mitsuhashi T A phase 1 dose-finding and pharmacokinetic study of gemcitabine with nab-paclitaxel in patients with metastatic breast cancer Cancer Chemother Pharmacol 2016 Aug78(2)289-94
Eli Lilly
Erbituxreg (cetuximab) + Taxane
EGFR inhibitor antineoplastic agent + Chemo
Headamp Neck Colorectal Cancer
TNBC
2007-2010
18
1 chemo
Cetuximab (epidermal growth factor receptor (EGFR) antagonist ) an initial loading dose of cetuximab 400 mgm2 followed by a weekly dose of 250 mgm2Paclitaxel (microtubule inhibitor) 80 mgm2 or Docetaxel at an initial dose of 30 mgm2 was administered weekly
56 CR 22 PR
83 Dermatologic toxicity11 Grade3+
Nechushtan H Vainer G Stainberg H Salmon AY Hamburger T Peretz T A phase 12 of a combination of cetuximab and taxane for triple negative breast cancer patients Breast 2014 Aug23(4)435-8
Polyphor
Balixafortide (POL6326) + eribulin
CXCR4 antagonist + tubulin-based antimitotic
Heavily pretreated Relapsed MBC
2014-2016
56
3rd line 3 chemo
3+3 dose escalation The highest dose was established as eribulin 14 mgmsup2 on days 2 and 9 and balixafortide 55 mgkg on days 1minus3 and 8minus10 of the 21-day cycle
30 PR
41 Gr34 Neutropenia11 Gr34 Leucopenia11 Gr34 Febrileneutropenia2 Related mortalities
Apr 2018 Fast Track for HER2-MBC who have failed 2prior regimens
Pernas S Martin M Kaufman PA Gil-Martin M Gomez Pardo P Lopez-Tarruella S Manso L Ciruelos E Perez-Fidalgo JA Hernando C Ademuyiwa FO Weilbaecher K Mayer I Pluard TJ Martinez Garcia M Vahdat L Perez-Garcia J Wach A Barker D Fung S Romagnoli B Cortes J Balixafortide plus eribulin in HER2-negative metastatic breast cancer a phase 1 single-arm dose-escalation trial Lancet Oncol 2018 Jun19(6)812-824
11 PRndashbut only + letrozole (No Resp on monotherapy)
61 Gr34 Neutropenia39 Gr34 Leucopenia
$933M in 1Q2018 $31B in 2017
Tamura K Mukai H Naito Y Yonemori K Kodaira M Tanabe Y Yamamoto N Osera S Sasaki M Mori Y Hashigaki S Nagasawa T Umeyama Y Yoshino T Phase I study of palbociclib a cyclin-dependent kinase 46 inhibitor in Japanese patients Cancer Sci 2016 Jun107(6)755-63 doi 101111cas12932 Epub 2016 May 11
Pfizer
Ibrancereg (palbociclib)
CDK 46 Inhibitor
HR+ HER2- MBC
Heavily pretreated Relapsed Metastatic Cancer
2004-2008
41 (5 BC)
chemo naiumlve (17) 1-2 (51)3 (29) 3+ (2)
Palbociclib 25-150 mg dose ranging
0
20 Gr34 Neutropenia23 Gr34 Leucopenia
$933M in 1Q2018 $31B in 2017
Flaherty KT Lorusso PM Demichele A Abramson VG Courtney R Randolph SS Shaik MN Wilner KD ODwyer PJ Schwartz GK Phase I dose-escalation trial of the oral cyclin-dependent kinase 46 inhibitor PD 0332991 administered using a 21-day schedule in patients with advanced cancer Clin Cancer Res 2012 Jan 1518(2)568-76 doi 1011581078-0432CCR-11-0509 Epub 2011 Nov 16
Novartis
Kisqalireg (ribociclib)
CDK 46 Inhibitors
Premenopausal HR+ HER2- MBC
Heavily pretreated Relapsed Metastatic Cancer
2016
132 (20 BC)
0-1 (25) 2-3 (42) 4+ (32)
Ribociclib 50 mg ranging up to 1200 mg dose escalation
23 PRndashincluded 1 in BC (5 of BC pts)
27 Gr34 Neutropenia17 Gr34 Leucopenia
Peak sales projected at $25B
Infante JR Cassier PA Gerecitano JF Witteveen PO Chugh R Ribrag V Chakraborty A Matano A Dobson JR Crystal AS Parasuraman S Shapiro GI A Phase I Study of the Cyclin-Dependent Kinase 46 Inhibitor Ribociclib (LEE011) in Patients with Advanced Solid Tumors and Lymphomas Clin Cancer Res 2016 Dec 122(23)5696-5705 Epub 2016 Aug 19
Eli Lilly
Verzenioreg (abemaciclib)
CDK 46 Inhibitors
HR+HER2minusMBC
Heavily pretreated Relapsed Metastatic Cancer
2016
12 (1 BC)
1 (312) 2 (212) 3+ (7)
Abemaciclib 100 mg ranging up to 200 mg dose escalation
17 PR (included 1 in BC)
17 Gr34 Neutropenia33 Gr34 Leucopenia
Peak sales projected at $2B
Fujiwara Y Tamura K Kondo S Tanabe Y Iwasa S Shimomura A Kitano S Ogasawara K Turner PK Mori J Asou H Chan EM Yamamoto N Phase 1 study of abemaciclib an inhibitor of CDK 4 and 6 as a single agent for Japanese patients with advanced cancer Cancer Chemother Pharmacol 2016 Aug78(2)281-8 doi 101007s00280-016-3085-8 Epub 2016 Jun 16
Mukai H Saeki T Shimada K Naito Y Matsubara N Nakanishi T Obaishi H Namiki M Sasaki Y Phase 1 combination study of eribulin mesylate with trastuzumab for advanced or recurrent human epidermal growth factor receptor 2 positive breast cancer Invest New Drugs 2015 Feb33(1)119-27
AstraZeneca
Lynparza (Olaparib)+ Cediranib
PARP inhibitor+ inhibitor of VEGF RTK
HR+ HER2- MBC
BC amp OC
13
28 (8 BC)
3 for BC
Olaparib (a poly (ADP-ribose) polymerase (PARP) inhibitor) amp Cediranib (Vascular endothelial growth factor receptor (VEGFR) 1 2 and 3 tyrosine kinase inhibitor)3 at dose level (DL) 0 (cediranib 20mg olaparib 100mg) 3 at DL1 (cediranib 20mg olaparib 200mg) 7 at DL2 (cediranib 30mg olaparib 200mg) 6 at DL3 (cediranib 30mg olaparib 400mg)
Liu JF Tolaney SM Birrer M Fleming GF Buss MK Dahlberg SE Lee H Whalen C Tyburski K Winer E Ivy P Matulonis UA A Phase 1 trial of the poly(ADP-ribose) polymerase inhibitor olaparib (AZD2281) in combination with the anti-angiogenic cediranib (AZD2171) in recurrent epithelial ovarian or triple-negative breast cancer Eur J Cancer 2013 Sep49(14)2972-8
ReyonPharma
VM206RY
Heterologous prime-boost with a truncated HER2 sequence
HER2+ Stg IIIampIV BC
15
9
2 chemo
Plasmid DNA (pHM-GM-CSF expressing truncated HER2 amp GM-CSF) amp adenoviral vector (Ad-HM containing modified HER2) (2 4 and 8 mgpatientvisit) of pHM-GM-CSF 3x IM weeks 0 2 and 4 Ad-HM 3 times 109 virus particles at week 6
11 PR
4 pts 7 minor AEs
Unclear
Kim SB Ahn JH Kim J Jung KH A phase 1 study of a heterologous prime-boost vaccination involving a truncated HER2 sequence in patients with HER2-expressing breast cancer Mol Ther Methods Clin Dev 2015 Sep 30215031 doi 101038mtm201531 eCollection 2015
Rodon J Peacuterez-Fidalgo A Krop IE Burris H Guerrero-Zotano A Britten CD Becerra C Schellens J Richards DA Schuler M Abu-Khalaf M Johnson FM Ranson M Edenfield J Silva AP Hackl W Quadt C Demanse D Duval V Baselga J Phase 11b dose escalation and expansion study of BEZ235 a dual PI3KmTOR inhibitor in patients with advanced solid tumors including patients with advanced breast cancer Cancer Chemother Pharmacol 2018 Jun 7 doi 101007s00280-018-3610-z [Epub ahead of print]
Celgene(Abraxane)
Gemcitabine + Abraxane (nab-paclitaxel)
Chemo+ Chemo
OC BC NSCLC PC + LC OC BC KS
MBC
16
9
Adjuv chemo (100)chemo post-adjuv (33)
Gem (nucleoside metabolic inhibitor 1250 mgm2) on days 1 and 8 nab-Pac (microtubule inhibitor) starting dose of 180 mgm2 (cohort 1) 220 mgm2 (cohort 2) and 260 mgm2 (cohort 3) on day 1 of the 21-day cycle using a 3 + 3 design
0
MTD not reached29 Gr3 Neutropenia59 Gr1 Peripheralneuropathy
Yoshitomi S Taira N Doihara H Mizoo T Nogami T Iwamoto T Motoki T Shien T Ogasawara Y Matsuoka J Tsuji H Mitsuhashi T A phase 1 dose-finding and pharmacokinetic study of gemcitabine with nab-paclitaxel in patients with metastatic breast cancer Cancer Chemother Pharmacol 2016 Aug78(2)289-94
Eli Lilly
Erbituxreg (cetuximab) + Taxane
EGFR inhibitor antineoplastic agent + Chemo
Head amp NeckColorectal
TNBC
07-10
18
1 chemo
Cetuximab (epidermal growth factor receptor (EGFR) antagonist ) an initial loading dose of cetuximab 400 mgm2 followed by a weekly dose of 250 mgm2Paclitaxel (microtubule inhibitor) 80 mgm2 or Docetaxel at an initial dose of 30 mgm2 was administered weekly
56 CR 22 PR
83 Dermatologic toxicity11 Grade3+
Nechushtan H Vainer G Stainberg H Salmon AY Hamburger T Peretz T A phase 12 of a combination of cetuximab and taxane for triple negative breast cancer patients Breast 2014 Aug23(4)435-8
Polyphor
Balixafortide (POL6326) + eribulin
CXCR4 antagonist + tubulin-based antimitotic
Heavily pretreatedRelapsed MBC
14-16
56
3rd line 3 chemo
3+3 dose escalation The highest dose was established as eribulin 14 mgmsup2 on days 2 and 9 and balixafortide 55 mgkg on days 1minus3 and 8minus10 of the 21-day cycle
30 PR
41 Gr34 Neutropenia11 Gr34 Leucopenia11 Gr34 Febrileneutropenia2 Related mortalities
42018 Fast Track (HER2-MBC failed 2 prior regimens)
Pernas S Martin M Kaufman PA Gil-Martin M Gomez Pardo P Lopez-Tarruella S Manso L Ciruelos E Perez-Fidalgo JA Hernando C Ademuyiwa FO Weilbaecher K Mayer I Pluard TJ Martinez Garcia M Vahdat L Perez-Garcia J Wach A Barker D Fung S Romagnoli B Cortes J Balixafortide plus eribulin in HER2-negative metastatic breast cancer a phase 1 single-arm dose-escalation trial Lancet Oncol 2018 Jun19(6)812-824
1 PRndashbut only + letrozoleNo Resp on monotherapy
61 Gr34 Neutropenia39 Gr34 Leucopenia
$933M (1Q18)$31B (2017)
Tamura K Mukai H Naito Y Yonemori K Kodaira M Tanabe Y Yamamoto N Osera S Sasaki M Mori Y Hashigaki S Nagasawa T Umeyama Y Yoshino T Phase I study of palbociclib a cyclin-dependent kinase 46 inhibitor in Japanese patients Cancer Sci 2016 Jun107(6)755-63 doi 101111cas12932 Epub 2016 May 11
Pfizer
Ibrancereg (palbociclib)
CDK 46 Inhibitor
HR+ HER2- MBC
Heavily pretreatedRelapsed Met Cancer
04-08
41 (5 BC)
chemo naiumlve (17)1-2(51) 3(29) 3+(2)
Palbociclib 25-150 mg dose ranging
0
20 Gr34 Neutropenia23 Gr34 Leucopenia
$933M (1Q18)$31B (2017)
Flaherty KT Lorusso PM Demichele A Abramson VG Courtney R Randolph SS Shaik MN Wilner KD ODwyer PJ Schwartz GK Phase I dose-escalation trial of the oral cyclin-dependent kinase 46 inhibitor PD 0332991 administered using a 21-day schedule in patients with advanced cancer Clin Cancer Res 2012 Jan 1518(2)568-76 doi 1011581078-0432CCR-11-0509 Epub 2011 Nov 16
Novartis
Kisqalireg (ribociclib)
CDK 46 Inhibitor
Premenopausal HR+ HER2- MBC
Heavily pretreatedRelapsed Met Cancer
16
132 (20 BC)
0-1 (25) 2-3 (42)4+ (32)
Ribociclib 50 mg ranging up to 1200 mg dose escalation
23 PR-included 1 BC (5 of BC pts)
27 Gr34 Neutropenia17 Gr34 Leucopenia
Peak sales est at $25B
Infante JR Cassier PA Gerecitano JF Witteveen PO Chugh R Ribrag V Chakraborty A Matano A Dobson JR Crystal AS Parasuraman S Shapiro GI A Phase I Study of the Cyclin-Dependent Kinase 46 Inhibitor Ribociclib (LEE011) in Patients with Advanced Solid Tumors and Lymphomas Clin Cancer Res 2016 Dec 122(23)5696-5705 Epub 2016 Aug 19
Eli Lilly
Verzenioreg (abemaciclib)
CDK 46 Inhibitor
HR+HER2minusMBC
Heavily pretreatedRelapsed Met Cancer
16
12 (1 BC)
1 (312) 2 (212) 3+(7)
Abemaciclib 100 mg ranging up to 200 mg dose escalation
17 PR (included 1 BC)
17 Gr34 Neutropenia33 Gr34 Leucopenia
Peak sales est at $2B
Fujiwara Y Tamura K Kondo S Tanabe Y Iwasa S Shimomura A Kitano S Ogasawara K Turner PK Mori J Asou H Chan EM Yamamoto N Phase 1 study of abemaciclib an inhibitor of CDK 4 and 6 as a single agent for Japanese patients with advanced cancer Cancer Chemother Pharmacol 2016 Aug78(2)281-8 doi 101007s00280-016-3085-8 Epub 2016 Jun 16
Mukai H Saeki T Shimada K Naito Y Matsubara N Nakanishi T Obaishi H Namiki M Sasaki Y Phase 1 combination study of eribulin mesylate with trastuzumab for advanced or recurrent human epidermal growth factor receptor 2 positive breast cancer Invest New Drugs 2015 Feb33(1)119-27
AstraZeneca
Lynparza (Olaparib) + Cediranib
PARP inhibitor + inhibitor of VEGF receptor tyrosine kinases
HR+ HER2- MBC
BC amp OC
2013
28 (8 BC)
3 for BC
Olaparib (a poly (ADP-ribose) polymerase (PARP) inhibitor) amp Cediranib (Vascular endothelial growth factor receptor (VEGFR) 1 2 and 3 tyrosine kinase inhibitor)3 at dose level (DL) 0 (cediranib 20mg olaparib 100mg) 3 at DL1 (cediranib 20mg olaparib 200mg) 7 at DL2 (cediranib 30mg olaparib 200mg) 6 at DL3 (cediranib 30mg olaparib 400mg)
Liu JF Tolaney SM Birrer M Fleming GF Buss MK Dahlberg SE Lee H Whalen C Tyburski K Winer E Ivy P Matulonis UA A Phase 1 trial of the poly(ADP-ribose) polymerase inhibitor olaparib (AZD2281) in combination with the anti-angiogenic cediranib (AZD2171) in recurrent epithelial ovarian or triple-negative breast cancer Eur J Cancer 2013 Sep49(14)2972-8
Reyon Pharmaceutical
VM206RY
Heterologous prime-boost with a truncated HER2 sequence
HER2+ Stage IIIampIV BC
2015
9
2 chemo
Plasmid DNA (pHM-GM-CSF expressing truncated HER2 amp GM-CSF) amp adenoviral vector (Ad-HM containing modified HER2) (2 4 and 8 mgpatientvisit) of pHM-GM-CSF 3x IM weeks 0 2 and 4 Ad-HM 3 times 109 virus particles at week 6
11 PR
4 pts showed 7 minor AEs
Unclear
Kim SB Ahn JH Kim J Jung KH A phase 1 study of a heterologous prime-boost vaccination involving a truncated HER2 sequence in patients with HER2-expressing breast cancer Mol Ther Methods Clin Dev 2015 Sep 30215031 doi 101038mtm201531 eCollection 2015
Rodon J Peacuterez-Fidalgo A Krop IE Burris H Guerrero-Zotano A Britten CD Becerra C Schellens J Richards DA Schuler M Abu-Khalaf M Johnson FM Ranson M Edenfield J Silva AP Hackl W Quadt C Demanse D Duval V Baselga J Phase 11b dose escalation and expansion study of BEZ235 a dual PI3KmTOR inhibitor in patients with advanced solid tumors including patients with advanced breast cancer Cancer Chemother Pharmacol 2018 Jun 7 doi 101007s00280-018-3610-z [Epub ahead of print]
Celgene (Abraxane)
Gemcitabine + Abraxane (nab-paclitaxel)
Chemo + Chemo
OC BC NSCLC amp Panc cancer + Lung OC BC Kaposi sarcoma
MBC
2016
9
Adjuvant chemo (100)chemo post-adjuvant (33)
Gem (nucleoside metabolic inhibitor 1250 mgm2) on days 1 and 8 nab-Pac (microtubule inhibitor) starting dose of 180 mgm2 (cohort 1) 220 mgm2 (cohort 2) and 260 mgm2 (cohort 3) on day 1 of the 21-day cycle using a 3 + 3 design
0
MTD not reached29 Gr3 Neutropenia59 Gr1 Peripheralneuropathy
Yoshitomi S Taira N Doihara H Mizoo T Nogami T Iwamoto T Motoki T Shien T Ogasawara Y Matsuoka J Tsuji H Mitsuhashi T A phase 1 dose-finding and pharmacokinetic study of gemcitabine with nab-paclitaxel in patients with metastatic breast cancer Cancer Chemother Pharmacol 2016 Aug78(2)289-94
Eli Lilly
Erbituxreg (cetuximab) + Taxane
EGFR inhibitor antineoplastic agent + Chemo
Headamp Neck Colorectal Cancer
TNBC
2007-2010
18
1 chemo
Cetuximab (epidermal growth factor receptor (EGFR) antagonist ) an initial loading dose of cetuximab 400 mgm2 followed by a weekly dose of 250 mgm2Paclitaxel (microtubule inhibitor) 80 mgm2 or Docetaxel at an initial dose of 30 mgm2 was administered weekly
56 CR 22 PR
83 Dermatologic toxicity11 Grade3+
Nechushtan H Vainer G Stainberg H Salmon AY Hamburger T Peretz T A phase 12 of a combination of cetuximab and taxane for triple negative breast cancer patients Breast 2014 Aug23(4)435-8
Polyphor
Balixafortide (POL6326) + eribulin
CXCR4 antagonist + tubulin-based antimitotic
Heavily pretreated Relapsed MBC
2014-2016
56
3rd line 3 chemo
3+3 dose escalation The highest dose was established as eribulin 14 mgmsup2 on days 2 and 9 and balixafortide 55 mgkg on days 1minus3 and 8minus10 of the 21-day cycle
30 PR
41 Gr34 Neutropenia11 Gr34 Leucopenia11 Gr34 Febrileneutropenia2 Related mortalities
Apr 2018 Fast Track for HER2-MBC who have failed 2prior regimens
Pernas S Martin M Kaufman PA Gil-Martin M Gomez Pardo P Lopez-Tarruella S Manso L Ciruelos E Perez-Fidalgo JA Hernando C Ademuyiwa FO Weilbaecher K Mayer I Pluard TJ Martinez Garcia M Vahdat L Perez-Garcia J Wach A Barker D Fung S Romagnoli B Cortes J Balixafortide plus eribulin in HER2-negative metastatic breast cancer a phase 1 single-arm dose-escalation trial Lancet Oncol 2018 Jun19(6)812-824
11 PRndashbut only + letrozole (No Resp on monotherapy)
61 Gr34 Neutropenia39 Gr34 Leucopenia
$933M in 1Q2018 $31B in 2017
Tamura K Mukai H Naito Y Yonemori K Kodaira M Tanabe Y Yamamoto N Osera S Sasaki M Mori Y Hashigaki S Nagasawa T Umeyama Y Yoshino T Phase I study of palbociclib a cyclin-dependent kinase 46 inhibitor in Japanese patients Cancer Sci 2016 Jun107(6)755-63 doi 101111cas12932 Epub 2016 May 11
Pfizer
Ibrancereg (palbociclib)
CDK 46 Inhibitor
HR+ HER2- MBC
Heavily pretreated Relapsed Metastatic Cancer
2004-2008
41 (5 BC)
chemo naiumlve (17) 1-2 (51)3 (29) 3+ (2)
Palbociclib 25-150 mg dose ranging
0
20 Gr34 Neutropenia23 Gr34 Leucopenia
$933M in 1Q2018 $31B in 2017
Flaherty KT Lorusso PM Demichele A Abramson VG Courtney R Randolph SS Shaik MN Wilner KD ODwyer PJ Schwartz GK Phase I dose-escalation trial of the oral cyclin-dependent kinase 46 inhibitor PD 0332991 administered using a 21-day schedule in patients with advanced cancer Clin Cancer Res 2012 Jan 1518(2)568-76 doi 1011581078-0432CCR-11-0509 Epub 2011 Nov 16
Novartis
Kisqalireg (ribociclib)
CDK 46 Inhibitors
Premenopausal HR+ HER2- MBC
Heavily pretreated Relapsed Metastatic Cancer
2016
132 (20 BC)
0-1 (25) 2-3 (42) 4+ (32)
Ribociclib 50 mg ranging up to 1200 mg dose escalation
23 PRndashincluded 1 in BC (5 of BC pts)
27 Gr34 Neutropenia17 Gr34 Leucopenia
Peak sales projected at $25B
Infante JR Cassier PA Gerecitano JF Witteveen PO Chugh R Ribrag V Chakraborty A Matano A Dobson JR Crystal AS Parasuraman S Shapiro GI A Phase I Study of the Cyclin-Dependent Kinase 46 Inhibitor Ribociclib (LEE011) in Patients with Advanced Solid Tumors and Lymphomas Clin Cancer Res 2016 Dec 122(23)5696-5705 Epub 2016 Aug 19
Eli Lilly
Verzenioreg (abemaciclib)
CDK 46 Inhibitors
HR+HER2minusMBC
Heavily pretreated Relapsed Metastatic Cancer
2016
12 (1 BC)
1 (312) 2 (212) 3+ (7)
Abemaciclib 100 mg ranging up to 200 mg dose escalation
17 PR (included 1 in BC)
17 Gr34 Neutropenia33 Gr34 Leucopenia
Peak sales projected at $2B
Fujiwara Y Tamura K Kondo S Tanabe Y Iwasa S Shimomura A Kitano S Ogasawara K Turner PK Mori J Asou H Chan EM Yamamoto N Phase 1 study of abemaciclib an inhibitor of CDK 4 and 6 as a single agent for Japanese patients with advanced cancer Cancer Chemother Pharmacol 2016 Aug78(2)281-8 doi 101007s00280-016-3085-8 Epub 2016 Jun 16
Mukai H Saeki T Shimada K Naito Y Matsubara N Nakanishi T Obaishi H Namiki M Sasaki Y Phase 1 combination study of eribulin mesylate with trastuzumab for advanced or recurrent human epidermal growth factor receptor 2 positive breast cancer Invest New Drugs 2015 Feb33(1)119-27
AstraZeneca
Lynparza (Olaparib)+ Cediranib
PARP inhibitor+ inhibitor of VEGF RTK
HR+ HER2- MBC
BC amp OC
13
28 (8 BC)
3 for BC
Olaparib (a poly (ADP-ribose) polymerase (PARP) inhibitor) amp Cediranib (Vascular endothelial growth factor receptor (VEGFR) 1 2 and 3 tyrosine kinase inhibitor)3 at dose level (DL) 0 (cediranib 20mg olaparib 100mg) 3 at DL1 (cediranib 20mg olaparib 200mg) 7 at DL2 (cediranib 30mg olaparib 200mg) 6 at DL3 (cediranib 30mg olaparib 400mg)
Liu JF Tolaney SM Birrer M Fleming GF Buss MK Dahlberg SE Lee H Whalen C Tyburski K Winer E Ivy P Matulonis UA A Phase 1 trial of the poly(ADP-ribose) polymerase inhibitor olaparib (AZD2281) in combination with the anti-angiogenic cediranib (AZD2171) in recurrent epithelial ovarian or triple-negative breast cancer Eur J Cancer 2013 Sep49(14)2972-8
ReyonPharma
VM206RY
Heterologous prime-boost with a truncated HER2 sequence
HER2+ Stg IIIampIV BC
15
9
2 chemo
Plasmid DNA (pHM-GM-CSF expressing truncated HER2 amp GM-CSF) amp adenoviral vector (Ad-HM containing modified HER2) (2 4 and 8 mgpatientvisit) of pHM-GM-CSF 3x IM weeks 0 2 and 4 Ad-HM 3 times 109 virus particles at week 6
11 PR
4 pts 7 minor AEs
Unclear
Kim SB Ahn JH Kim J Jung KH A phase 1 study of a heterologous prime-boost vaccination involving a truncated HER2 sequence in patients with HER2-expressing breast cancer Mol Ther Methods Clin Dev 2015 Sep 30215031 doi 101038mtm201531 eCollection 2015
Rodon J Peacuterez-Fidalgo A Krop IE Burris H Guerrero-Zotano A Britten CD Becerra C Schellens J Richards DA Schuler M Abu-Khalaf M Johnson FM Ranson M Edenfield J Silva AP Hackl W Quadt C Demanse D Duval V Baselga J Phase 11b dose escalation and expansion study of BEZ235 a dual PI3KmTOR inhibitor in patients with advanced solid tumors including patients with advanced breast cancer Cancer Chemother Pharmacol 2018 Jun 7 doi 101007s00280-018-3610-z [Epub ahead of print]
Celgene(Abraxane)
Gemcitabine + Abraxane (nab-paclitaxel)
Chemo+ Chemo
OC BC NSCLC PC + LC OC BC KS
MBC
16
9
Adjuv chemo (100)chemo post-adjuv (33)
Gem (nucleoside metabolic inhibitor 1250 mgm2) on days 1 and 8 nab-Pac (microtubule inhibitor) starting dose of 180 mgm2 (cohort 1) 220 mgm2 (cohort 2) and 260 mgm2 (cohort 3) on day 1 of the 21-day cycle using a 3 + 3 design
0
MTD not reached29 Gr3 Neutropenia59 Gr1 Peripheralneuropathy
Yoshitomi S Taira N Doihara H Mizoo T Nogami T Iwamoto T Motoki T Shien T Ogasawara Y Matsuoka J Tsuji H Mitsuhashi T A phase 1 dose-finding and pharmacokinetic study of gemcitabine with nab-paclitaxel in patients with metastatic breast cancer Cancer Chemother Pharmacol 2016 Aug78(2)289-94
Eli Lilly
Erbituxreg (cetuximab) + Taxane
EGFR inhibitor antineoplastic agent + Chemo
Head amp NeckColorectal
TNBC
07-10
18
1 chemo
Cetuximab (epidermal growth factor receptor (EGFR) antagonist ) an initial loading dose of cetuximab 400 mgm2 followed by a weekly dose of 250 mgm2Paclitaxel (microtubule inhibitor) 80 mgm2 or Docetaxel at an initial dose of 30 mgm2 was administered weekly
56 CR 22 PR
83 Dermatologic toxicity11 Grade3+
Nechushtan H Vainer G Stainberg H Salmon AY Hamburger T Peretz T A phase 12 of a combination of cetuximab and taxane for triple negative breast cancer patients Breast 2014 Aug23(4)435-8
Polyphor
Balixafortide (POL6326) + eribulin
CXCR4 antagonist + tubulin-based antimitotic
Heavily pretreatedRelapsed MBC
14-16
56
3rd line 3 chemo
3+3 dose escalation The highest dose was established as eribulin 14 mgmsup2 on days 2 and 9 and balixafortide 55 mgkg on days 1minus3 and 8minus10 of the 21-day cycle
30 PR
41 Gr34 Neutropenia11 Gr34 Leucopenia11 Gr34 Febrileneutropenia2 Related mortalities
42018 Fast Track (HER2-MBC failed 2 prior regimens)
Pernas S Martin M Kaufman PA Gil-Martin M Gomez Pardo P Lopez-Tarruella S Manso L Ciruelos E Perez-Fidalgo JA Hernando C Ademuyiwa FO Weilbaecher K Mayer I Pluard TJ Martinez Garcia M Vahdat L Perez-Garcia J Wach A Barker D Fung S Romagnoli B Cortes J Balixafortide plus eribulin in HER2-negative metastatic breast cancer a phase 1 single-arm dose-escalation trial Lancet Oncol 2018 Jun19(6)812-824
1 PRndashbut only + letrozoleNo Resp on monotherapy
61 Gr34 Neutropenia39 Gr34 Leucopenia
$933M (1Q18)$31B (2017)
Tamura K Mukai H Naito Y Yonemori K Kodaira M Tanabe Y Yamamoto N Osera S Sasaki M Mori Y Hashigaki S Nagasawa T Umeyama Y Yoshino T Phase I study of palbociclib a cyclin-dependent kinase 46 inhibitor in Japanese patients Cancer Sci 2016 Jun107(6)755-63 doi 101111cas12932 Epub 2016 May 11
Pfizer
Ibrancereg (palbociclib)
CDK 46 Inhibitor
HR+ HER2- MBC
Heavily pretreatedRelapsed Met Cancer
04-08
41 (5 BC)
chemo naiumlve (17)1-2(51) 3(29) 3+(2)
Palbociclib 25-150 mg dose ranging
0
20 Gr34 Neutropenia23 Gr34 Leucopenia
$933M (1Q18)$31B (2017)
Flaherty KT Lorusso PM Demichele A Abramson VG Courtney R Randolph SS Shaik MN Wilner KD ODwyer PJ Schwartz GK Phase I dose-escalation trial of the oral cyclin-dependent kinase 46 inhibitor PD 0332991 administered using a 21-day schedule in patients with advanced cancer Clin Cancer Res 2012 Jan 1518(2)568-76 doi 1011581078-0432CCR-11-0509 Epub 2011 Nov 16
Novartis
Kisqalireg (ribociclib)
CDK 46 Inhibitor
Premenopausal HR+ HER2- MBC
Heavily pretreatedRelapsed Met Cancer
16
132 (20 BC)
0-1 (25) 2-3 (42)4+ (32)
Ribociclib 50 mg ranging up to 1200 mg dose escalation
23 PR-included 1 BC (5 of BC pts)
27 Gr34 Neutropenia17 Gr34 Leucopenia
Peak sales est at $25B
Infante JR Cassier PA Gerecitano JF Witteveen PO Chugh R Ribrag V Chakraborty A Matano A Dobson JR Crystal AS Parasuraman S Shapiro GI A Phase I Study of the Cyclin-Dependent Kinase 46 Inhibitor Ribociclib (LEE011) in Patients with Advanced Solid Tumors and Lymphomas Clin Cancer Res 2016 Dec 122(23)5696-5705 Epub 2016 Aug 19
Eli Lilly
Verzenioreg (abemaciclib)
CDK 46 Inhibitor
HR+HER2minusMBC
Heavily pretreatedRelapsed Met Cancer
16
12 (1 BC)
1 (312) 2 (212) 3+(7)
Abemaciclib 100 mg ranging up to 200 mg dose escalation
17 PR (included 1 BC)
17 Gr34 Neutropenia33 Gr34 Leucopenia
Peak sales est at $2B
Fujiwara Y Tamura K Kondo S Tanabe Y Iwasa S Shimomura A Kitano S Ogasawara K Turner PK Mori J Asou H Chan EM Yamamoto N Phase 1 study of abemaciclib an inhibitor of CDK 4 and 6 as a single agent for Japanese patients with advanced cancer Cancer Chemother Pharmacol 2016 Aug78(2)281-8 doi 101007s00280-016-3085-8 Epub 2016 Jun 16
41 Gr34 Neutropenia11 Gr34 Leucopenia11 Gr34 Febrileneutropenia2 Related mortalities
30 PRs in combination with Halaven
Bria-IMTTM
20
Injection site reactions No related SAEs or SUSARs
Tumor vol darr ampor darr circul tumor cells)All Comers 21(419) 26(519)One or More HLA matches 27(415) 33(515)Two or More HLA matches 50 (24) 75 (34))
Drug
Technology
Approved for
Market (US)
Ibrance (palbociclib)
CDK 46 Inhibitor
HR+HER2- MBC in combination with fluvestrant or aromatase inhibitor
$933M in 1Q2018 $3126M in 2017
Kisqali (ribociclib)
CDK 46 Inhibitor
2017 HR+HER2- MBC in combination with fluvestrant or aromatase inhibitor
Peak sales projected at $25B
Verzenio (abemaciclib)
CDK 46 Inhibitor
2017 HR+HER2- MBC in combination with fluvestrant or aromatase inhibitor
Peak sales projected at $2B
Lynparza (olaparib)
Poly (ADP-ribose) polymerase (PARP) inhibitor
2017 ovarian amp breast cancer
$997M in 2017
Halaven (eribulin mesylate)
Tubulin-based antimitotic
2H2017 3rd line MBC amp liposarcoma
$181M in 2017
balixafortide
CXCR4 antagonist
Fast track designation in 2018 for HER2- MBC who have failed 2 prior regimens
Involved in over 10 drugs brought to the market
Experienced Management Team
Management
William V Williams MD FACP President amp CEO VP Exploratory Development Incyte Corporation VP Experimental Medicine GlaxoSmithKline Head Rheumatology Research University of Pennsylvania Facilitated entry of over 20 compounds into the clinic including ruxolitinib (Jakafi)
baricitinib amp epacadostat NDAs including Jakafi Boniva Bexxar Author of over 120 peer-reviewed publications amp over 20 patents
Gadi Levin CA MBA CFO CFO of Labstyle Innovations Ltd VP of Finance for two Israeli investment houses in the fields of private equity
hedge funds and real estate Financial Consultant various firms Accountant Arthur Andersen
Markus Lacher PhD Senior Director RampD Founder T cell Therapeutics Inc an immuno-oncology company Sr Clinical Scientist Cesca Therapeutics Inc a clinical-stage autologous cell
therapy company Scientist at BioTime Inc and OncoCyte Corporation Editorial advisory board Recent Patents on Anti-Cancer Drug Discovery
Farrah Dean MSc MBA Manager Corp Development Investor relations CytRx Corporation amp CCG Investor Relations Senior Associate Equity Analyst Oppenheimer amp Co Rodman amp Renshaw amp
Brian Metcalf PhD Recently retired as CSO from Global Blood Therapeutics Former Head of Research amp Development Incyte Corporation Former Head of Medicinal Chemistry SmithKline Beecham
Douglas Faller MD PhD Professor of Medicine Pediatrics Biochemistry Microbiology Pathology and
Laboratory Medicine HematologistOncologist former Director of the Cancer Center Boston University School of Medicine
Founder of several successful biotechnology companies
Robert Williams PhD University Distinguished Professor of Chemistry Colorado State University Founder of several successful biotechnology companies including Microcide Xcyte
Therapies HemaQuest Arch Therapeutics and Cetya Therapeutics
Thomas Kieber-Emmons PhD Deputy Director University of Arkansas Cancer Center Expert in targeted cancer immunotherapies structural biology and computational
chemistry
Maria Trojanowska PhD Professor of Medicine Boston University School of Medicine Director The Arthritis Center
16
Veteran Board of Directors
Board of Directors
Saeid Babaei PhD MBA Chairman Entrepreneur 20 yrs of biotech leadership roles Current CEO AbCelex VP Bus Develop Lorus Therap Dir of Corp Develop Northern Therapeutics
Rahoul Sharan CA Director Chairman Potash Ridge Director of the Board Ansell Capital Corp Parallel Resources amp Galaxy Capital
Corporation
Martin Schmieg CPA Director CFO Sirna Therapeutics Inc amp Isolagen Inc CEO Freedom-2 Inc (now PharmaCyte Inc) Advisor Caladrius Biosciences Inc Beckman Coulter Genomics Calimmune
Charles Wiseman MD Co-Founder amp Director Director Immunotherapy Lab St Vincent Medical Center Chief Breast Cancer Basic Research Lab Univ of Texas MD Anderson Hospital amp
Tumour Institute Assist Prof Dept of Molecular Carcinogenesis amp Virology MD Anderson Acting Chief Div of Oncology White Memorial Medical Center LA
William V Williams MD FACP President amp CEO VP Exploratory Development Incyte Corporation VP Experimental Medicine GlaxoSmithKline Head Rheumatology Research University of Pennsylvania
Prior Affiliations
17
Drug Approvals by BriaCell Management Team
Bexxarreg (tositumomab and Iodine I131 tositumomab) Treatment of CD20 antigen-expressing relapsed or refractory low grade follicular or transformed non-Hodgkins lymphoma
Myleranreg (busulfan) for chronic myelogenous leukemia Defense of formulation change sNDA
Hycamtinreg (topotecan) for ovarian cancer Pediatric use sNDA
Navelbinereg (vinorelbine tartrate) for non-small cell lung cancer Pediatric use sNDA
Bonivareg (ibandronate) monthly oral treatment of osteoporosis
Bonivareg (ibandronate) quarterly intraveous treatment of osteoporosis
Zofranreg (ondansetron) for prevention of nausea and vomiting Pediatric use sNDA
Jakafireg (ruxolitinib) for myelofibrosis Jakafireg (ruxolitinib) for polycythemia vera
Olumiantreg (baricitinib) for rheumatoid arthritis Approved in USA Japan and Europe
18
Share Metrics
BCTV BCTXF 19
Data as of 1092018
Ticker TSX BCTV
US Ticker OTCQBBCTXF
Share Price (CAD) as of Oct 9 2018 $012
52-Week Range (CAD) $009-019
Shares Outstanding as of Oct 9 2018 1611M
Market Cap as of Oct 9 2018 (CAD) $193M
Cash and Short Term Investments as of July 31 2018 (CAD) $23M
Total Shareholders Equity as of July 31 2018 (CAD) $12M
Number of Warrants $014-$035 (CAD) as of Oct 9 2018 601M
Number of Compensation Warrants $014-$030 (CAD) as of Oct 9 2018 45M
Number of Options $014- $026 (CAD$) as of Oct 9 2018 93M
Developing Bria-OTStrade the First Off-the-Shelf Personalized Immunotherapy
Targeting Adv Breast Cancer Unmet medical need (42000 death in the US in 2017 ) $1 Bil- $5 Bil market opportunity depending on patient treatment stage
Impressive results in 2 proof-of-concept clinical trials Rapid Response Rate Repeated following re-treatment Excellent Safety Profile
Completed enrollment in Phase IIIa clinical trial of Bria-IMTtrade with outstanding safety amp efficacy data Initiated Phase IIa Combination Study of Bria-IMTtrade with Keytrudareg (Merck amp Co Inc)
Developing Bria-OTStrade along with BriaDXtrade its companion diagnostic test Ability to match and treat ~90 of patient population with Off-the-Shelf personalized immunotherapy
Experienced Management has been involved in over 10 drug approvals
Patient B001 Breast 70 No 1101 - 3501 4001 Negative -
Bria-IMTtradeHuman Proof-of-Concept Trials in Breast Cancer (Patient A002)
24
Proof-of-Concept Results Resulted in BriaCellrsquos Immunotherapy Strategy Use BriaDXtrade diagnostic to select only those patients matching Bria-IMTtrade Use BriaDXtrade diagnostic test to select Bria-OTStrade alleles matching ~90 of all patients
Bria-IMTtradeCurrent Phase IIIa Data Supports HLA Matching Hypothesis Six patients treated in 2017 Bria-IMTtrade was safe and well tolerated
Patient 01-002 73-year-old woman with breast cancer diagnosed in 1995 Developed liver metastases in2010 and lung metastases in 2017 Previously treated with 7 rounds of chemotherapy with 8 differentchemotherapy agents Received 5 cycles of Bria-IMTtrade over 3 months then monthly cycles (6 months total)Evaluated after 3 months and 6 months After 3 months despite the extensive prior therapy her scans notedthat ldquothere has been a clear response in the multiple bilateral pulmonary nodulesrdquo The response wasmaintained after 6 months of Bria-IMTtrade treatment She matches Bria-IMTtrade at 2 HLA alleles
The liver tumors were stable to slightly increased at 3 months and then progressed after 6 months
This supports our hypothesis of heightened anti-tumor activity in patients with a matched HLA types Clear path to develop BriaDXtrade to select the patients using HLA testing
1 RLL 29 Not Detectable Not Detectable2 LUL apical pleural based 34 tiny nodule lt 1mm scar tiny nodule lt 1mm scar3 xxx 39 Not Detectable Not Detectable4 40 Not Detectable Not Detectable5 RLL 45 Not Detectable Not Detectable6 LLL 49 Not Detectable Not Detectable7 xxx 52 Not Detectable Not Detectable8 RLL 52 Not Detectable Not Detectable9 RLL 56 Not Detectable Not Detectable
10 RLL costophrenic recess 56 Not Detectable Not Detectable11 XXX 58 Not Detectable Not Detectable12 LUL 60 Not Detectable Not Detectable13 XXX 67 15 1514 RUL 72 15 1515 LLL 76 Not Detectable Not Detectable16 RUL Noncalcified Nodule 77 Not Detectable Not Detectable17 RLL costophrenic recess 79 10 1018 RUL 82 Not Detectable Not Detectable19 RLL 90 Not Detectable Not Detectable20 RLL 91 lt 01 lt 0121 xxx xxx Not Detectable Not Detectable
27
Clinical Development Update ndash Summary 2018 September 26
Completed enrollment of Adv Breast cancer patients in the Phase IIIa ldquomonotherapyrdquo study of Bria-IMTtrade
We have confirmed our mechanism of action and achieved proof of concept
Initial safety data appears superior to that of the other advanced or approved drugs for breast cancer when they were at a similar clinical stage of development
Initial efficacy data is similar or superior to those of other advanced or approved drugs for breast cancer when they were at a similar clinical stage of development
Initiated Combination Study of Bria-IMTtrade with Keytrudareg or Yervoyreg in Adv breast cancer patients expecting even better response rates than those in the ldquomonotherapyrdquo study Initial safety data is expected in 4Q2018 Initial efficacy data is expected in 1Q2019
Bria-OTStrade the first off-the-shelf personalized treatment for advanced breast cancer is expected to enter the clinic in 2019
28
Bria-IMTtrade Excellent Safety Data - To Date
To date Bria-IMTtrade has been dosed in 24 patients (4 in 2004-2005 20 in 2017-2018)
Interim Data (20 patients)-Ongoing Phase IIIa Study (2017-2018)
Bria-IMTtrade has been very well tolerated (ge60 doses given to date) The majority of adverse events (AEs) were limited to expected minor local irritation at the
injection sites No related grade gt3 or unexpected AEs No related serious AEs No serious unexpected related AEs Most patients who have dropped out did so due to worsening of their underlying disease
Based on the current study Bria-IMTtrade has an excellent safety profile
29
Bria-IMTtrade - Efficacy as Predicted
Interim Data (19 patients)-Ongoing Phase IIIa Study (2017-2018) amp Original Study (2004-2005)
PD-L1 expression on circulating cancer cells amp cancer-associated cells in 100 of patients (to date) Strong rationale for combination with checkpoint inhibitors like Keytruda
30
Bria-IMTtrade appears to be most effective in patients who match with Bria-IMT trade at 2 HLA loci (types) further supporting our ldquoHLA Matching Hypothesisrdquo and the development of Bria-OTS trade to cover 90 of the patient population
Combination with immune checkpoint inhibitors may induce a more potent anti-cancer response leading to our strategy of combination studies of Bria-IMT trade with Keytruda or Yervoy
Patients (n) HLA Match
Tumor Shrinkage
Biological Response
4 ge2 50 7515 ge1 27 334 0 0 0
Biological response includes tumor shrinkage or lower circulating cancer associated cells
The confirmatory Bria-IMTtrade monotherapy Phase IIa trial has completed enrollment Additional Support for the HLA-matching hypothesis has been obtained
Bria-IMTtrade Combination Therapy study with immune checkpoint inhibitors Keytrudareg if PD-L12 positive (ge1) Yervoyreg if PD-L12 negative (lt1) Accepting patients from the monotherapy study who develop progressive disease Also enrolling patients directly into this study to enhance experience with the combination In discussion with other pharmaceutical companies to evaluate additional combinations with other
immunotherapies
Bria-OTStrade Off-the-Shelf Personalized Targeted Immunotherapy Developing Bria-OTStrade to co-express GM-CSF and interferon-α Pre-manufacture additional HLA alleles ndash Total of 15 alleles (8 Class I and 7 Class II) Co-development of BriaDXtrade companion diagnostic for HLA typing Combination therapy clinical trial with immune checkpoint inhibitors for non-responders using
information from the Bria-IMTtrade Combination Therapy Study
33
Development Timeline ndash Breast Cancer
20192018 2020 2021
Phase IIIaBria-IMTtrade
Monotherapy
Currently Enrolling Phase IIaBria-IMTtrade + Checkpoint
Currently in discussions with potential partnersPhase II Bria-IMTtrade plus Additional Combinations (1Q19 4Q22)(eg PD-1 Inhibitor PD-L1 inhibitor anti-CTLA4 anti-GITR anti-OX40)
1Q 2Q 3Q 4Q
2023
Bria-OTStrade Off-The-Shelf Personalized ImmunotherapyMonotherapy and Potential Partnered Combo Therapy
(2H19 Ongoing)
Bria-OTStradeOff-the-Shelf Cell Line cGMP Manufacturing
and BriaDXtrade(1Q18 1Q19)
Registration Studies (1Q20 2H22)Bria-IMTtrade with Checkpoint InhibitorsBria-OTStrade +- Checkpoint Inhibitors
34
Immuno-oncology Deals
Recent deals of small biotechs with big pharma in immuno-oncology
35
Date PartnershipDevelopment stage at the time of the deal Deal size
07122018 Immatics-Genmab Preclinical Up to $28B
04042018 OSE Immunotherapeutics-Boehringer Ingelheim Preclinical Up to euro113B ($139B)
02092018 Pieris Pharmaceuticals-Seattle Genetics Preclinical Up to $123B
2142018 Nektar-BMS Ph III Up to $36B
01222018 Juno-Celgene Ph II $9B (Acquisition)
11142017 Loxo-Bayer Larotrectinib (Ph II) LOXO-195 (Ph III) Up to $155B
1032017 CytomX-Amgen Preclinical Up to $15B
03202017 CytomX--BMS Ph III Up to $36B
6282016 Xencor-Novartis Preclinical Up to $24B
Early Stage Clinical Studies (Comparison)
We compared the interim data of Ph IIIa study of Bria-IMTtrade in advanced breast cancer with thedata in the early stage clinical studies of recently approved breast cancer drugs and one fasttracked product candidate
Apples to apples comparison Early Stage Clinical Studies in oncology are typically done in patientswith no other therapeutic options Thus the patients have very advanced disease and response ratesare typically quite low
The patients in our Ph IIIa study have been heavily pre-treated (median 45 prior regimens)Some recent studies of relevance in breast cancer are noted in the following slides
36
Breast Cancer Market Opportunity
Drug Technology Approved for Market (US)Ibrance (palbociclib) CDK 46 Inhibitor HR+HER2- MBC in combination with
fluvestrant or aromatase inhibitor$933M in 1Q2018 $3126M in 2017
Kisqali (ribociclib) CDK 46 Inhibitor 2017 HR+HER2- MBC in combination with fluvestrant or aromatase inhibitor
Peak sales projected at $25B
Verzenio (abemaciclib) CDK 46 Inhibitor 2017 HR+HER2- MBC in combination with fluvestrant or aromatase inhibitor
balixafortide CXCR4 antagonist Fast track designation in 2018 for HER2- MBC who have failed 2 prior regimens
The market for breast cancer drugs is a multibillion dollar market with new drugs being approvedon an ongoing basis indicating the shortage of safe and effective treatments for this deadly disease
37
Competitors- Phase III Clinical Data Bria-IMTtrade shows superior safety and similar to superior efficacy data compared with those of the multi-billion dollar drugs when they were at a similar early stage of clinical development
Injection site reactions No related SAEs or SUSARs
Tumor vol darr ampor darr circul tumor cellsAll Comers 21(419) 26(519)One or More HLA matches 27(415) 33(515)Two or More HLA matches 50 (24) 75 (34)
Sheet1 (3)
Comp -Slides
Data
HLA (2)
HLA
Data (Ph1-2+4Pt)
Competitors (2018)-Slide
Competitors (2018)
In the Pipeline Protein Kinase C delta (PKCδ) Inhibitors
30 of all human malignancies display activating RAS mutations Another 60 showing over-activity of Ras-signaling pathways
Ras has been termed ldquoundruggablerdquo (no one has been able to make a Ras inhibitor drug)
BriaCellrsquos novel proprietary PKCδ inhibitors have shown activity against multiple RAS transformed tumors Lung cancer Melanoma Breast cancer Neuroendocrine cancer Pancreatic cancer Colorectal cancer
This target has an attractive safety profile based on in vivo studies and knock out mouse studies
PKCδ inhibitors should qualify for an accelerated clinical development plan and regulatory pathway
Could be in clinic within 24 months
Cost-Effective Additional Shot-on-Goal and additional partnership opportunities
Early-Stage Preclinical Program
39
Protein Kinase C delta (PKCδ) Inhibitors
Activated PKCδ inhibits RAS degradation which in turn stimulates tumor growth
Koo et al Oncotarget 621328 2016
30 of all human malignancies display activating RASmutations with another 60 showing over-activity of Ras-signaling pathways
BriaCellrsquos novel proprietary PKCδ inhibitors have shownactivity against multiple RAS transformed tumors
This target has an attractive safety profile based on in vivostudies and knock out mouse studies
PKCδ also has potential activity as an immunotherapeuticby blocking TGFβ signaling
PKCδ inhibitors are applicable to specific niche tumor typeswhich provide an accelerated clinical development plan
Structural aspects of first generation inhibitor rottlerin and staurosporine (pan-PKC activator) were combined to create second generation inhibitor KAM1
Third generation inhibitors such as BJE6-106 have improved potency and selectivity Fourth generation inhibitors under development to optimize drug-like characteristics PKCδ inhibitors lack endothelial cell cytotoxicity amp PKCδ deficient mice develop normally and are fertile Potentially no marked intrinsic toxicity by inhibiting PKCδ
Mukai H Saeki T Shimada K Naito Y Matsubara N Nakanishi T Obaishi H Namiki M Sasaki Y Phase 1 combination study of eribulin mesylate with trastuzumab for advanced or recurrent human epidermal growth factor receptor 2 positive breast cancer Invest New Drugs 2015 Feb33(1)119-27
AstraZeneca
Lynparza (Olaparib) + Cediranib
PARP inhibitor + inhibitor of VEGF receptor tyrosine kinases
HR+ HER2- MBC
BC amp OC
2013
28 (8 BC)
3 for BC
Olaparib (a poly (ADP-ribose) polymerase (PARP) inhibitor) amp Cediranib (Vascular endothelial growth factor receptor (VEGFR) 1 2 and 3 tyrosine kinase inhibitor)3 at dose level (DL) 0 (cediranib 20mg olaparib 100mg) 3 at DL1 (cediranib 20mg olaparib 200mg) 7 at DL2 (cediranib 30mg olaparib 200mg) 6 at DL3 (cediranib 30mg olaparib 400mg)
Liu JF Tolaney SM Birrer M Fleming GF Buss MK Dahlberg SE Lee H Whalen C Tyburski K Winer E Ivy P Matulonis UA A Phase 1 trial of the poly(ADP-ribose) polymerase inhibitor olaparib (AZD2281) in combination with the anti-angiogenic cediranib (AZD2171) in recurrent epithelial ovarian or triple-negative breast cancer Eur J Cancer 2013 Sep49(14)2972-8
Reyon Pharmaceutical
VM206RY
Heterologous prime-boost with a truncated HER2 sequence
HER2+ Stage IIIampIV BC
2015
9
2 chemo
Plasmid DNA (pHM-GM-CSF expressing truncated HER2 amp GM-CSF) amp adenoviral vector (Ad-HM containing modified HER2) (2 4 and 8 mgpatientvisit) of pHM-GM-CSF 3x IM weeks 0 2 and 4 Ad-HM 3 times 109 virus particles at week 6
11 PR
4 pts showed 7 minor AEs
Unclear
Kim SB Ahn JH Kim J Jung KH A phase 1 study of a heterologous prime-boost vaccination involving a truncated HER2 sequence in patients with HER2-expressing breast cancer Mol Ther Methods Clin Dev 2015 Sep 30215031 doi 101038mtm201531 eCollection 2015
Rodon J Peacuterez-Fidalgo A Krop IE Burris H Guerrero-Zotano A Britten CD Becerra C Schellens J Richards DA Schuler M Abu-Khalaf M Johnson FM Ranson M Edenfield J Silva AP Hackl W Quadt C Demanse D Duval V Baselga J Phase 11b dose escalation and expansion study of BEZ235 a dual PI3KmTOR inhibitor in patients with advanced solid tumors including patients with advanced breast cancer Cancer Chemother Pharmacol 2018 Jun 7 doi 101007s00280-018-3610-z [Epub ahead of print]
Celgene (Abraxane)
Gemcitabine + Abraxane (nab-paclitaxel)
Chemo + Chemo
OC BC NSCLC amp Panc cancer + Lung OC BC Kaposi sarcoma
MBC
2016
9
Adjuvant chemo (100)chemo post-adjuvant (33)
Gem (nucleoside metabolic inhibitor 1250 mgm2) on days 1 and 8 nab-Pac (microtubule inhibitor) starting dose of 180 mgm2 (cohort 1) 220 mgm2 (cohort 2) and 260 mgm2 (cohort 3) on day 1 of the 21-day cycle using a 3 + 3 design
0
MTD not reached29 Gr3 Neutropenia59 Gr1 Peripheralneuropathy
Yoshitomi S Taira N Doihara H Mizoo T Nogami T Iwamoto T Motoki T Shien T Ogasawara Y Matsuoka J Tsuji H Mitsuhashi T A phase 1 dose-finding and pharmacokinetic study of gemcitabine with nab-paclitaxel in patients with metastatic breast cancer Cancer Chemother Pharmacol 2016 Aug78(2)289-94
Eli Lilly
Erbituxreg (cetuximab) + Taxane
EGFR inhibitor antineoplastic agent + Chemo
Headamp Neck Colorectal Cancer
TNBC
2007-2010
18
1 chemo
Cetuximab (epidermal growth factor receptor (EGFR) antagonist ) an initial loading dose of cetuximab 400 mgm2 followed by a weekly dose of 250 mgm2Paclitaxel (microtubule inhibitor) 80 mgm2 or Docetaxel at an initial dose of 30 mgm2 was administered weekly
56 CR 22 PR
83 Dermatologic toxicity11 Grade3+
Nechushtan H Vainer G Stainberg H Salmon AY Hamburger T Peretz T A phase 12 of a combination of cetuximab and taxane for triple negative breast cancer patients Breast 2014 Aug23(4)435-8
Polyphor
Balixafortide (POL6326) + eribulin
CXCR4 antagonist + tubulin-based antimitotic
Heavily pretreated Relapsed MBC
2014-2016
56
3rd line 3 chemo
3+3 dose escalation The highest dose was established as eribulin 14 mgmsup2 on days 2 and 9 and balixafortide 55 mgkg on days 1minus3 and 8minus10 of the 21-day cycle
30 PR
41 Gr34 Neutropenia11 Gr34 Leucopenia11 Gr34 Febrileneutropenia2 Related mortalities
Apr 2018 Fast Track for HER2-MBC who have failed 2prior regimens
Pernas S Martin M Kaufman PA Gil-Martin M Gomez Pardo P Lopez-Tarruella S Manso L Ciruelos E Perez-Fidalgo JA Hernando C Ademuyiwa FO Weilbaecher K Mayer I Pluard TJ Martinez Garcia M Vahdat L Perez-Garcia J Wach A Barker D Fung S Romagnoli B Cortes J Balixafortide plus eribulin in HER2-negative metastatic breast cancer a phase 1 single-arm dose-escalation trial Lancet Oncol 2018 Jun19(6)812-824
11 PRndashbut only + letrozole (No Resp on monotherapy)
61 Gr34 Neutropenia39 Gr34 Leucopenia
$933M in 1Q2018 $31B in 2017
Tamura K Mukai H Naito Y Yonemori K Kodaira M Tanabe Y Yamamoto N Osera S Sasaki M Mori Y Hashigaki S Nagasawa T Umeyama Y Yoshino T Phase I study of palbociclib a cyclin-dependent kinase 46 inhibitor in Japanese patients Cancer Sci 2016 Jun107(6)755-63 doi 101111cas12932 Epub 2016 May 11
Pfizer
Ibrancereg (palbociclib)
CDK 46 Inhibitor
HR+ HER2- MBC
Heavily pretreated Relapsed Metastatic Cancer
2004-2008
41 (5 BC)
chemo naiumlve (17) 1-2 (51)3 (29) 3+ (2)
Palbociclib 25-150 mg dose ranging
0
20 Gr34 Neutropenia23 Gr34 Leucopenia
$933M in 1Q2018 $31B in 2017
Flaherty KT Lorusso PM Demichele A Abramson VG Courtney R Randolph SS Shaik MN Wilner KD ODwyer PJ Schwartz GK Phase I dose-escalation trial of the oral cyclin-dependent kinase 46 inhibitor PD 0332991 administered using a 21-day schedule in patients with advanced cancer Clin Cancer Res 2012 Jan 1518(2)568-76 doi 1011581078-0432CCR-11-0509 Epub 2011 Nov 16
Novartis
Kisqalireg (ribociclib)
CDK 46 Inhibitors
Premenopausal HR+ HER2- MBC
Heavily pretreated Relapsed Metastatic Cancer
2016
132 (20 BC)
0-1 (25) 2-3 (42) 4+ (32)
Ribociclib 50 mg ranging up to 1200 mg dose escalation
23 PRndashincluded 1 in BC (5 of BC pts)
27 Gr34 Neutropenia17 Gr34 Leucopenia
Peak sales projected at $25B
Infante JR Cassier PA Gerecitano JF Witteveen PO Chugh R Ribrag V Chakraborty A Matano A Dobson JR Crystal AS Parasuraman S Shapiro GI A Phase I Study of the Cyclin-Dependent Kinase 46 Inhibitor Ribociclib (LEE011) in Patients with Advanced Solid Tumors and Lymphomas Clin Cancer Res 2016 Dec 122(23)5696-5705 Epub 2016 Aug 19
Eli Lilly
Verzenioreg (abemaciclib)
CDK 46 Inhibitors
HR+HER2minusMBC
Heavily pretreated Relapsed Metastatic Cancer
2016
12 (1 BC)
1 (312) 2 (212) 3+ (7)
Abemaciclib 100 mg ranging up to 200 mg dose escalation
17 PR (included 1 in BC)
17 Gr34 Neutropenia33 Gr34 Leucopenia
Peak sales projected at $2B
Fujiwara Y Tamura K Kondo S Tanabe Y Iwasa S Shimomura A Kitano S Ogasawara K Turner PK Mori J Asou H Chan EM Yamamoto N Phase 1 study of abemaciclib an inhibitor of CDK 4 and 6 as a single agent for Japanese patients with advanced cancer Cancer Chemother Pharmacol 2016 Aug78(2)281-8 doi 101007s00280-016-3085-8 Epub 2016 Jun 16
Mukai H Saeki T Shimada K Naito Y Matsubara N Nakanishi T Obaishi H Namiki M Sasaki Y Phase 1 combination study of eribulin mesylate with trastuzumab for advanced or recurrent human epidermal growth factor receptor 2 positive breast cancer Invest New Drugs 2015 Feb33(1)119-27
AstraZeneca
Lynparza (Olaparib)+ Cediranib
PARP inhibitor+ inhibitor of VEGF RTK
HR+ HER2- MBC
BC amp OC
13
28 (8 BC)
3 for BC
Olaparib (a poly (ADP-ribose) polymerase (PARP) inhibitor) amp Cediranib (Vascular endothelial growth factor receptor (VEGFR) 1 2 and 3 tyrosine kinase inhibitor)3 at dose level (DL) 0 (cediranib 20mg olaparib 100mg) 3 at DL1 (cediranib 20mg olaparib 200mg) 7 at DL2 (cediranib 30mg olaparib 200mg) 6 at DL3 (cediranib 30mg olaparib 400mg)
Liu JF Tolaney SM Birrer M Fleming GF Buss MK Dahlberg SE Lee H Whalen C Tyburski K Winer E Ivy P Matulonis UA A Phase 1 trial of the poly(ADP-ribose) polymerase inhibitor olaparib (AZD2281) in combination with the anti-angiogenic cediranib (AZD2171) in recurrent epithelial ovarian or triple-negative breast cancer Eur J Cancer 2013 Sep49(14)2972-8
ReyonPharma
VM206RY
Heterologous prime-boost with a truncated HER2 sequence
HER2+ Stg IIIampIV BC
15
9
2 chemo
Plasmid DNA (pHM-GM-CSF expressing truncated HER2 amp GM-CSF) amp adenoviral vector (Ad-HM containing modified HER2) (2 4 and 8 mgpatientvisit) of pHM-GM-CSF 3x IM weeks 0 2 and 4 Ad-HM 3 times 109 virus particles at week 6
11 PR
4 pts 7 minor AEs
Unclear
Kim SB Ahn JH Kim J Jung KH A phase 1 study of a heterologous prime-boost vaccination involving a truncated HER2 sequence in patients with HER2-expressing breast cancer Mol Ther Methods Clin Dev 2015 Sep 30215031 doi 101038mtm201531 eCollection 2015
Rodon J Peacuterez-Fidalgo A Krop IE Burris H Guerrero-Zotano A Britten CD Becerra C Schellens J Richards DA Schuler M Abu-Khalaf M Johnson FM Ranson M Edenfield J Silva AP Hackl W Quadt C Demanse D Duval V Baselga J Phase 11b dose escalation and expansion study of BEZ235 a dual PI3KmTOR inhibitor in patients with advanced solid tumors including patients with advanced breast cancer Cancer Chemother Pharmacol 2018 Jun 7 doi 101007s00280-018-3610-z [Epub ahead of print]
Celgene(Abraxane)
Gemcitabine + Abraxane (nab-paclitaxel)
Chemo+ Chemo
OC BC NSCLC PC + LC OC BC KS
MBC
16
9
Adjuv chemo (100)chemo post-adjuv (33)
Gem (nucleoside metabolic inhibitor 1250 mgm2) on days 1 and 8 nab-Pac (microtubule inhibitor) starting dose of 180 mgm2 (cohort 1) 220 mgm2 (cohort 2) and 260 mgm2 (cohort 3) on day 1 of the 21-day cycle using a 3 + 3 design
0
MTD not reached29 Gr3 Neutropenia59 Gr1 Peripheralneuropathy
Yoshitomi S Taira N Doihara H Mizoo T Nogami T Iwamoto T Motoki T Shien T Ogasawara Y Matsuoka J Tsuji H Mitsuhashi T A phase 1 dose-finding and pharmacokinetic study of gemcitabine with nab-paclitaxel in patients with metastatic breast cancer Cancer Chemother Pharmacol 2016 Aug78(2)289-94
Eli Lilly
Erbituxreg (cetuximab) + Taxane
EGFR inhibitor antineoplastic agent + Chemo
Head amp NeckColorectal
TNBC
07-10
18
1 chemo
Cetuximab (epidermal growth factor receptor (EGFR) antagonist ) an initial loading dose of cetuximab 400 mgm2 followed by a weekly dose of 250 mgm2Paclitaxel (microtubule inhibitor) 80 mgm2 or Docetaxel at an initial dose of 30 mgm2 was administered weekly
56 CR 22 PR
83 Dermatologic toxicity11 Grade3+
Nechushtan H Vainer G Stainberg H Salmon AY Hamburger T Peretz T A phase 12 of a combination of cetuximab and taxane for triple negative breast cancer patients Breast 2014 Aug23(4)435-8
Polyphor
Balixafortide (POL6326) + eribulin
CXCR4 antagonist + tubulin-based antimitotic
Heavily pretreatedRelapsed MBC
14-16
56
3rd line 3 chemo
3+3 dose escalation The highest dose was established as eribulin 14 mgmsup2 on days 2 and 9 and balixafortide 55 mgkg on days 1minus3 and 8minus10 of the 21-day cycle
30 PR
41 Gr34 Neutropenia11 Gr34 Leucopenia11 Gr34 Febrileneutropenia2 Related mortalities
42018 Fast Track (HER2-MBC failed 2 prior regimens)
Pernas S Martin M Kaufman PA Gil-Martin M Gomez Pardo P Lopez-Tarruella S Manso L Ciruelos E Perez-Fidalgo JA Hernando C Ademuyiwa FO Weilbaecher K Mayer I Pluard TJ Martinez Garcia M Vahdat L Perez-Garcia J Wach A Barker D Fung S Romagnoli B Cortes J Balixafortide plus eribulin in HER2-negative metastatic breast cancer a phase 1 single-arm dose-escalation trial Lancet Oncol 2018 Jun19(6)812-824
1 PRndashbut only + letrozoleNo Resp on monotherapy
61 Gr34 Neutropenia39 Gr34 Leucopenia
$933M (1Q18)$31B (2017)
Tamura K Mukai H Naito Y Yonemori K Kodaira M Tanabe Y Yamamoto N Osera S Sasaki M Mori Y Hashigaki S Nagasawa T Umeyama Y Yoshino T Phase I study of palbociclib a cyclin-dependent kinase 46 inhibitor in Japanese patients Cancer Sci 2016 Jun107(6)755-63 doi 101111cas12932 Epub 2016 May 11
Pfizer
Ibrancereg (palbociclib)
CDK 46 Inhibitor
HR+ HER2- MBC
Heavily pretreatedRelapsed Met Cancer
04-08
41 (5 BC)
chemo naiumlve (17)1-2(51) 3(29) 3+(2)
Palbociclib 25-150 mg dose ranging
0
20 Gr34 Neutropenia23 Gr34 Leucopenia
$933M (1Q18)$31B (2017)
Flaherty KT Lorusso PM Demichele A Abramson VG Courtney R Randolph SS Shaik MN Wilner KD ODwyer PJ Schwartz GK Phase I dose-escalation trial of the oral cyclin-dependent kinase 46 inhibitor PD 0332991 administered using a 21-day schedule in patients with advanced cancer Clin Cancer Res 2012 Jan 1518(2)568-76 doi 1011581078-0432CCR-11-0509 Epub 2011 Nov 16
Novartis
Kisqalireg (ribociclib)
CDK 46 Inhibitor
Premenopausal HR+ HER2- MBC
Heavily pretreatedRelapsed Met Cancer
16
132 (20 BC)
0-1 (25) 2-3 (42)4+ (32)
Ribociclib 50 mg ranging up to 1200 mg dose escalation
23 PR-included 1 BC (5 of BC pts)
27 Gr34 Neutropenia17 Gr34 Leucopenia
Peak sales est at $25B
Infante JR Cassier PA Gerecitano JF Witteveen PO Chugh R Ribrag V Chakraborty A Matano A Dobson JR Crystal AS Parasuraman S Shapiro GI A Phase I Study of the Cyclin-Dependent Kinase 46 Inhibitor Ribociclib (LEE011) in Patients with Advanced Solid Tumors and Lymphomas Clin Cancer Res 2016 Dec 122(23)5696-5705 Epub 2016 Aug 19
Eli Lilly
Verzenioreg (abemaciclib)
CDK 46 Inhibitor
HR+HER2minusMBC
Heavily pretreatedRelapsed Met Cancer
16
12 (1 BC)
1 (312) 2 (212) 3+(7)
Abemaciclib 100 mg ranging up to 200 mg dose escalation
17 PR (included 1 BC)
17 Gr34 Neutropenia33 Gr34 Leucopenia
Peak sales est at $2B
Fujiwara Y Tamura K Kondo S Tanabe Y Iwasa S Shimomura A Kitano S Ogasawara K Turner PK Mori J Asou H Chan EM Yamamoto N Phase 1 study of abemaciclib an inhibitor of CDK 4 and 6 as a single agent for Japanese patients with advanced cancer Cancer Chemother Pharmacol 2016 Aug78(2)281-8 doi 101007s00280-016-3085-8 Epub 2016 Jun 16
Mukai H Saeki T Shimada K Naito Y Matsubara N Nakanishi T Obaishi H Namiki M Sasaki Y Phase 1 combination study of eribulin mesylate with trastuzumab for advanced or recurrent human epidermal growth factor receptor 2 positive breast cancer Invest New Drugs 2015 Feb33(1)119-27
AstraZeneca
Lynparza (Olaparib) + Cediranib
PARP inhibitor + inhibitor of VEGF receptor tyrosine kinases
HR+ HER2- MBC
BC amp OC
2013
28 (8 BC)
3 for BC
Olaparib (a poly (ADP-ribose) polymerase (PARP) inhibitor) amp Cediranib (Vascular endothelial growth factor receptor (VEGFR) 1 2 and 3 tyrosine kinase inhibitor)3 at dose level (DL) 0 (cediranib 20mg olaparib 100mg) 3 at DL1 (cediranib 20mg olaparib 200mg) 7 at DL2 (cediranib 30mg olaparib 200mg) 6 at DL3 (cediranib 30mg olaparib 400mg)
Liu JF Tolaney SM Birrer M Fleming GF Buss MK Dahlberg SE Lee H Whalen C Tyburski K Winer E Ivy P Matulonis UA A Phase 1 trial of the poly(ADP-ribose) polymerase inhibitor olaparib (AZD2281) in combination with the anti-angiogenic cediranib (AZD2171) in recurrent epithelial ovarian or triple-negative breast cancer Eur J Cancer 2013 Sep49(14)2972-8
Reyon Pharmaceutical
VM206RY
Heterologous prime-boost with a truncated HER2 sequence
HER2+ Stage IIIampIV BC
2015
9
2 chemo
Plasmid DNA (pHM-GM-CSF expressing truncated HER2 amp GM-CSF) amp adenoviral vector (Ad-HM containing modified HER2) (2 4 and 8 mgpatientvisit) of pHM-GM-CSF 3x IM weeks 0 2 and 4 Ad-HM 3 times 109 virus particles at week 6
11 PR
4 pts showed 7 minor AEs
Unclear
Kim SB Ahn JH Kim J Jung KH A phase 1 study of a heterologous prime-boost vaccination involving a truncated HER2 sequence in patients with HER2-expressing breast cancer Mol Ther Methods Clin Dev 2015 Sep 30215031 doi 101038mtm201531 eCollection 2015
Rodon J Peacuterez-Fidalgo A Krop IE Burris H Guerrero-Zotano A Britten CD Becerra C Schellens J Richards DA Schuler M Abu-Khalaf M Johnson FM Ranson M Edenfield J Silva AP Hackl W Quadt C Demanse D Duval V Baselga J Phase 11b dose escalation and expansion study of BEZ235 a dual PI3KmTOR inhibitor in patients with advanced solid tumors including patients with advanced breast cancer Cancer Chemother Pharmacol 2018 Jun 7 doi 101007s00280-018-3610-z [Epub ahead of print]
Celgene (Abraxane)
Gemcitabine + Abraxane (nab-paclitaxel)
Chemo + Chemo
OC BC NSCLC amp Panc cancer + Lung OC BC Kaposi sarcoma
MBC
2016
9
Adjuvant chemo (100)chemo post-adjuvant (33)
Gem (nucleoside metabolic inhibitor 1250 mgm2) on days 1 and 8 nab-Pac (microtubule inhibitor) starting dose of 180 mgm2 (cohort 1) 220 mgm2 (cohort 2) and 260 mgm2 (cohort 3) on day 1 of the 21-day cycle using a 3 + 3 design
0
MTD not reached29 Gr3 Neutropenia59 Gr1 Peripheralneuropathy
Yoshitomi S Taira N Doihara H Mizoo T Nogami T Iwamoto T Motoki T Shien T Ogasawara Y Matsuoka J Tsuji H Mitsuhashi T A phase 1 dose-finding and pharmacokinetic study of gemcitabine with nab-paclitaxel in patients with metastatic breast cancer Cancer Chemother Pharmacol 2016 Aug78(2)289-94
Eli Lilly
Erbituxreg (cetuximab) + Taxane
EGFR inhibitor antineoplastic agent + Chemo
Headamp Neck Colorectal Cancer
TNBC
2007-2010
18
1 chemo
Cetuximab (epidermal growth factor receptor (EGFR) antagonist ) an initial loading dose of cetuximab 400 mgm2 followed by a weekly dose of 250 mgm2Paclitaxel (microtubule inhibitor) 80 mgm2 or Docetaxel at an initial dose of 30 mgm2 was administered weekly
56 CR 22 PR
83 Dermatologic toxicity11 Grade3+
Nechushtan H Vainer G Stainberg H Salmon AY Hamburger T Peretz T A phase 12 of a combination of cetuximab and taxane for triple negative breast cancer patients Breast 2014 Aug23(4)435-8
Polyphor
Balixafortide (POL6326) + eribulin
CXCR4 antagonist + tubulin-based antimitotic
Heavily pretreated Relapsed MBC
2014-2016
56
3rd line 3 chemo
3+3 dose escalation The highest dose was established as eribulin 14 mgmsup2 on days 2 and 9 and balixafortide 55 mgkg on days 1minus3 and 8minus10 of the 21-day cycle
30 PR
41 Gr34 Neutropenia11 Gr34 Leucopenia11 Gr34 Febrileneutropenia2 Related mortalities
Apr 2018 Fast Track for HER2-MBC who have failed 2prior regimens
Pernas S Martin M Kaufman PA Gil-Martin M Gomez Pardo P Lopez-Tarruella S Manso L Ciruelos E Perez-Fidalgo JA Hernando C Ademuyiwa FO Weilbaecher K Mayer I Pluard TJ Martinez Garcia M Vahdat L Perez-Garcia J Wach A Barker D Fung S Romagnoli B Cortes J Balixafortide plus eribulin in HER2-negative metastatic breast cancer a phase 1 single-arm dose-escalation trial Lancet Oncol 2018 Jun19(6)812-824
11 PRndashbut only + letrozole (No Resp on monotherapy)
61 Gr34 Neutropenia39 Gr34 Leucopenia
$933M in 1Q2018 $31B in 2017
Tamura K Mukai H Naito Y Yonemori K Kodaira M Tanabe Y Yamamoto N Osera S Sasaki M Mori Y Hashigaki S Nagasawa T Umeyama Y Yoshino T Phase I study of palbociclib a cyclin-dependent kinase 46 inhibitor in Japanese patients Cancer Sci 2016 Jun107(6)755-63 doi 101111cas12932 Epub 2016 May 11
Pfizer
Ibrancereg (palbociclib)
CDK 46 Inhibitor
HR+ HER2- MBC
Heavily pretreated Relapsed Metastatic Cancer
2004-2008
41 (5 BC)
chemo naiumlve (17) 1-2 (51)3 (29) 3+ (2)
Palbociclib 25-150 mg dose ranging
0
20 Gr34 Neutropenia23 Gr34 Leucopenia
$933M in 1Q2018 $31B in 2017
Flaherty KT Lorusso PM Demichele A Abramson VG Courtney R Randolph SS Shaik MN Wilner KD ODwyer PJ Schwartz GK Phase I dose-escalation trial of the oral cyclin-dependent kinase 46 inhibitor PD 0332991 administered using a 21-day schedule in patients with advanced cancer Clin Cancer Res 2012 Jan 1518(2)568-76 doi 1011581078-0432CCR-11-0509 Epub 2011 Nov 16
Novartis
Kisqalireg (ribociclib)
CDK 46 Inhibitors
Premenopausal HR+ HER2- MBC
Heavily pretreated Relapsed Metastatic Cancer
2016
132 (20 BC)
0-1 (25) 2-3 (42) 4+ (32)
Ribociclib 50 mg ranging up to 1200 mg dose escalation
23 PRndashincluded 1 in BC (5 of BC pts)
27 Gr34 Neutropenia17 Gr34 Leucopenia
Peak sales projected at $25B
Infante JR Cassier PA Gerecitano JF Witteveen PO Chugh R Ribrag V Chakraborty A Matano A Dobson JR Crystal AS Parasuraman S Shapiro GI A Phase I Study of the Cyclin-Dependent Kinase 46 Inhibitor Ribociclib (LEE011) in Patients with Advanced Solid Tumors and Lymphomas Clin Cancer Res 2016 Dec 122(23)5696-5705 Epub 2016 Aug 19
Eli Lilly
Verzenioreg (abemaciclib)
CDK 46 Inhibitors
HR+HER2minusMBC
Heavily pretreated Relapsed Metastatic Cancer
2016
12 (1 BC)
1 (312) 2 (212) 3+ (7)
Abemaciclib 100 mg ranging up to 200 mg dose escalation
17 PR (included 1 in BC)
17 Gr34 Neutropenia33 Gr34 Leucopenia
Peak sales projected at $2B
Fujiwara Y Tamura K Kondo S Tanabe Y Iwasa S Shimomura A Kitano S Ogasawara K Turner PK Mori J Asou H Chan EM Yamamoto N Phase 1 study of abemaciclib an inhibitor of CDK 4 and 6 as a single agent for Japanese patients with advanced cancer Cancer Chemother Pharmacol 2016 Aug78(2)281-8 doi 101007s00280-016-3085-8 Epub 2016 Jun 16
Mukai H Saeki T Shimada K Naito Y Matsubara N Nakanishi T Obaishi H Namiki M Sasaki Y Phase 1 combination study of eribulin mesylate with trastuzumab for advanced or recurrent human epidermal growth factor receptor 2 positive breast cancer Invest New Drugs 2015 Feb33(1)119-27
AstraZeneca
Lynparza (Olaparib)+ Cediranib
PARP inhibitor+ inhibitor of VEGF RTK
HR+ HER2- MBC
BC amp OC
13
28 (8 BC)
3 for BC
Olaparib (a poly (ADP-ribose) polymerase (PARP) inhibitor) amp Cediranib (Vascular endothelial growth factor receptor (VEGFR) 1 2 and 3 tyrosine kinase inhibitor)3 at dose level (DL) 0 (cediranib 20mg olaparib 100mg) 3 at DL1 (cediranib 20mg olaparib 200mg) 7 at DL2 (cediranib 30mg olaparib 200mg) 6 at DL3 (cediranib 30mg olaparib 400mg)
Liu JF Tolaney SM Birrer M Fleming GF Buss MK Dahlberg SE Lee H Whalen C Tyburski K Winer E Ivy P Matulonis UA A Phase 1 trial of the poly(ADP-ribose) polymerase inhibitor olaparib (AZD2281) in combination with the anti-angiogenic cediranib (AZD2171) in recurrent epithelial ovarian or triple-negative breast cancer Eur J Cancer 2013 Sep49(14)2972-8
ReyonPharma
VM206RY
Heterologous prime-boost with a truncated HER2 sequence
HER2+ Stg IIIampIV BC
15
9
2 chemo
Plasmid DNA (pHM-GM-CSF expressing truncated HER2 amp GM-CSF) amp adenoviral vector (Ad-HM containing modified HER2) (2 4 and 8 mgpatientvisit) of pHM-GM-CSF 3x IM weeks 0 2 and 4 Ad-HM 3 times 109 virus particles at week 6
11 PR
4 pts 7 minor AEs
Unclear
Kim SB Ahn JH Kim J Jung KH A phase 1 study of a heterologous prime-boost vaccination involving a truncated HER2 sequence in patients with HER2-expressing breast cancer Mol Ther Methods Clin Dev 2015 Sep 30215031 doi 101038mtm201531 eCollection 2015
Rodon J Peacuterez-Fidalgo A Krop IE Burris H Guerrero-Zotano A Britten CD Becerra C Schellens J Richards DA Schuler M Abu-Khalaf M Johnson FM Ranson M Edenfield J Silva AP Hackl W Quadt C Demanse D Duval V Baselga J Phase 11b dose escalation and expansion study of BEZ235 a dual PI3KmTOR inhibitor in patients with advanced solid tumors including patients with advanced breast cancer Cancer Chemother Pharmacol 2018 Jun 7 doi 101007s00280-018-3610-z [Epub ahead of print]
Celgene(Abraxane)
Gemcitabine + Abraxane (nab-paclitaxel)
Chemo+ Chemo
OC BC NSCLC PC + LC OC BC KS
MBC
16
9
Adjuv chemo (100)chemo post-adjuv (33)
Gem (nucleoside metabolic inhibitor 1250 mgm2) on days 1 and 8 nab-Pac (microtubule inhibitor) starting dose of 180 mgm2 (cohort 1) 220 mgm2 (cohort 2) and 260 mgm2 (cohort 3) on day 1 of the 21-day cycle using a 3 + 3 design
0
MTD not reached29 Gr3 Neutropenia59 Gr1 Peripheralneuropathy
Yoshitomi S Taira N Doihara H Mizoo T Nogami T Iwamoto T Motoki T Shien T Ogasawara Y Matsuoka J Tsuji H Mitsuhashi T A phase 1 dose-finding and pharmacokinetic study of gemcitabine with nab-paclitaxel in patients with metastatic breast cancer Cancer Chemother Pharmacol 2016 Aug78(2)289-94
Eli Lilly
Erbituxreg (cetuximab) + Taxane
EGFR inhibitor antineoplastic agent + Chemo
Head amp NeckColorectal
TNBC
07-10
18
1 chemo
Cetuximab (epidermal growth factor receptor (EGFR) antagonist ) an initial loading dose of cetuximab 400 mgm2 followed by a weekly dose of 250 mgm2Paclitaxel (microtubule inhibitor) 80 mgm2 or Docetaxel at an initial dose of 30 mgm2 was administered weekly
56 CR 22 PR
83 Dermatologic toxicity11 Grade3+
Nechushtan H Vainer G Stainberg H Salmon AY Hamburger T Peretz T A phase 12 of a combination of cetuximab and taxane for triple negative breast cancer patients Breast 2014 Aug23(4)435-8
Polyphor
Balixafortide (POL6326) + eribulin
CXCR4 antagonist + tubulin-based antimitotic
Heavily pretreatedRelapsed MBC
14-16
56
3rd line 3 chemo
3+3 dose escalation The highest dose was established as eribulin 14 mgmsup2 on days 2 and 9 and balixafortide 55 mgkg on days 1minus3 and 8minus10 of the 21-day cycle
30 PR
41 Gr34 Neutropenia11 Gr34 Leucopenia11 Gr34 Febrileneutropenia2 Related mortalities
42018 Fast Track (HER2-MBC failed 2 prior regimens)
Pernas S Martin M Kaufman PA Gil-Martin M Gomez Pardo P Lopez-Tarruella S Manso L Ciruelos E Perez-Fidalgo JA Hernando C Ademuyiwa FO Weilbaecher K Mayer I Pluard TJ Martinez Garcia M Vahdat L Perez-Garcia J Wach A Barker D Fung S Romagnoli B Cortes J Balixafortide plus eribulin in HER2-negative metastatic breast cancer a phase 1 single-arm dose-escalation trial Lancet Oncol 2018 Jun19(6)812-824
1 PRndashbut only + letrozoleNo Resp on monotherapy
61 Gr34 Neutropenia39 Gr34 Leucopenia
$933M (1Q18)$31B (2017)
Tamura K Mukai H Naito Y Yonemori K Kodaira M Tanabe Y Yamamoto N Osera S Sasaki M Mori Y Hashigaki S Nagasawa T Umeyama Y Yoshino T Phase I study of palbociclib a cyclin-dependent kinase 46 inhibitor in Japanese patients Cancer Sci 2016 Jun107(6)755-63 doi 101111cas12932 Epub 2016 May 11
Pfizer
Ibrancereg (palbociclib)
CDK 46 Inhibitor
HR+ HER2- MBC
Heavily pretreatedRelapsed Met Cancer
04-08
41 (5 BC)
chemo naiumlve (17)1-2(51) 3(29) 3+(2)
Palbociclib 25-150 mg dose ranging
0
20 Gr34 Neutropenia23 Gr34 Leucopenia
$933M (1Q18)$31B (2017)
Flaherty KT Lorusso PM Demichele A Abramson VG Courtney R Randolph SS Shaik MN Wilner KD ODwyer PJ Schwartz GK Phase I dose-escalation trial of the oral cyclin-dependent kinase 46 inhibitor PD 0332991 administered using a 21-day schedule in patients with advanced cancer Clin Cancer Res 2012 Jan 1518(2)568-76 doi 1011581078-0432CCR-11-0509 Epub 2011 Nov 16
Novartis
Kisqalireg (ribociclib)
CDK 46 Inhibitor
Premenopausal HR+ HER2- MBC
Heavily pretreatedRelapsed Met Cancer
16
132 (20 BC)
0-1 (25) 2-3 (42)4+ (32)
Ribociclib 50 mg ranging up to 1200 mg dose escalation
23 PR-included 1 BC (5 of BC pts)
27 Gr34 Neutropenia17 Gr34 Leucopenia
Peak sales est at $25B
Infante JR Cassier PA Gerecitano JF Witteveen PO Chugh R Ribrag V Chakraborty A Matano A Dobson JR Crystal AS Parasuraman S Shapiro GI A Phase I Study of the Cyclin-Dependent Kinase 46 Inhibitor Ribociclib (LEE011) in Patients with Advanced Solid Tumors and Lymphomas Clin Cancer Res 2016 Dec 122(23)5696-5705 Epub 2016 Aug 19
Eli Lilly
Verzenioreg (abemaciclib)
CDK 46 Inhibitor
HR+HER2minusMBC
Heavily pretreatedRelapsed Met Cancer
16
12 (1 BC)
1 (312) 2 (212) 3+(7)
Abemaciclib 100 mg ranging up to 200 mg dose escalation
17 PR (included 1 BC)
17 Gr34 Neutropenia33 Gr34 Leucopenia
Peak sales est at $2B
Fujiwara Y Tamura K Kondo S Tanabe Y Iwasa S Shimomura A Kitano S Ogasawara K Turner PK Mori J Asou H Chan EM Yamamoto N Phase 1 study of abemaciclib an inhibitor of CDK 4 and 6 as a single agent for Japanese patients with advanced cancer Cancer Chemother Pharmacol 2016 Aug78(2)281-8 doi 101007s00280-016-3085-8 Epub 2016 Jun 16
Brian Metcalf PhD Recently retired as CSO from Global Blood Therapeutics Former Head of Research amp Development Incyte Corporation Former Head of Medicinal Chemistry SmithKline Beecham
Douglas Faller MD PhD Professor of Medicine Pediatrics Biochemistry Microbiology Pathology and
Laboratory Medicine HematologistOncologist former Director of the Cancer Center Boston University School of Medicine
Founder of several successful biotechnology companies
Robert Williams PhD University Distinguished Professor of Chemistry Colorado State University Founder of several successful biotechnology companies including Microcide Xcyte
Therapies HemaQuest Arch Therapeutics and Cetya Therapeutics
Thomas Kieber-Emmons PhD Deputy Director University of Arkansas Cancer Center Expert in targeted cancer immunotherapies structural biology and computational
chemistry
Maria Trojanowska PhD Professor of Medicine Boston University School of Medicine Director The Arthritis Center
16
Veteran Board of Directors
Board of Directors
Saeid Babaei PhD MBA Chairman Entrepreneur 20 yrs of biotech leadership roles Current CEO AbCelex VP Bus Develop Lorus Therap Dir of Corp Develop Northern Therapeutics
Rahoul Sharan CA Director Chairman Potash Ridge Director of the Board Ansell Capital Corp Parallel Resources amp Galaxy Capital
Corporation
Martin Schmieg CPA Director CFO Sirna Therapeutics Inc amp Isolagen Inc CEO Freedom-2 Inc (now PharmaCyte Inc) Advisor Caladrius Biosciences Inc Beckman Coulter Genomics Calimmune
Charles Wiseman MD Co-Founder amp Director Director Immunotherapy Lab St Vincent Medical Center Chief Breast Cancer Basic Research Lab Univ of Texas MD Anderson Hospital amp
Tumour Institute Assist Prof Dept of Molecular Carcinogenesis amp Virology MD Anderson Acting Chief Div of Oncology White Memorial Medical Center LA
William V Williams MD FACP President amp CEO VP Exploratory Development Incyte Corporation VP Experimental Medicine GlaxoSmithKline Head Rheumatology Research University of Pennsylvania
Prior Affiliations
17
Drug Approvals by BriaCell Management Team
Bexxarreg (tositumomab and Iodine I131 tositumomab) Treatment of CD20 antigen-expressing relapsed or refractory low grade follicular or transformed non-Hodgkins lymphoma
Myleranreg (busulfan) for chronic myelogenous leukemia Defense of formulation change sNDA
Hycamtinreg (topotecan) for ovarian cancer Pediatric use sNDA
Navelbinereg (vinorelbine tartrate) for non-small cell lung cancer Pediatric use sNDA
Bonivareg (ibandronate) monthly oral treatment of osteoporosis
Bonivareg (ibandronate) quarterly intraveous treatment of osteoporosis
Zofranreg (ondansetron) for prevention of nausea and vomiting Pediatric use sNDA
Jakafireg (ruxolitinib) for myelofibrosis Jakafireg (ruxolitinib) for polycythemia vera
Olumiantreg (baricitinib) for rheumatoid arthritis Approved in USA Japan and Europe
18
Share Metrics
BCTV BCTXF 19
Data as of 1092018
Ticker TSX BCTV
US Ticker OTCQBBCTXF
Share Price (CAD) as of Oct 9 2018 $012
52-Week Range (CAD) $009-019
Shares Outstanding as of Oct 9 2018 1611M
Market Cap as of Oct 9 2018 (CAD) $193M
Cash and Short Term Investments as of July 31 2018 (CAD) $23M
Total Shareholders Equity as of July 31 2018 (CAD) $12M
Number of Warrants $014-$035 (CAD) as of Oct 9 2018 601M
Number of Compensation Warrants $014-$030 (CAD) as of Oct 9 2018 45M
Number of Options $014- $026 (CAD$) as of Oct 9 2018 93M
Developing Bria-OTStrade the First Off-the-Shelf Personalized Immunotherapy
Targeting Adv Breast Cancer Unmet medical need (42000 death in the US in 2017 ) $1 Bil- $5 Bil market opportunity depending on patient treatment stage
Impressive results in 2 proof-of-concept clinical trials Rapid Response Rate Repeated following re-treatment Excellent Safety Profile
Completed enrollment in Phase IIIa clinical trial of Bria-IMTtrade with outstanding safety amp efficacy data Initiated Phase IIa Combination Study of Bria-IMTtrade with Keytrudareg (Merck amp Co Inc)
Developing Bria-OTStrade along with BriaDXtrade its companion diagnostic test Ability to match and treat ~90 of patient population with Off-the-Shelf personalized immunotherapy
Experienced Management has been involved in over 10 drug approvals
Patient B001 Breast 70 No 1101 - 3501 4001 Negative -
Bria-IMTtradeHuman Proof-of-Concept Trials in Breast Cancer (Patient A002)
24
Proof-of-Concept Results Resulted in BriaCellrsquos Immunotherapy Strategy Use BriaDXtrade diagnostic to select only those patients matching Bria-IMTtrade Use BriaDXtrade diagnostic test to select Bria-OTStrade alleles matching ~90 of all patients
Bria-IMTtradeCurrent Phase IIIa Data Supports HLA Matching Hypothesis Six patients treated in 2017 Bria-IMTtrade was safe and well tolerated
Patient 01-002 73-year-old woman with breast cancer diagnosed in 1995 Developed liver metastases in2010 and lung metastases in 2017 Previously treated with 7 rounds of chemotherapy with 8 differentchemotherapy agents Received 5 cycles of Bria-IMTtrade over 3 months then monthly cycles (6 months total)Evaluated after 3 months and 6 months After 3 months despite the extensive prior therapy her scans notedthat ldquothere has been a clear response in the multiple bilateral pulmonary nodulesrdquo The response wasmaintained after 6 months of Bria-IMTtrade treatment She matches Bria-IMTtrade at 2 HLA alleles
The liver tumors were stable to slightly increased at 3 months and then progressed after 6 months
This supports our hypothesis of heightened anti-tumor activity in patients with a matched HLA types Clear path to develop BriaDXtrade to select the patients using HLA testing
1 RLL 29 Not Detectable Not Detectable2 LUL apical pleural based 34 tiny nodule lt 1mm scar tiny nodule lt 1mm scar3 xxx 39 Not Detectable Not Detectable4 40 Not Detectable Not Detectable5 RLL 45 Not Detectable Not Detectable6 LLL 49 Not Detectable Not Detectable7 xxx 52 Not Detectable Not Detectable8 RLL 52 Not Detectable Not Detectable9 RLL 56 Not Detectable Not Detectable
10 RLL costophrenic recess 56 Not Detectable Not Detectable11 XXX 58 Not Detectable Not Detectable12 LUL 60 Not Detectable Not Detectable13 XXX 67 15 1514 RUL 72 15 1515 LLL 76 Not Detectable Not Detectable16 RUL Noncalcified Nodule 77 Not Detectable Not Detectable17 RLL costophrenic recess 79 10 1018 RUL 82 Not Detectable Not Detectable19 RLL 90 Not Detectable Not Detectable20 RLL 91 lt 01 lt 0121 xxx xxx Not Detectable Not Detectable
27
Clinical Development Update ndash Summary 2018 September 26
Completed enrollment of Adv Breast cancer patients in the Phase IIIa ldquomonotherapyrdquo study of Bria-IMTtrade
We have confirmed our mechanism of action and achieved proof of concept
Initial safety data appears superior to that of the other advanced or approved drugs for breast cancer when they were at a similar clinical stage of development
Initial efficacy data is similar or superior to those of other advanced or approved drugs for breast cancer when they were at a similar clinical stage of development
Initiated Combination Study of Bria-IMTtrade with Keytrudareg or Yervoyreg in Adv breast cancer patients expecting even better response rates than those in the ldquomonotherapyrdquo study Initial safety data is expected in 4Q2018 Initial efficacy data is expected in 1Q2019
Bria-OTStrade the first off-the-shelf personalized treatment for advanced breast cancer is expected to enter the clinic in 2019
28
Bria-IMTtrade Excellent Safety Data - To Date
To date Bria-IMTtrade has been dosed in 24 patients (4 in 2004-2005 20 in 2017-2018)
Interim Data (20 patients)-Ongoing Phase IIIa Study (2017-2018)
Bria-IMTtrade has been very well tolerated (ge60 doses given to date) The majority of adverse events (AEs) were limited to expected minor local irritation at the
injection sites No related grade gt3 or unexpected AEs No related serious AEs No serious unexpected related AEs Most patients who have dropped out did so due to worsening of their underlying disease
Based on the current study Bria-IMTtrade has an excellent safety profile
29
Bria-IMTtrade - Efficacy as Predicted
Interim Data (19 patients)-Ongoing Phase IIIa Study (2017-2018) amp Original Study (2004-2005)
PD-L1 expression on circulating cancer cells amp cancer-associated cells in 100 of patients (to date) Strong rationale for combination with checkpoint inhibitors like Keytruda
30
Bria-IMTtrade appears to be most effective in patients who match with Bria-IMT trade at 2 HLA loci (types) further supporting our ldquoHLA Matching Hypothesisrdquo and the development of Bria-OTS trade to cover 90 of the patient population
Combination with immune checkpoint inhibitors may induce a more potent anti-cancer response leading to our strategy of combination studies of Bria-IMT trade with Keytruda or Yervoy
Patients (n) HLA Match
Tumor Shrinkage
Biological Response
4 ge2 50 7515 ge1 27 334 0 0 0
Biological response includes tumor shrinkage or lower circulating cancer associated cells
The confirmatory Bria-IMTtrade monotherapy Phase IIa trial has completed enrollment Additional Support for the HLA-matching hypothesis has been obtained
Bria-IMTtrade Combination Therapy study with immune checkpoint inhibitors Keytrudareg if PD-L12 positive (ge1) Yervoyreg if PD-L12 negative (lt1) Accepting patients from the monotherapy study who develop progressive disease Also enrolling patients directly into this study to enhance experience with the combination In discussion with other pharmaceutical companies to evaluate additional combinations with other
immunotherapies
Bria-OTStrade Off-the-Shelf Personalized Targeted Immunotherapy Developing Bria-OTStrade to co-express GM-CSF and interferon-α Pre-manufacture additional HLA alleles ndash Total of 15 alleles (8 Class I and 7 Class II) Co-development of BriaDXtrade companion diagnostic for HLA typing Combination therapy clinical trial with immune checkpoint inhibitors for non-responders using
information from the Bria-IMTtrade Combination Therapy Study
33
Development Timeline ndash Breast Cancer
20192018 2020 2021
Phase IIIaBria-IMTtrade
Monotherapy
Currently Enrolling Phase IIaBria-IMTtrade + Checkpoint
Currently in discussions with potential partnersPhase II Bria-IMTtrade plus Additional Combinations (1Q19 4Q22)(eg PD-1 Inhibitor PD-L1 inhibitor anti-CTLA4 anti-GITR anti-OX40)
1Q 2Q 3Q 4Q
2023
Bria-OTStrade Off-The-Shelf Personalized ImmunotherapyMonotherapy and Potential Partnered Combo Therapy
(2H19 Ongoing)
Bria-OTStradeOff-the-Shelf Cell Line cGMP Manufacturing
and BriaDXtrade(1Q18 1Q19)
Registration Studies (1Q20 2H22)Bria-IMTtrade with Checkpoint InhibitorsBria-OTStrade +- Checkpoint Inhibitors
34
Immuno-oncology Deals
Recent deals of small biotechs with big pharma in immuno-oncology
35
Date PartnershipDevelopment stage at the time of the deal Deal size
07122018 Immatics-Genmab Preclinical Up to $28B
04042018 OSE Immunotherapeutics-Boehringer Ingelheim Preclinical Up to euro113B ($139B)
02092018 Pieris Pharmaceuticals-Seattle Genetics Preclinical Up to $123B
2142018 Nektar-BMS Ph III Up to $36B
01222018 Juno-Celgene Ph II $9B (Acquisition)
11142017 Loxo-Bayer Larotrectinib (Ph II) LOXO-195 (Ph III) Up to $155B
1032017 CytomX-Amgen Preclinical Up to $15B
03202017 CytomX--BMS Ph III Up to $36B
6282016 Xencor-Novartis Preclinical Up to $24B
Early Stage Clinical Studies (Comparison)
We compared the interim data of Ph IIIa study of Bria-IMTtrade in advanced breast cancer with thedata in the early stage clinical studies of recently approved breast cancer drugs and one fasttracked product candidate
Apples to apples comparison Early Stage Clinical Studies in oncology are typically done in patientswith no other therapeutic options Thus the patients have very advanced disease and response ratesare typically quite low
The patients in our Ph IIIa study have been heavily pre-treated (median 45 prior regimens)Some recent studies of relevance in breast cancer are noted in the following slides
36
Breast Cancer Market Opportunity
Drug Technology Approved for Market (US)Ibrance (palbociclib) CDK 46 Inhibitor HR+HER2- MBC in combination with
fluvestrant or aromatase inhibitor$933M in 1Q2018 $3126M in 2017
Kisqali (ribociclib) CDK 46 Inhibitor 2017 HR+HER2- MBC in combination with fluvestrant or aromatase inhibitor
Peak sales projected at $25B
Verzenio (abemaciclib) CDK 46 Inhibitor 2017 HR+HER2- MBC in combination with fluvestrant or aromatase inhibitor
balixafortide CXCR4 antagonist Fast track designation in 2018 for HER2- MBC who have failed 2 prior regimens
The market for breast cancer drugs is a multibillion dollar market with new drugs being approvedon an ongoing basis indicating the shortage of safe and effective treatments for this deadly disease
37
Competitors- Phase III Clinical Data Bria-IMTtrade shows superior safety and similar to superior efficacy data compared with those of the multi-billion dollar drugs when they were at a similar early stage of clinical development
Injection site reactions No related SAEs or SUSARs
Tumor vol darr ampor darr circul tumor cellsAll Comers 21(419) 26(519)One or More HLA matches 27(415) 33(515)Two or More HLA matches 50 (24) 75 (34)
Sheet1 (3)
Comp -Slides
Data
HLA (2)
HLA
Data (Ph1-2+4Pt)
Competitors (2018)-Slide
Competitors (2018)
In the Pipeline Protein Kinase C delta (PKCδ) Inhibitors
30 of all human malignancies display activating RAS mutations Another 60 showing over-activity of Ras-signaling pathways
Ras has been termed ldquoundruggablerdquo (no one has been able to make a Ras inhibitor drug)
BriaCellrsquos novel proprietary PKCδ inhibitors have shown activity against multiple RAS transformed tumors Lung cancer Melanoma Breast cancer Neuroendocrine cancer Pancreatic cancer Colorectal cancer
This target has an attractive safety profile based on in vivo studies and knock out mouse studies
PKCδ inhibitors should qualify for an accelerated clinical development plan and regulatory pathway
Could be in clinic within 24 months
Cost-Effective Additional Shot-on-Goal and additional partnership opportunities
Early-Stage Preclinical Program
39
Protein Kinase C delta (PKCδ) Inhibitors
Activated PKCδ inhibits RAS degradation which in turn stimulates tumor growth
Koo et al Oncotarget 621328 2016
30 of all human malignancies display activating RASmutations with another 60 showing over-activity of Ras-signaling pathways
BriaCellrsquos novel proprietary PKCδ inhibitors have shownactivity against multiple RAS transformed tumors
This target has an attractive safety profile based on in vivostudies and knock out mouse studies
PKCδ also has potential activity as an immunotherapeuticby blocking TGFβ signaling
PKCδ inhibitors are applicable to specific niche tumor typeswhich provide an accelerated clinical development plan
Structural aspects of first generation inhibitor rottlerin and staurosporine (pan-PKC activator) were combined to create second generation inhibitor KAM1
Third generation inhibitors such as BJE6-106 have improved potency and selectivity Fourth generation inhibitors under development to optimize drug-like characteristics PKCδ inhibitors lack endothelial cell cytotoxicity amp PKCδ deficient mice develop normally and are fertile Potentially no marked intrinsic toxicity by inhibiting PKCδ
Mukai H Saeki T Shimada K Naito Y Matsubara N Nakanishi T Obaishi H Namiki M Sasaki Y Phase 1 combination study of eribulin mesylate with trastuzumab for advanced or recurrent human epidermal growth factor receptor 2 positive breast cancer Invest New Drugs 2015 Feb33(1)119-27
AstraZeneca
Lynparza (Olaparib) + Cediranib
PARP inhibitor + inhibitor of VEGF receptor tyrosine kinases
HR+ HER2- MBC
BC amp OC
2013
28 (8 BC)
3 for BC
Olaparib (a poly (ADP-ribose) polymerase (PARP) inhibitor) amp Cediranib (Vascular endothelial growth factor receptor (VEGFR) 1 2 and 3 tyrosine kinase inhibitor)3 at dose level (DL) 0 (cediranib 20mg olaparib 100mg) 3 at DL1 (cediranib 20mg olaparib 200mg) 7 at DL2 (cediranib 30mg olaparib 200mg) 6 at DL3 (cediranib 30mg olaparib 400mg)
Liu JF Tolaney SM Birrer M Fleming GF Buss MK Dahlberg SE Lee H Whalen C Tyburski K Winer E Ivy P Matulonis UA A Phase 1 trial of the poly(ADP-ribose) polymerase inhibitor olaparib (AZD2281) in combination with the anti-angiogenic cediranib (AZD2171) in recurrent epithelial ovarian or triple-negative breast cancer Eur J Cancer 2013 Sep49(14)2972-8
Reyon Pharmaceutical
VM206RY
Heterologous prime-boost with a truncated HER2 sequence
HER2+ Stage IIIampIV BC
2015
9
2 chemo
Plasmid DNA (pHM-GM-CSF expressing truncated HER2 amp GM-CSF) amp adenoviral vector (Ad-HM containing modified HER2) (2 4 and 8 mgpatientvisit) of pHM-GM-CSF 3x IM weeks 0 2 and 4 Ad-HM 3 times 109 virus particles at week 6
11 PR
4 pts showed 7 minor AEs
Unclear
Kim SB Ahn JH Kim J Jung KH A phase 1 study of a heterologous prime-boost vaccination involving a truncated HER2 sequence in patients with HER2-expressing breast cancer Mol Ther Methods Clin Dev 2015 Sep 30215031 doi 101038mtm201531 eCollection 2015
Rodon J Peacuterez-Fidalgo A Krop IE Burris H Guerrero-Zotano A Britten CD Becerra C Schellens J Richards DA Schuler M Abu-Khalaf M Johnson FM Ranson M Edenfield J Silva AP Hackl W Quadt C Demanse D Duval V Baselga J Phase 11b dose escalation and expansion study of BEZ235 a dual PI3KmTOR inhibitor in patients with advanced solid tumors including patients with advanced breast cancer Cancer Chemother Pharmacol 2018 Jun 7 doi 101007s00280-018-3610-z [Epub ahead of print]
Celgene (Abraxane)
Gemcitabine + Abraxane (nab-paclitaxel)
Chemo + Chemo
OC BC NSCLC amp Panc cancer + Lung OC BC Kaposi sarcoma
MBC
2016
9
Adjuvant chemo (100)chemo post-adjuvant (33)
Gem (nucleoside metabolic inhibitor 1250 mgm2) on days 1 and 8 nab-Pac (microtubule inhibitor) starting dose of 180 mgm2 (cohort 1) 220 mgm2 (cohort 2) and 260 mgm2 (cohort 3) on day 1 of the 21-day cycle using a 3 + 3 design
0
MTD not reached29 Gr3 Neutropenia59 Gr1 Peripheralneuropathy
Yoshitomi S Taira N Doihara H Mizoo T Nogami T Iwamoto T Motoki T Shien T Ogasawara Y Matsuoka J Tsuji H Mitsuhashi T A phase 1 dose-finding and pharmacokinetic study of gemcitabine with nab-paclitaxel in patients with metastatic breast cancer Cancer Chemother Pharmacol 2016 Aug78(2)289-94
Eli Lilly
Erbituxreg (cetuximab) + Taxane
EGFR inhibitor antineoplastic agent + Chemo
Headamp Neck Colorectal Cancer
TNBC
2007-2010
18
1 chemo
Cetuximab (epidermal growth factor receptor (EGFR) antagonist ) an initial loading dose of cetuximab 400 mgm2 followed by a weekly dose of 250 mgm2Paclitaxel (microtubule inhibitor) 80 mgm2 or Docetaxel at an initial dose of 30 mgm2 was administered weekly
56 CR 22 PR
83 Dermatologic toxicity11 Grade3+
Nechushtan H Vainer G Stainberg H Salmon AY Hamburger T Peretz T A phase 12 of a combination of cetuximab and taxane for triple negative breast cancer patients Breast 2014 Aug23(4)435-8
Polyphor
Balixafortide (POL6326) + eribulin
CXCR4 antagonist + tubulin-based antimitotic
Heavily pretreated Relapsed MBC
2014-2016
56
3rd line 3 chemo
3+3 dose escalation The highest dose was established as eribulin 14 mgmsup2 on days 2 and 9 and balixafortide 55 mgkg on days 1minus3 and 8minus10 of the 21-day cycle
30 PR
41 Gr34 Neutropenia11 Gr34 Leucopenia11 Gr34 Febrileneutropenia2 Related mortalities
Apr 2018 Fast Track for HER2-MBC who have failed 2prior regimens
Pernas S Martin M Kaufman PA Gil-Martin M Gomez Pardo P Lopez-Tarruella S Manso L Ciruelos E Perez-Fidalgo JA Hernando C Ademuyiwa FO Weilbaecher K Mayer I Pluard TJ Martinez Garcia M Vahdat L Perez-Garcia J Wach A Barker D Fung S Romagnoli B Cortes J Balixafortide plus eribulin in HER2-negative metastatic breast cancer a phase 1 single-arm dose-escalation trial Lancet Oncol 2018 Jun19(6)812-824
11 PRndashbut only + letrozole (No Resp on monotherapy)
61 Gr34 Neutropenia39 Gr34 Leucopenia
$933M in 1Q2018 $31B in 2017
Tamura K Mukai H Naito Y Yonemori K Kodaira M Tanabe Y Yamamoto N Osera S Sasaki M Mori Y Hashigaki S Nagasawa T Umeyama Y Yoshino T Phase I study of palbociclib a cyclin-dependent kinase 46 inhibitor in Japanese patients Cancer Sci 2016 Jun107(6)755-63 doi 101111cas12932 Epub 2016 May 11
Pfizer
Ibrancereg (palbociclib)
CDK 46 Inhibitor
HR+ HER2- MBC
Heavily pretreated Relapsed Metastatic Cancer
2004-2008
41 (5 BC)
chemo naiumlve (17) 1-2 (51)3 (29) 3+ (2)
Palbociclib 25-150 mg dose ranging
0
20 Gr34 Neutropenia23 Gr34 Leucopenia
$933M in 1Q2018 $31B in 2017
Flaherty KT Lorusso PM Demichele A Abramson VG Courtney R Randolph SS Shaik MN Wilner KD ODwyer PJ Schwartz GK Phase I dose-escalation trial of the oral cyclin-dependent kinase 46 inhibitor PD 0332991 administered using a 21-day schedule in patients with advanced cancer Clin Cancer Res 2012 Jan 1518(2)568-76 doi 1011581078-0432CCR-11-0509 Epub 2011 Nov 16
Novartis
Kisqalireg (ribociclib)
CDK 46 Inhibitors
Premenopausal HR+ HER2- MBC
Heavily pretreated Relapsed Metastatic Cancer
2016
132 (20 BC)
0-1 (25) 2-3 (42) 4+ (32)
Ribociclib 50 mg ranging up to 1200 mg dose escalation
23 PRndashincluded 1 in BC (5 of BC pts)
27 Gr34 Neutropenia17 Gr34 Leucopenia
Peak sales projected at $25B
Infante JR Cassier PA Gerecitano JF Witteveen PO Chugh R Ribrag V Chakraborty A Matano A Dobson JR Crystal AS Parasuraman S Shapiro GI A Phase I Study of the Cyclin-Dependent Kinase 46 Inhibitor Ribociclib (LEE011) in Patients with Advanced Solid Tumors and Lymphomas Clin Cancer Res 2016 Dec 122(23)5696-5705 Epub 2016 Aug 19
Eli Lilly
Verzenioreg (abemaciclib)
CDK 46 Inhibitors
HR+HER2minusMBC
Heavily pretreated Relapsed Metastatic Cancer
2016
12 (1 BC)
1 (312) 2 (212) 3+ (7)
Abemaciclib 100 mg ranging up to 200 mg dose escalation
17 PR (included 1 in BC)
17 Gr34 Neutropenia33 Gr34 Leucopenia
Peak sales projected at $2B
Fujiwara Y Tamura K Kondo S Tanabe Y Iwasa S Shimomura A Kitano S Ogasawara K Turner PK Mori J Asou H Chan EM Yamamoto N Phase 1 study of abemaciclib an inhibitor of CDK 4 and 6 as a single agent for Japanese patients with advanced cancer Cancer Chemother Pharmacol 2016 Aug78(2)281-8 doi 101007s00280-016-3085-8 Epub 2016 Jun 16
Mukai H Saeki T Shimada K Naito Y Matsubara N Nakanishi T Obaishi H Namiki M Sasaki Y Phase 1 combination study of eribulin mesylate with trastuzumab for advanced or recurrent human epidermal growth factor receptor 2 positive breast cancer Invest New Drugs 2015 Feb33(1)119-27
AstraZeneca
Lynparza (Olaparib)+ Cediranib
PARP inhibitor+ inhibitor of VEGF RTK
HR+ HER2- MBC
BC amp OC
13
28 (8 BC)
3 for BC
Olaparib (a poly (ADP-ribose) polymerase (PARP) inhibitor) amp Cediranib (Vascular endothelial growth factor receptor (VEGFR) 1 2 and 3 tyrosine kinase inhibitor)3 at dose level (DL) 0 (cediranib 20mg olaparib 100mg) 3 at DL1 (cediranib 20mg olaparib 200mg) 7 at DL2 (cediranib 30mg olaparib 200mg) 6 at DL3 (cediranib 30mg olaparib 400mg)
Liu JF Tolaney SM Birrer M Fleming GF Buss MK Dahlberg SE Lee H Whalen C Tyburski K Winer E Ivy P Matulonis UA A Phase 1 trial of the poly(ADP-ribose) polymerase inhibitor olaparib (AZD2281) in combination with the anti-angiogenic cediranib (AZD2171) in recurrent epithelial ovarian or triple-negative breast cancer Eur J Cancer 2013 Sep49(14)2972-8
ReyonPharma
VM206RY
Heterologous prime-boost with a truncated HER2 sequence
HER2+ Stg IIIampIV BC
15
9
2 chemo
Plasmid DNA (pHM-GM-CSF expressing truncated HER2 amp GM-CSF) amp adenoviral vector (Ad-HM containing modified HER2) (2 4 and 8 mgpatientvisit) of pHM-GM-CSF 3x IM weeks 0 2 and 4 Ad-HM 3 times 109 virus particles at week 6
11 PR
4 pts 7 minor AEs
Unclear
Kim SB Ahn JH Kim J Jung KH A phase 1 study of a heterologous prime-boost vaccination involving a truncated HER2 sequence in patients with HER2-expressing breast cancer Mol Ther Methods Clin Dev 2015 Sep 30215031 doi 101038mtm201531 eCollection 2015
Rodon J Peacuterez-Fidalgo A Krop IE Burris H Guerrero-Zotano A Britten CD Becerra C Schellens J Richards DA Schuler M Abu-Khalaf M Johnson FM Ranson M Edenfield J Silva AP Hackl W Quadt C Demanse D Duval V Baselga J Phase 11b dose escalation and expansion study of BEZ235 a dual PI3KmTOR inhibitor in patients with advanced solid tumors including patients with advanced breast cancer Cancer Chemother Pharmacol 2018 Jun 7 doi 101007s00280-018-3610-z [Epub ahead of print]
Celgene(Abraxane)
Gemcitabine + Abraxane (nab-paclitaxel)
Chemo+ Chemo
OC BC NSCLC PC + LC OC BC KS
MBC
16
9
Adjuv chemo (100)chemo post-adjuv (33)
Gem (nucleoside metabolic inhibitor 1250 mgm2) on days 1 and 8 nab-Pac (microtubule inhibitor) starting dose of 180 mgm2 (cohort 1) 220 mgm2 (cohort 2) and 260 mgm2 (cohort 3) on day 1 of the 21-day cycle using a 3 + 3 design
0
MTD not reached29 Gr3 Neutropenia59 Gr1 Peripheralneuropathy
Yoshitomi S Taira N Doihara H Mizoo T Nogami T Iwamoto T Motoki T Shien T Ogasawara Y Matsuoka J Tsuji H Mitsuhashi T A phase 1 dose-finding and pharmacokinetic study of gemcitabine with nab-paclitaxel in patients with metastatic breast cancer Cancer Chemother Pharmacol 2016 Aug78(2)289-94
Eli Lilly
Erbituxreg (cetuximab) + Taxane
EGFR inhibitor antineoplastic agent + Chemo
Head amp NeckColorectal
TNBC
07-10
18
1 chemo
Cetuximab (epidermal growth factor receptor (EGFR) antagonist ) an initial loading dose of cetuximab 400 mgm2 followed by a weekly dose of 250 mgm2Paclitaxel (microtubule inhibitor) 80 mgm2 or Docetaxel at an initial dose of 30 mgm2 was administered weekly
56 CR 22 PR
83 Dermatologic toxicity11 Grade3+
Nechushtan H Vainer G Stainberg H Salmon AY Hamburger T Peretz T A phase 12 of a combination of cetuximab and taxane for triple negative breast cancer patients Breast 2014 Aug23(4)435-8
Polyphor
Balixafortide (POL6326) + eribulin
CXCR4 antagonist + tubulin-based antimitotic
Heavily pretreatedRelapsed MBC
14-16
56
3rd line 3 chemo
3+3 dose escalation The highest dose was established as eribulin 14 mgmsup2 on days 2 and 9 and balixafortide 55 mgkg on days 1minus3 and 8minus10 of the 21-day cycle
30 PR
41 Gr34 Neutropenia11 Gr34 Leucopenia11 Gr34 Febrileneutropenia2 Related mortalities
42018 Fast Track (HER2-MBC failed 2 prior regimens)
Pernas S Martin M Kaufman PA Gil-Martin M Gomez Pardo P Lopez-Tarruella S Manso L Ciruelos E Perez-Fidalgo JA Hernando C Ademuyiwa FO Weilbaecher K Mayer I Pluard TJ Martinez Garcia M Vahdat L Perez-Garcia J Wach A Barker D Fung S Romagnoli B Cortes J Balixafortide plus eribulin in HER2-negative metastatic breast cancer a phase 1 single-arm dose-escalation trial Lancet Oncol 2018 Jun19(6)812-824
1 PRndashbut only + letrozoleNo Resp on monotherapy
61 Gr34 Neutropenia39 Gr34 Leucopenia
$933M (1Q18)$31B (2017)
Tamura K Mukai H Naito Y Yonemori K Kodaira M Tanabe Y Yamamoto N Osera S Sasaki M Mori Y Hashigaki S Nagasawa T Umeyama Y Yoshino T Phase I study of palbociclib a cyclin-dependent kinase 46 inhibitor in Japanese patients Cancer Sci 2016 Jun107(6)755-63 doi 101111cas12932 Epub 2016 May 11
Pfizer
Ibrancereg (palbociclib)
CDK 46 Inhibitor
HR+ HER2- MBC
Heavily pretreatedRelapsed Met Cancer
04-08
41 (5 BC)
chemo naiumlve (17)1-2(51) 3(29) 3+(2)
Palbociclib 25-150 mg dose ranging
0
20 Gr34 Neutropenia23 Gr34 Leucopenia
$933M (1Q18)$31B (2017)
Flaherty KT Lorusso PM Demichele A Abramson VG Courtney R Randolph SS Shaik MN Wilner KD ODwyer PJ Schwartz GK Phase I dose-escalation trial of the oral cyclin-dependent kinase 46 inhibitor PD 0332991 administered using a 21-day schedule in patients with advanced cancer Clin Cancer Res 2012 Jan 1518(2)568-76 doi 1011581078-0432CCR-11-0509 Epub 2011 Nov 16
Novartis
Kisqalireg (ribociclib)
CDK 46 Inhibitor
Premenopausal HR+ HER2- MBC
Heavily pretreatedRelapsed Met Cancer
16
132 (20 BC)
0-1 (25) 2-3 (42)4+ (32)
Ribociclib 50 mg ranging up to 1200 mg dose escalation
23 PR-included 1 BC (5 of BC pts)
27 Gr34 Neutropenia17 Gr34 Leucopenia
Peak sales est at $25B
Infante JR Cassier PA Gerecitano JF Witteveen PO Chugh R Ribrag V Chakraborty A Matano A Dobson JR Crystal AS Parasuraman S Shapiro GI A Phase I Study of the Cyclin-Dependent Kinase 46 Inhibitor Ribociclib (LEE011) in Patients with Advanced Solid Tumors and Lymphomas Clin Cancer Res 2016 Dec 122(23)5696-5705 Epub 2016 Aug 19
Eli Lilly
Verzenioreg (abemaciclib)
CDK 46 Inhibitor
HR+HER2minusMBC
Heavily pretreatedRelapsed Met Cancer
16
12 (1 BC)
1 (312) 2 (212) 3+(7)
Abemaciclib 100 mg ranging up to 200 mg dose escalation
17 PR (included 1 BC)
17 Gr34 Neutropenia33 Gr34 Leucopenia
Peak sales est at $2B
Fujiwara Y Tamura K Kondo S Tanabe Y Iwasa S Shimomura A Kitano S Ogasawara K Turner PK Mori J Asou H Chan EM Yamamoto N Phase 1 study of abemaciclib an inhibitor of CDK 4 and 6 as a single agent for Japanese patients with advanced cancer Cancer Chemother Pharmacol 2016 Aug78(2)281-8 doi 101007s00280-016-3085-8 Epub 2016 Jun 16
Mukai H Saeki T Shimada K Naito Y Matsubara N Nakanishi T Obaishi H Namiki M Sasaki Y Phase 1 combination study of eribulin mesylate with trastuzumab for advanced or recurrent human epidermal growth factor receptor 2 positive breast cancer Invest New Drugs 2015 Feb33(1)119-27
AstraZeneca
Lynparza (Olaparib) + Cediranib
PARP inhibitor + inhibitor of VEGF receptor tyrosine kinases
HR+ HER2- MBC
BC amp OC
2013
28 (8 BC)
3 for BC
Olaparib (a poly (ADP-ribose) polymerase (PARP) inhibitor) amp Cediranib (Vascular endothelial growth factor receptor (VEGFR) 1 2 and 3 tyrosine kinase inhibitor)3 at dose level (DL) 0 (cediranib 20mg olaparib 100mg) 3 at DL1 (cediranib 20mg olaparib 200mg) 7 at DL2 (cediranib 30mg olaparib 200mg) 6 at DL3 (cediranib 30mg olaparib 400mg)
Liu JF Tolaney SM Birrer M Fleming GF Buss MK Dahlberg SE Lee H Whalen C Tyburski K Winer E Ivy P Matulonis UA A Phase 1 trial of the poly(ADP-ribose) polymerase inhibitor olaparib (AZD2281) in combination with the anti-angiogenic cediranib (AZD2171) in recurrent epithelial ovarian or triple-negative breast cancer Eur J Cancer 2013 Sep49(14)2972-8
Reyon Pharmaceutical
VM206RY
Heterologous prime-boost with a truncated HER2 sequence
HER2+ Stage IIIampIV BC
2015
9
2 chemo
Plasmid DNA (pHM-GM-CSF expressing truncated HER2 amp GM-CSF) amp adenoviral vector (Ad-HM containing modified HER2) (2 4 and 8 mgpatientvisit) of pHM-GM-CSF 3x IM weeks 0 2 and 4 Ad-HM 3 times 109 virus particles at week 6
11 PR
4 pts showed 7 minor AEs
Unclear
Kim SB Ahn JH Kim J Jung KH A phase 1 study of a heterologous prime-boost vaccination involving a truncated HER2 sequence in patients with HER2-expressing breast cancer Mol Ther Methods Clin Dev 2015 Sep 30215031 doi 101038mtm201531 eCollection 2015
Rodon J Peacuterez-Fidalgo A Krop IE Burris H Guerrero-Zotano A Britten CD Becerra C Schellens J Richards DA Schuler M Abu-Khalaf M Johnson FM Ranson M Edenfield J Silva AP Hackl W Quadt C Demanse D Duval V Baselga J Phase 11b dose escalation and expansion study of BEZ235 a dual PI3KmTOR inhibitor in patients with advanced solid tumors including patients with advanced breast cancer Cancer Chemother Pharmacol 2018 Jun 7 doi 101007s00280-018-3610-z [Epub ahead of print]
Celgene (Abraxane)
Gemcitabine + Abraxane (nab-paclitaxel)
Chemo + Chemo
OC BC NSCLC amp Panc cancer + Lung OC BC Kaposi sarcoma
MBC
2016
9
Adjuvant chemo (100)chemo post-adjuvant (33)
Gem (nucleoside metabolic inhibitor 1250 mgm2) on days 1 and 8 nab-Pac (microtubule inhibitor) starting dose of 180 mgm2 (cohort 1) 220 mgm2 (cohort 2) and 260 mgm2 (cohort 3) on day 1 of the 21-day cycle using a 3 + 3 design
0
MTD not reached29 Gr3 Neutropenia59 Gr1 Peripheralneuropathy
Yoshitomi S Taira N Doihara H Mizoo T Nogami T Iwamoto T Motoki T Shien T Ogasawara Y Matsuoka J Tsuji H Mitsuhashi T A phase 1 dose-finding and pharmacokinetic study of gemcitabine with nab-paclitaxel in patients with metastatic breast cancer Cancer Chemother Pharmacol 2016 Aug78(2)289-94
Eli Lilly
Erbituxreg (cetuximab) + Taxane
EGFR inhibitor antineoplastic agent + Chemo
Headamp Neck Colorectal Cancer
TNBC
2007-2010
18
1 chemo
Cetuximab (epidermal growth factor receptor (EGFR) antagonist ) an initial loading dose of cetuximab 400 mgm2 followed by a weekly dose of 250 mgm2Paclitaxel (microtubule inhibitor) 80 mgm2 or Docetaxel at an initial dose of 30 mgm2 was administered weekly
56 CR 22 PR
83 Dermatologic toxicity11 Grade3+
Nechushtan H Vainer G Stainberg H Salmon AY Hamburger T Peretz T A phase 12 of a combination of cetuximab and taxane for triple negative breast cancer patients Breast 2014 Aug23(4)435-8
Polyphor
Balixafortide (POL6326) + eribulin
CXCR4 antagonist + tubulin-based antimitotic
Heavily pretreated Relapsed MBC
2014-2016
56
3rd line 3 chemo
3+3 dose escalation The highest dose was established as eribulin 14 mgmsup2 on days 2 and 9 and balixafortide 55 mgkg on days 1minus3 and 8minus10 of the 21-day cycle
30 PR
41 Gr34 Neutropenia11 Gr34 Leucopenia11 Gr34 Febrileneutropenia2 Related mortalities
Apr 2018 Fast Track for HER2-MBC who have failed 2prior regimens
Pernas S Martin M Kaufman PA Gil-Martin M Gomez Pardo P Lopez-Tarruella S Manso L Ciruelos E Perez-Fidalgo JA Hernando C Ademuyiwa FO Weilbaecher K Mayer I Pluard TJ Martinez Garcia M Vahdat L Perez-Garcia J Wach A Barker D Fung S Romagnoli B Cortes J Balixafortide plus eribulin in HER2-negative metastatic breast cancer a phase 1 single-arm dose-escalation trial Lancet Oncol 2018 Jun19(6)812-824
11 PRndashbut only + letrozole (No Resp on monotherapy)
61 Gr34 Neutropenia39 Gr34 Leucopenia
$933M in 1Q2018 $31B in 2017
Tamura K Mukai H Naito Y Yonemori K Kodaira M Tanabe Y Yamamoto N Osera S Sasaki M Mori Y Hashigaki S Nagasawa T Umeyama Y Yoshino T Phase I study of palbociclib a cyclin-dependent kinase 46 inhibitor in Japanese patients Cancer Sci 2016 Jun107(6)755-63 doi 101111cas12932 Epub 2016 May 11
Pfizer
Ibrancereg (palbociclib)
CDK 46 Inhibitor
HR+ HER2- MBC
Heavily pretreated Relapsed Metastatic Cancer
2004-2008
41 (5 BC)
chemo naiumlve (17) 1-2 (51)3 (29) 3+ (2)
Palbociclib 25-150 mg dose ranging
0
20 Gr34 Neutropenia23 Gr34 Leucopenia
$933M in 1Q2018 $31B in 2017
Flaherty KT Lorusso PM Demichele A Abramson VG Courtney R Randolph SS Shaik MN Wilner KD ODwyer PJ Schwartz GK Phase I dose-escalation trial of the oral cyclin-dependent kinase 46 inhibitor PD 0332991 administered using a 21-day schedule in patients with advanced cancer Clin Cancer Res 2012 Jan 1518(2)568-76 doi 1011581078-0432CCR-11-0509 Epub 2011 Nov 16
Novartis
Kisqalireg (ribociclib)
CDK 46 Inhibitors
Premenopausal HR+ HER2- MBC
Heavily pretreated Relapsed Metastatic Cancer
2016
132 (20 BC)
0-1 (25) 2-3 (42) 4+ (32)
Ribociclib 50 mg ranging up to 1200 mg dose escalation
23 PRndashincluded 1 in BC (5 of BC pts)
27 Gr34 Neutropenia17 Gr34 Leucopenia
Peak sales projected at $25B
Infante JR Cassier PA Gerecitano JF Witteveen PO Chugh R Ribrag V Chakraborty A Matano A Dobson JR Crystal AS Parasuraman S Shapiro GI A Phase I Study of the Cyclin-Dependent Kinase 46 Inhibitor Ribociclib (LEE011) in Patients with Advanced Solid Tumors and Lymphomas Clin Cancer Res 2016 Dec 122(23)5696-5705 Epub 2016 Aug 19
Eli Lilly
Verzenioreg (abemaciclib)
CDK 46 Inhibitors
HR+HER2minusMBC
Heavily pretreated Relapsed Metastatic Cancer
2016
12 (1 BC)
1 (312) 2 (212) 3+ (7)
Abemaciclib 100 mg ranging up to 200 mg dose escalation
17 PR (included 1 in BC)
17 Gr34 Neutropenia33 Gr34 Leucopenia
Peak sales projected at $2B
Fujiwara Y Tamura K Kondo S Tanabe Y Iwasa S Shimomura A Kitano S Ogasawara K Turner PK Mori J Asou H Chan EM Yamamoto N Phase 1 study of abemaciclib an inhibitor of CDK 4 and 6 as a single agent for Japanese patients with advanced cancer Cancer Chemother Pharmacol 2016 Aug78(2)281-8 doi 101007s00280-016-3085-8 Epub 2016 Jun 16
Mukai H Saeki T Shimada K Naito Y Matsubara N Nakanishi T Obaishi H Namiki M Sasaki Y Phase 1 combination study of eribulin mesylate with trastuzumab for advanced or recurrent human epidermal growth factor receptor 2 positive breast cancer Invest New Drugs 2015 Feb33(1)119-27
AstraZeneca
Lynparza (Olaparib)+ Cediranib
PARP inhibitor+ inhibitor of VEGF RTK
HR+ HER2- MBC
BC amp OC
13
28 (8 BC)
3 for BC
Olaparib (a poly (ADP-ribose) polymerase (PARP) inhibitor) amp Cediranib (Vascular endothelial growth factor receptor (VEGFR) 1 2 and 3 tyrosine kinase inhibitor)3 at dose level (DL) 0 (cediranib 20mg olaparib 100mg) 3 at DL1 (cediranib 20mg olaparib 200mg) 7 at DL2 (cediranib 30mg olaparib 200mg) 6 at DL3 (cediranib 30mg olaparib 400mg)
Liu JF Tolaney SM Birrer M Fleming GF Buss MK Dahlberg SE Lee H Whalen C Tyburski K Winer E Ivy P Matulonis UA A Phase 1 trial of the poly(ADP-ribose) polymerase inhibitor olaparib (AZD2281) in combination with the anti-angiogenic cediranib (AZD2171) in recurrent epithelial ovarian or triple-negative breast cancer Eur J Cancer 2013 Sep49(14)2972-8
ReyonPharma
VM206RY
Heterologous prime-boost with a truncated HER2 sequence
HER2+ Stg IIIampIV BC
15
9
2 chemo
Plasmid DNA (pHM-GM-CSF expressing truncated HER2 amp GM-CSF) amp adenoviral vector (Ad-HM containing modified HER2) (2 4 and 8 mgpatientvisit) of pHM-GM-CSF 3x IM weeks 0 2 and 4 Ad-HM 3 times 109 virus particles at week 6
11 PR
4 pts 7 minor AEs
Unclear
Kim SB Ahn JH Kim J Jung KH A phase 1 study of a heterologous prime-boost vaccination involving a truncated HER2 sequence in patients with HER2-expressing breast cancer Mol Ther Methods Clin Dev 2015 Sep 30215031 doi 101038mtm201531 eCollection 2015
Rodon J Peacuterez-Fidalgo A Krop IE Burris H Guerrero-Zotano A Britten CD Becerra C Schellens J Richards DA Schuler M Abu-Khalaf M Johnson FM Ranson M Edenfield J Silva AP Hackl W Quadt C Demanse D Duval V Baselga J Phase 11b dose escalation and expansion study of BEZ235 a dual PI3KmTOR inhibitor in patients with advanced solid tumors including patients with advanced breast cancer Cancer Chemother Pharmacol 2018 Jun 7 doi 101007s00280-018-3610-z [Epub ahead of print]
Celgene(Abraxane)
Gemcitabine + Abraxane (nab-paclitaxel)
Chemo+ Chemo
OC BC NSCLC PC + LC OC BC KS
MBC
16
9
Adjuv chemo (100)chemo post-adjuv (33)
Gem (nucleoside metabolic inhibitor 1250 mgm2) on days 1 and 8 nab-Pac (microtubule inhibitor) starting dose of 180 mgm2 (cohort 1) 220 mgm2 (cohort 2) and 260 mgm2 (cohort 3) on day 1 of the 21-day cycle using a 3 + 3 design
0
MTD not reached29 Gr3 Neutropenia59 Gr1 Peripheralneuropathy
Yoshitomi S Taira N Doihara H Mizoo T Nogami T Iwamoto T Motoki T Shien T Ogasawara Y Matsuoka J Tsuji H Mitsuhashi T A phase 1 dose-finding and pharmacokinetic study of gemcitabine with nab-paclitaxel in patients with metastatic breast cancer Cancer Chemother Pharmacol 2016 Aug78(2)289-94
Eli Lilly
Erbituxreg (cetuximab) + Taxane
EGFR inhibitor antineoplastic agent + Chemo
Head amp NeckColorectal
TNBC
07-10
18
1 chemo
Cetuximab (epidermal growth factor receptor (EGFR) antagonist ) an initial loading dose of cetuximab 400 mgm2 followed by a weekly dose of 250 mgm2Paclitaxel (microtubule inhibitor) 80 mgm2 or Docetaxel at an initial dose of 30 mgm2 was administered weekly
56 CR 22 PR
83 Dermatologic toxicity11 Grade3+
Nechushtan H Vainer G Stainberg H Salmon AY Hamburger T Peretz T A phase 12 of a combination of cetuximab and taxane for triple negative breast cancer patients Breast 2014 Aug23(4)435-8
Polyphor
Balixafortide (POL6326) + eribulin
CXCR4 antagonist + tubulin-based antimitotic
Heavily pretreatedRelapsed MBC
14-16
56
3rd line 3 chemo
3+3 dose escalation The highest dose was established as eribulin 14 mgmsup2 on days 2 and 9 and balixafortide 55 mgkg on days 1minus3 and 8minus10 of the 21-day cycle
30 PR
41 Gr34 Neutropenia11 Gr34 Leucopenia11 Gr34 Febrileneutropenia2 Related mortalities
42018 Fast Track (HER2-MBC failed 2 prior regimens)
Pernas S Martin M Kaufman PA Gil-Martin M Gomez Pardo P Lopez-Tarruella S Manso L Ciruelos E Perez-Fidalgo JA Hernando C Ademuyiwa FO Weilbaecher K Mayer I Pluard TJ Martinez Garcia M Vahdat L Perez-Garcia J Wach A Barker D Fung S Romagnoli B Cortes J Balixafortide plus eribulin in HER2-negative metastatic breast cancer a phase 1 single-arm dose-escalation trial Lancet Oncol 2018 Jun19(6)812-824
1 PRndashbut only + letrozoleNo Resp on monotherapy
61 Gr34 Neutropenia39 Gr34 Leucopenia
$933M (1Q18)$31B (2017)
Tamura K Mukai H Naito Y Yonemori K Kodaira M Tanabe Y Yamamoto N Osera S Sasaki M Mori Y Hashigaki S Nagasawa T Umeyama Y Yoshino T Phase I study of palbociclib a cyclin-dependent kinase 46 inhibitor in Japanese patients Cancer Sci 2016 Jun107(6)755-63 doi 101111cas12932 Epub 2016 May 11
Pfizer
Ibrancereg (palbociclib)
CDK 46 Inhibitor
HR+ HER2- MBC
Heavily pretreatedRelapsed Met Cancer
04-08
41 (5 BC)
chemo naiumlve (17)1-2(51) 3(29) 3+(2)
Palbociclib 25-150 mg dose ranging
0
20 Gr34 Neutropenia23 Gr34 Leucopenia
$933M (1Q18)$31B (2017)
Flaherty KT Lorusso PM Demichele A Abramson VG Courtney R Randolph SS Shaik MN Wilner KD ODwyer PJ Schwartz GK Phase I dose-escalation trial of the oral cyclin-dependent kinase 46 inhibitor PD 0332991 administered using a 21-day schedule in patients with advanced cancer Clin Cancer Res 2012 Jan 1518(2)568-76 doi 1011581078-0432CCR-11-0509 Epub 2011 Nov 16
Novartis
Kisqalireg (ribociclib)
CDK 46 Inhibitor
Premenopausal HR+ HER2- MBC
Heavily pretreatedRelapsed Met Cancer
16
132 (20 BC)
0-1 (25) 2-3 (42)4+ (32)
Ribociclib 50 mg ranging up to 1200 mg dose escalation
23 PR-included 1 BC (5 of BC pts)
27 Gr34 Neutropenia17 Gr34 Leucopenia
Peak sales est at $25B
Infante JR Cassier PA Gerecitano JF Witteveen PO Chugh R Ribrag V Chakraborty A Matano A Dobson JR Crystal AS Parasuraman S Shapiro GI A Phase I Study of the Cyclin-Dependent Kinase 46 Inhibitor Ribociclib (LEE011) in Patients with Advanced Solid Tumors and Lymphomas Clin Cancer Res 2016 Dec 122(23)5696-5705 Epub 2016 Aug 19
Eli Lilly
Verzenioreg (abemaciclib)
CDK 46 Inhibitor
HR+HER2minusMBC
Heavily pretreatedRelapsed Met Cancer
16
12 (1 BC)
1 (312) 2 (212) 3+(7)
Abemaciclib 100 mg ranging up to 200 mg dose escalation
17 PR (included 1 BC)
17 Gr34 Neutropenia33 Gr34 Leucopenia
Peak sales est at $2B
Fujiwara Y Tamura K Kondo S Tanabe Y Iwasa S Shimomura A Kitano S Ogasawara K Turner PK Mori J Asou H Chan EM Yamamoto N Phase 1 study of abemaciclib an inhibitor of CDK 4 and 6 as a single agent for Japanese patients with advanced cancer Cancer Chemother Pharmacol 2016 Aug78(2)281-8 doi 101007s00280-016-3085-8 Epub 2016 Jun 16
41 Gr34 Neutropenia11 Gr34 Leucopenia11 Gr34 Febrileneutropenia2 Related mortalities
30 PRs in combination with Halaven
Bria-IMTTM
20
Injection site reactions No related SAEs or SUSARs
Tumor vol darr ampor darr circul tumor cells)All Comers 21(419) 26(519)One or More HLA matches 27(415) 33(515)Two or More HLA matches 50 (24) 75 (34))
Drug
Technology
Approved for
Market (US)
Ibrance (palbociclib)
CDK 46 Inhibitor
HR+HER2- MBC in combination with fluvestrant or aromatase inhibitor
$933M in 1Q2018 $3126M in 2017
Kisqali (ribociclib)
CDK 46 Inhibitor
2017 HR+HER2- MBC in combination with fluvestrant or aromatase inhibitor
Peak sales projected at $25B
Verzenio (abemaciclib)
CDK 46 Inhibitor
2017 HR+HER2- MBC in combination with fluvestrant or aromatase inhibitor
Peak sales projected at $2B
Lynparza (olaparib)
Poly (ADP-ribose) polymerase (PARP) inhibitor
2017 ovarian amp breast cancer
$997M in 2017
Halaven (eribulin mesylate)
Tubulin-based antimitotic
2H2017 3rd line MBC amp liposarcoma
$181M in 2017
balixafortide
CXCR4 antagonist
Fast track designation in 2018 for HER2- MBC who have failed 2 prior regimens
Veteran Board of Directors
Board of Directors
Saeid Babaei PhD MBA Chairman Entrepreneur 20 yrs of biotech leadership roles Current CEO AbCelex VP Bus Develop Lorus Therap Dir of Corp Develop Northern Therapeutics
Rahoul Sharan CA Director Chairman Potash Ridge Director of the Board Ansell Capital Corp Parallel Resources amp Galaxy Capital
Corporation
Martin Schmieg CPA Director CFO Sirna Therapeutics Inc amp Isolagen Inc CEO Freedom-2 Inc (now PharmaCyte Inc) Advisor Caladrius Biosciences Inc Beckman Coulter Genomics Calimmune
Charles Wiseman MD Co-Founder amp Director Director Immunotherapy Lab St Vincent Medical Center Chief Breast Cancer Basic Research Lab Univ of Texas MD Anderson Hospital amp
Tumour Institute Assist Prof Dept of Molecular Carcinogenesis amp Virology MD Anderson Acting Chief Div of Oncology White Memorial Medical Center LA
William V Williams MD FACP President amp CEO VP Exploratory Development Incyte Corporation VP Experimental Medicine GlaxoSmithKline Head Rheumatology Research University of Pennsylvania
Prior Affiliations
17
Drug Approvals by BriaCell Management Team
Bexxarreg (tositumomab and Iodine I131 tositumomab) Treatment of CD20 antigen-expressing relapsed or refractory low grade follicular or transformed non-Hodgkins lymphoma
Myleranreg (busulfan) for chronic myelogenous leukemia Defense of formulation change sNDA
Hycamtinreg (topotecan) for ovarian cancer Pediatric use sNDA
Navelbinereg (vinorelbine tartrate) for non-small cell lung cancer Pediatric use sNDA
Bonivareg (ibandronate) monthly oral treatment of osteoporosis
Bonivareg (ibandronate) quarterly intraveous treatment of osteoporosis
Zofranreg (ondansetron) for prevention of nausea and vomiting Pediatric use sNDA
Jakafireg (ruxolitinib) for myelofibrosis Jakafireg (ruxolitinib) for polycythemia vera
Olumiantreg (baricitinib) for rheumatoid arthritis Approved in USA Japan and Europe
18
Share Metrics
BCTV BCTXF 19
Data as of 1092018
Ticker TSX BCTV
US Ticker OTCQBBCTXF
Share Price (CAD) as of Oct 9 2018 $012
52-Week Range (CAD) $009-019
Shares Outstanding as of Oct 9 2018 1611M
Market Cap as of Oct 9 2018 (CAD) $193M
Cash and Short Term Investments as of July 31 2018 (CAD) $23M
Total Shareholders Equity as of July 31 2018 (CAD) $12M
Number of Warrants $014-$035 (CAD) as of Oct 9 2018 601M
Number of Compensation Warrants $014-$030 (CAD) as of Oct 9 2018 45M
Number of Options $014- $026 (CAD$) as of Oct 9 2018 93M
Developing Bria-OTStrade the First Off-the-Shelf Personalized Immunotherapy
Targeting Adv Breast Cancer Unmet medical need (42000 death in the US in 2017 ) $1 Bil- $5 Bil market opportunity depending on patient treatment stage
Impressive results in 2 proof-of-concept clinical trials Rapid Response Rate Repeated following re-treatment Excellent Safety Profile
Completed enrollment in Phase IIIa clinical trial of Bria-IMTtrade with outstanding safety amp efficacy data Initiated Phase IIa Combination Study of Bria-IMTtrade with Keytrudareg (Merck amp Co Inc)
Developing Bria-OTStrade along with BriaDXtrade its companion diagnostic test Ability to match and treat ~90 of patient population with Off-the-Shelf personalized immunotherapy
Experienced Management has been involved in over 10 drug approvals
Patient B001 Breast 70 No 1101 - 3501 4001 Negative -
Bria-IMTtradeHuman Proof-of-Concept Trials in Breast Cancer (Patient A002)
24
Proof-of-Concept Results Resulted in BriaCellrsquos Immunotherapy Strategy Use BriaDXtrade diagnostic to select only those patients matching Bria-IMTtrade Use BriaDXtrade diagnostic test to select Bria-OTStrade alleles matching ~90 of all patients
Bria-IMTtradeCurrent Phase IIIa Data Supports HLA Matching Hypothesis Six patients treated in 2017 Bria-IMTtrade was safe and well tolerated
Patient 01-002 73-year-old woman with breast cancer diagnosed in 1995 Developed liver metastases in2010 and lung metastases in 2017 Previously treated with 7 rounds of chemotherapy with 8 differentchemotherapy agents Received 5 cycles of Bria-IMTtrade over 3 months then monthly cycles (6 months total)Evaluated after 3 months and 6 months After 3 months despite the extensive prior therapy her scans notedthat ldquothere has been a clear response in the multiple bilateral pulmonary nodulesrdquo The response wasmaintained after 6 months of Bria-IMTtrade treatment She matches Bria-IMTtrade at 2 HLA alleles
The liver tumors were stable to slightly increased at 3 months and then progressed after 6 months
This supports our hypothesis of heightened anti-tumor activity in patients with a matched HLA types Clear path to develop BriaDXtrade to select the patients using HLA testing
1 RLL 29 Not Detectable Not Detectable2 LUL apical pleural based 34 tiny nodule lt 1mm scar tiny nodule lt 1mm scar3 xxx 39 Not Detectable Not Detectable4 40 Not Detectable Not Detectable5 RLL 45 Not Detectable Not Detectable6 LLL 49 Not Detectable Not Detectable7 xxx 52 Not Detectable Not Detectable8 RLL 52 Not Detectable Not Detectable9 RLL 56 Not Detectable Not Detectable
10 RLL costophrenic recess 56 Not Detectable Not Detectable11 XXX 58 Not Detectable Not Detectable12 LUL 60 Not Detectable Not Detectable13 XXX 67 15 1514 RUL 72 15 1515 LLL 76 Not Detectable Not Detectable16 RUL Noncalcified Nodule 77 Not Detectable Not Detectable17 RLL costophrenic recess 79 10 1018 RUL 82 Not Detectable Not Detectable19 RLL 90 Not Detectable Not Detectable20 RLL 91 lt 01 lt 0121 xxx xxx Not Detectable Not Detectable
27
Clinical Development Update ndash Summary 2018 September 26
Completed enrollment of Adv Breast cancer patients in the Phase IIIa ldquomonotherapyrdquo study of Bria-IMTtrade
We have confirmed our mechanism of action and achieved proof of concept
Initial safety data appears superior to that of the other advanced or approved drugs for breast cancer when they were at a similar clinical stage of development
Initial efficacy data is similar or superior to those of other advanced or approved drugs for breast cancer when they were at a similar clinical stage of development
Initiated Combination Study of Bria-IMTtrade with Keytrudareg or Yervoyreg in Adv breast cancer patients expecting even better response rates than those in the ldquomonotherapyrdquo study Initial safety data is expected in 4Q2018 Initial efficacy data is expected in 1Q2019
Bria-OTStrade the first off-the-shelf personalized treatment for advanced breast cancer is expected to enter the clinic in 2019
28
Bria-IMTtrade Excellent Safety Data - To Date
To date Bria-IMTtrade has been dosed in 24 patients (4 in 2004-2005 20 in 2017-2018)
Interim Data (20 patients)-Ongoing Phase IIIa Study (2017-2018)
Bria-IMTtrade has been very well tolerated (ge60 doses given to date) The majority of adverse events (AEs) were limited to expected minor local irritation at the
injection sites No related grade gt3 or unexpected AEs No related serious AEs No serious unexpected related AEs Most patients who have dropped out did so due to worsening of their underlying disease
Based on the current study Bria-IMTtrade has an excellent safety profile
29
Bria-IMTtrade - Efficacy as Predicted
Interim Data (19 patients)-Ongoing Phase IIIa Study (2017-2018) amp Original Study (2004-2005)
PD-L1 expression on circulating cancer cells amp cancer-associated cells in 100 of patients (to date) Strong rationale for combination with checkpoint inhibitors like Keytruda
30
Bria-IMTtrade appears to be most effective in patients who match with Bria-IMT trade at 2 HLA loci (types) further supporting our ldquoHLA Matching Hypothesisrdquo and the development of Bria-OTS trade to cover 90 of the patient population
Combination with immune checkpoint inhibitors may induce a more potent anti-cancer response leading to our strategy of combination studies of Bria-IMT trade with Keytruda or Yervoy
Patients (n) HLA Match
Tumor Shrinkage
Biological Response
4 ge2 50 7515 ge1 27 334 0 0 0
Biological response includes tumor shrinkage or lower circulating cancer associated cells
The confirmatory Bria-IMTtrade monotherapy Phase IIa trial has completed enrollment Additional Support for the HLA-matching hypothesis has been obtained
Bria-IMTtrade Combination Therapy study with immune checkpoint inhibitors Keytrudareg if PD-L12 positive (ge1) Yervoyreg if PD-L12 negative (lt1) Accepting patients from the monotherapy study who develop progressive disease Also enrolling patients directly into this study to enhance experience with the combination In discussion with other pharmaceutical companies to evaluate additional combinations with other
immunotherapies
Bria-OTStrade Off-the-Shelf Personalized Targeted Immunotherapy Developing Bria-OTStrade to co-express GM-CSF and interferon-α Pre-manufacture additional HLA alleles ndash Total of 15 alleles (8 Class I and 7 Class II) Co-development of BriaDXtrade companion diagnostic for HLA typing Combination therapy clinical trial with immune checkpoint inhibitors for non-responders using
information from the Bria-IMTtrade Combination Therapy Study
33
Development Timeline ndash Breast Cancer
20192018 2020 2021
Phase IIIaBria-IMTtrade
Monotherapy
Currently Enrolling Phase IIaBria-IMTtrade + Checkpoint
Currently in discussions with potential partnersPhase II Bria-IMTtrade plus Additional Combinations (1Q19 4Q22)(eg PD-1 Inhibitor PD-L1 inhibitor anti-CTLA4 anti-GITR anti-OX40)
1Q 2Q 3Q 4Q
2023
Bria-OTStrade Off-The-Shelf Personalized ImmunotherapyMonotherapy and Potential Partnered Combo Therapy
(2H19 Ongoing)
Bria-OTStradeOff-the-Shelf Cell Line cGMP Manufacturing
and BriaDXtrade(1Q18 1Q19)
Registration Studies (1Q20 2H22)Bria-IMTtrade with Checkpoint InhibitorsBria-OTStrade +- Checkpoint Inhibitors
34
Immuno-oncology Deals
Recent deals of small biotechs with big pharma in immuno-oncology
35
Date PartnershipDevelopment stage at the time of the deal Deal size
07122018 Immatics-Genmab Preclinical Up to $28B
04042018 OSE Immunotherapeutics-Boehringer Ingelheim Preclinical Up to euro113B ($139B)
02092018 Pieris Pharmaceuticals-Seattle Genetics Preclinical Up to $123B
2142018 Nektar-BMS Ph III Up to $36B
01222018 Juno-Celgene Ph II $9B (Acquisition)
11142017 Loxo-Bayer Larotrectinib (Ph II) LOXO-195 (Ph III) Up to $155B
1032017 CytomX-Amgen Preclinical Up to $15B
03202017 CytomX--BMS Ph III Up to $36B
6282016 Xencor-Novartis Preclinical Up to $24B
Early Stage Clinical Studies (Comparison)
We compared the interim data of Ph IIIa study of Bria-IMTtrade in advanced breast cancer with thedata in the early stage clinical studies of recently approved breast cancer drugs and one fasttracked product candidate
Apples to apples comparison Early Stage Clinical Studies in oncology are typically done in patientswith no other therapeutic options Thus the patients have very advanced disease and response ratesare typically quite low
The patients in our Ph IIIa study have been heavily pre-treated (median 45 prior regimens)Some recent studies of relevance in breast cancer are noted in the following slides
36
Breast Cancer Market Opportunity
Drug Technology Approved for Market (US)Ibrance (palbociclib) CDK 46 Inhibitor HR+HER2- MBC in combination with
fluvestrant or aromatase inhibitor$933M in 1Q2018 $3126M in 2017
Kisqali (ribociclib) CDK 46 Inhibitor 2017 HR+HER2- MBC in combination with fluvestrant or aromatase inhibitor
Peak sales projected at $25B
Verzenio (abemaciclib) CDK 46 Inhibitor 2017 HR+HER2- MBC in combination with fluvestrant or aromatase inhibitor
balixafortide CXCR4 antagonist Fast track designation in 2018 for HER2- MBC who have failed 2 prior regimens
The market for breast cancer drugs is a multibillion dollar market with new drugs being approvedon an ongoing basis indicating the shortage of safe and effective treatments for this deadly disease
37
Competitors- Phase III Clinical Data Bria-IMTtrade shows superior safety and similar to superior efficacy data compared with those of the multi-billion dollar drugs when they were at a similar early stage of clinical development
Injection site reactions No related SAEs or SUSARs
Tumor vol darr ampor darr circul tumor cellsAll Comers 21(419) 26(519)One or More HLA matches 27(415) 33(515)Two or More HLA matches 50 (24) 75 (34)
Sheet1 (3)
Comp -Slides
Data
HLA (2)
HLA
Data (Ph1-2+4Pt)
Competitors (2018)-Slide
Competitors (2018)
In the Pipeline Protein Kinase C delta (PKCδ) Inhibitors
30 of all human malignancies display activating RAS mutations Another 60 showing over-activity of Ras-signaling pathways
Ras has been termed ldquoundruggablerdquo (no one has been able to make a Ras inhibitor drug)
BriaCellrsquos novel proprietary PKCδ inhibitors have shown activity against multiple RAS transformed tumors Lung cancer Melanoma Breast cancer Neuroendocrine cancer Pancreatic cancer Colorectal cancer
This target has an attractive safety profile based on in vivo studies and knock out mouse studies
PKCδ inhibitors should qualify for an accelerated clinical development plan and regulatory pathway
Could be in clinic within 24 months
Cost-Effective Additional Shot-on-Goal and additional partnership opportunities
Early-Stage Preclinical Program
39
Protein Kinase C delta (PKCδ) Inhibitors
Activated PKCδ inhibits RAS degradation which in turn stimulates tumor growth
Koo et al Oncotarget 621328 2016
30 of all human malignancies display activating RASmutations with another 60 showing over-activity of Ras-signaling pathways
BriaCellrsquos novel proprietary PKCδ inhibitors have shownactivity against multiple RAS transformed tumors
This target has an attractive safety profile based on in vivostudies and knock out mouse studies
PKCδ also has potential activity as an immunotherapeuticby blocking TGFβ signaling
PKCδ inhibitors are applicable to specific niche tumor typeswhich provide an accelerated clinical development plan
Structural aspects of first generation inhibitor rottlerin and staurosporine (pan-PKC activator) were combined to create second generation inhibitor KAM1
Third generation inhibitors such as BJE6-106 have improved potency and selectivity Fourth generation inhibitors under development to optimize drug-like characteristics PKCδ inhibitors lack endothelial cell cytotoxicity amp PKCδ deficient mice develop normally and are fertile Potentially no marked intrinsic toxicity by inhibiting PKCδ
Mukai H Saeki T Shimada K Naito Y Matsubara N Nakanishi T Obaishi H Namiki M Sasaki Y Phase 1 combination study of eribulin mesylate with trastuzumab for advanced or recurrent human epidermal growth factor receptor 2 positive breast cancer Invest New Drugs 2015 Feb33(1)119-27
AstraZeneca
Lynparza (Olaparib) + Cediranib
PARP inhibitor + inhibitor of VEGF receptor tyrosine kinases
HR+ HER2- MBC
BC amp OC
2013
28 (8 BC)
3 for BC
Olaparib (a poly (ADP-ribose) polymerase (PARP) inhibitor) amp Cediranib (Vascular endothelial growth factor receptor (VEGFR) 1 2 and 3 tyrosine kinase inhibitor)3 at dose level (DL) 0 (cediranib 20mg olaparib 100mg) 3 at DL1 (cediranib 20mg olaparib 200mg) 7 at DL2 (cediranib 30mg olaparib 200mg) 6 at DL3 (cediranib 30mg olaparib 400mg)
Liu JF Tolaney SM Birrer M Fleming GF Buss MK Dahlberg SE Lee H Whalen C Tyburski K Winer E Ivy P Matulonis UA A Phase 1 trial of the poly(ADP-ribose) polymerase inhibitor olaparib (AZD2281) in combination with the anti-angiogenic cediranib (AZD2171) in recurrent epithelial ovarian or triple-negative breast cancer Eur J Cancer 2013 Sep49(14)2972-8
Reyon Pharmaceutical
VM206RY
Heterologous prime-boost with a truncated HER2 sequence
HER2+ Stage IIIampIV BC
2015
9
2 chemo
Plasmid DNA (pHM-GM-CSF expressing truncated HER2 amp GM-CSF) amp adenoviral vector (Ad-HM containing modified HER2) (2 4 and 8 mgpatientvisit) of pHM-GM-CSF 3x IM weeks 0 2 and 4 Ad-HM 3 times 109 virus particles at week 6
11 PR
4 pts showed 7 minor AEs
Unclear
Kim SB Ahn JH Kim J Jung KH A phase 1 study of a heterologous prime-boost vaccination involving a truncated HER2 sequence in patients with HER2-expressing breast cancer Mol Ther Methods Clin Dev 2015 Sep 30215031 doi 101038mtm201531 eCollection 2015
Rodon J Peacuterez-Fidalgo A Krop IE Burris H Guerrero-Zotano A Britten CD Becerra C Schellens J Richards DA Schuler M Abu-Khalaf M Johnson FM Ranson M Edenfield J Silva AP Hackl W Quadt C Demanse D Duval V Baselga J Phase 11b dose escalation and expansion study of BEZ235 a dual PI3KmTOR inhibitor in patients with advanced solid tumors including patients with advanced breast cancer Cancer Chemother Pharmacol 2018 Jun 7 doi 101007s00280-018-3610-z [Epub ahead of print]
Celgene (Abraxane)
Gemcitabine + Abraxane (nab-paclitaxel)
Chemo + Chemo
OC BC NSCLC amp Panc cancer + Lung OC BC Kaposi sarcoma
MBC
2016
9
Adjuvant chemo (100)chemo post-adjuvant (33)
Gem (nucleoside metabolic inhibitor 1250 mgm2) on days 1 and 8 nab-Pac (microtubule inhibitor) starting dose of 180 mgm2 (cohort 1) 220 mgm2 (cohort 2) and 260 mgm2 (cohort 3) on day 1 of the 21-day cycle using a 3 + 3 design
0
MTD not reached29 Gr3 Neutropenia59 Gr1 Peripheralneuropathy
Yoshitomi S Taira N Doihara H Mizoo T Nogami T Iwamoto T Motoki T Shien T Ogasawara Y Matsuoka J Tsuji H Mitsuhashi T A phase 1 dose-finding and pharmacokinetic study of gemcitabine with nab-paclitaxel in patients with metastatic breast cancer Cancer Chemother Pharmacol 2016 Aug78(2)289-94
Eli Lilly
Erbituxreg (cetuximab) + Taxane
EGFR inhibitor antineoplastic agent + Chemo
Headamp Neck Colorectal Cancer
TNBC
2007-2010
18
1 chemo
Cetuximab (epidermal growth factor receptor (EGFR) antagonist ) an initial loading dose of cetuximab 400 mgm2 followed by a weekly dose of 250 mgm2Paclitaxel (microtubule inhibitor) 80 mgm2 or Docetaxel at an initial dose of 30 mgm2 was administered weekly
56 CR 22 PR
83 Dermatologic toxicity11 Grade3+
Nechushtan H Vainer G Stainberg H Salmon AY Hamburger T Peretz T A phase 12 of a combination of cetuximab and taxane for triple negative breast cancer patients Breast 2014 Aug23(4)435-8
Polyphor
Balixafortide (POL6326) + eribulin
CXCR4 antagonist + tubulin-based antimitotic
Heavily pretreated Relapsed MBC
2014-2016
56
3rd line 3 chemo
3+3 dose escalation The highest dose was established as eribulin 14 mgmsup2 on days 2 and 9 and balixafortide 55 mgkg on days 1minus3 and 8minus10 of the 21-day cycle
30 PR
41 Gr34 Neutropenia11 Gr34 Leucopenia11 Gr34 Febrileneutropenia2 Related mortalities
Apr 2018 Fast Track for HER2-MBC who have failed 2prior regimens
Pernas S Martin M Kaufman PA Gil-Martin M Gomez Pardo P Lopez-Tarruella S Manso L Ciruelos E Perez-Fidalgo JA Hernando C Ademuyiwa FO Weilbaecher K Mayer I Pluard TJ Martinez Garcia M Vahdat L Perez-Garcia J Wach A Barker D Fung S Romagnoli B Cortes J Balixafortide plus eribulin in HER2-negative metastatic breast cancer a phase 1 single-arm dose-escalation trial Lancet Oncol 2018 Jun19(6)812-824
11 PRndashbut only + letrozole (No Resp on monotherapy)
61 Gr34 Neutropenia39 Gr34 Leucopenia
$933M in 1Q2018 $31B in 2017
Tamura K Mukai H Naito Y Yonemori K Kodaira M Tanabe Y Yamamoto N Osera S Sasaki M Mori Y Hashigaki S Nagasawa T Umeyama Y Yoshino T Phase I study of palbociclib a cyclin-dependent kinase 46 inhibitor in Japanese patients Cancer Sci 2016 Jun107(6)755-63 doi 101111cas12932 Epub 2016 May 11
Pfizer
Ibrancereg (palbociclib)
CDK 46 Inhibitor
HR+ HER2- MBC
Heavily pretreated Relapsed Metastatic Cancer
2004-2008
41 (5 BC)
chemo naiumlve (17) 1-2 (51)3 (29) 3+ (2)
Palbociclib 25-150 mg dose ranging
0
20 Gr34 Neutropenia23 Gr34 Leucopenia
$933M in 1Q2018 $31B in 2017
Flaherty KT Lorusso PM Demichele A Abramson VG Courtney R Randolph SS Shaik MN Wilner KD ODwyer PJ Schwartz GK Phase I dose-escalation trial of the oral cyclin-dependent kinase 46 inhibitor PD 0332991 administered using a 21-day schedule in patients with advanced cancer Clin Cancer Res 2012 Jan 1518(2)568-76 doi 1011581078-0432CCR-11-0509 Epub 2011 Nov 16
Novartis
Kisqalireg (ribociclib)
CDK 46 Inhibitors
Premenopausal HR+ HER2- MBC
Heavily pretreated Relapsed Metastatic Cancer
2016
132 (20 BC)
0-1 (25) 2-3 (42) 4+ (32)
Ribociclib 50 mg ranging up to 1200 mg dose escalation
23 PRndashincluded 1 in BC (5 of BC pts)
27 Gr34 Neutropenia17 Gr34 Leucopenia
Peak sales projected at $25B
Infante JR Cassier PA Gerecitano JF Witteveen PO Chugh R Ribrag V Chakraborty A Matano A Dobson JR Crystal AS Parasuraman S Shapiro GI A Phase I Study of the Cyclin-Dependent Kinase 46 Inhibitor Ribociclib (LEE011) in Patients with Advanced Solid Tumors and Lymphomas Clin Cancer Res 2016 Dec 122(23)5696-5705 Epub 2016 Aug 19
Eli Lilly
Verzenioreg (abemaciclib)
CDK 46 Inhibitors
HR+HER2minusMBC
Heavily pretreated Relapsed Metastatic Cancer
2016
12 (1 BC)
1 (312) 2 (212) 3+ (7)
Abemaciclib 100 mg ranging up to 200 mg dose escalation
17 PR (included 1 in BC)
17 Gr34 Neutropenia33 Gr34 Leucopenia
Peak sales projected at $2B
Fujiwara Y Tamura K Kondo S Tanabe Y Iwasa S Shimomura A Kitano S Ogasawara K Turner PK Mori J Asou H Chan EM Yamamoto N Phase 1 study of abemaciclib an inhibitor of CDK 4 and 6 as a single agent for Japanese patients with advanced cancer Cancer Chemother Pharmacol 2016 Aug78(2)281-8 doi 101007s00280-016-3085-8 Epub 2016 Jun 16
Mukai H Saeki T Shimada K Naito Y Matsubara N Nakanishi T Obaishi H Namiki M Sasaki Y Phase 1 combination study of eribulin mesylate with trastuzumab for advanced or recurrent human epidermal growth factor receptor 2 positive breast cancer Invest New Drugs 2015 Feb33(1)119-27
AstraZeneca
Lynparza (Olaparib)+ Cediranib
PARP inhibitor+ inhibitor of VEGF RTK
HR+ HER2- MBC
BC amp OC
13
28 (8 BC)
3 for BC
Olaparib (a poly (ADP-ribose) polymerase (PARP) inhibitor) amp Cediranib (Vascular endothelial growth factor receptor (VEGFR) 1 2 and 3 tyrosine kinase inhibitor)3 at dose level (DL) 0 (cediranib 20mg olaparib 100mg) 3 at DL1 (cediranib 20mg olaparib 200mg) 7 at DL2 (cediranib 30mg olaparib 200mg) 6 at DL3 (cediranib 30mg olaparib 400mg)
Liu JF Tolaney SM Birrer M Fleming GF Buss MK Dahlberg SE Lee H Whalen C Tyburski K Winer E Ivy P Matulonis UA A Phase 1 trial of the poly(ADP-ribose) polymerase inhibitor olaparib (AZD2281) in combination with the anti-angiogenic cediranib (AZD2171) in recurrent epithelial ovarian or triple-negative breast cancer Eur J Cancer 2013 Sep49(14)2972-8
ReyonPharma
VM206RY
Heterologous prime-boost with a truncated HER2 sequence
HER2+ Stg IIIampIV BC
15
9
2 chemo
Plasmid DNA (pHM-GM-CSF expressing truncated HER2 amp GM-CSF) amp adenoviral vector (Ad-HM containing modified HER2) (2 4 and 8 mgpatientvisit) of pHM-GM-CSF 3x IM weeks 0 2 and 4 Ad-HM 3 times 109 virus particles at week 6
11 PR
4 pts 7 minor AEs
Unclear
Kim SB Ahn JH Kim J Jung KH A phase 1 study of a heterologous prime-boost vaccination involving a truncated HER2 sequence in patients with HER2-expressing breast cancer Mol Ther Methods Clin Dev 2015 Sep 30215031 doi 101038mtm201531 eCollection 2015
Rodon J Peacuterez-Fidalgo A Krop IE Burris H Guerrero-Zotano A Britten CD Becerra C Schellens J Richards DA Schuler M Abu-Khalaf M Johnson FM Ranson M Edenfield J Silva AP Hackl W Quadt C Demanse D Duval V Baselga J Phase 11b dose escalation and expansion study of BEZ235 a dual PI3KmTOR inhibitor in patients with advanced solid tumors including patients with advanced breast cancer Cancer Chemother Pharmacol 2018 Jun 7 doi 101007s00280-018-3610-z [Epub ahead of print]
Celgene(Abraxane)
Gemcitabine + Abraxane (nab-paclitaxel)
Chemo+ Chemo
OC BC NSCLC PC + LC OC BC KS
MBC
16
9
Adjuv chemo (100)chemo post-adjuv (33)
Gem (nucleoside metabolic inhibitor 1250 mgm2) on days 1 and 8 nab-Pac (microtubule inhibitor) starting dose of 180 mgm2 (cohort 1) 220 mgm2 (cohort 2) and 260 mgm2 (cohort 3) on day 1 of the 21-day cycle using a 3 + 3 design
0
MTD not reached29 Gr3 Neutropenia59 Gr1 Peripheralneuropathy
Yoshitomi S Taira N Doihara H Mizoo T Nogami T Iwamoto T Motoki T Shien T Ogasawara Y Matsuoka J Tsuji H Mitsuhashi T A phase 1 dose-finding and pharmacokinetic study of gemcitabine with nab-paclitaxel in patients with metastatic breast cancer Cancer Chemother Pharmacol 2016 Aug78(2)289-94
Eli Lilly
Erbituxreg (cetuximab) + Taxane
EGFR inhibitor antineoplastic agent + Chemo
Head amp NeckColorectal
TNBC
07-10
18
1 chemo
Cetuximab (epidermal growth factor receptor (EGFR) antagonist ) an initial loading dose of cetuximab 400 mgm2 followed by a weekly dose of 250 mgm2Paclitaxel (microtubule inhibitor) 80 mgm2 or Docetaxel at an initial dose of 30 mgm2 was administered weekly
56 CR 22 PR
83 Dermatologic toxicity11 Grade3+
Nechushtan H Vainer G Stainberg H Salmon AY Hamburger T Peretz T A phase 12 of a combination of cetuximab and taxane for triple negative breast cancer patients Breast 2014 Aug23(4)435-8
Polyphor
Balixafortide (POL6326) + eribulin
CXCR4 antagonist + tubulin-based antimitotic
Heavily pretreatedRelapsed MBC
14-16
56
3rd line 3 chemo
3+3 dose escalation The highest dose was established as eribulin 14 mgmsup2 on days 2 and 9 and balixafortide 55 mgkg on days 1minus3 and 8minus10 of the 21-day cycle
30 PR
41 Gr34 Neutropenia11 Gr34 Leucopenia11 Gr34 Febrileneutropenia2 Related mortalities
42018 Fast Track (HER2-MBC failed 2 prior regimens)
Pernas S Martin M Kaufman PA Gil-Martin M Gomez Pardo P Lopez-Tarruella S Manso L Ciruelos E Perez-Fidalgo JA Hernando C Ademuyiwa FO Weilbaecher K Mayer I Pluard TJ Martinez Garcia M Vahdat L Perez-Garcia J Wach A Barker D Fung S Romagnoli B Cortes J Balixafortide plus eribulin in HER2-negative metastatic breast cancer a phase 1 single-arm dose-escalation trial Lancet Oncol 2018 Jun19(6)812-824
1 PRndashbut only + letrozoleNo Resp on monotherapy
61 Gr34 Neutropenia39 Gr34 Leucopenia
$933M (1Q18)$31B (2017)
Tamura K Mukai H Naito Y Yonemori K Kodaira M Tanabe Y Yamamoto N Osera S Sasaki M Mori Y Hashigaki S Nagasawa T Umeyama Y Yoshino T Phase I study of palbociclib a cyclin-dependent kinase 46 inhibitor in Japanese patients Cancer Sci 2016 Jun107(6)755-63 doi 101111cas12932 Epub 2016 May 11
Pfizer
Ibrancereg (palbociclib)
CDK 46 Inhibitor
HR+ HER2- MBC
Heavily pretreatedRelapsed Met Cancer
04-08
41 (5 BC)
chemo naiumlve (17)1-2(51) 3(29) 3+(2)
Palbociclib 25-150 mg dose ranging
0
20 Gr34 Neutropenia23 Gr34 Leucopenia
$933M (1Q18)$31B (2017)
Flaherty KT Lorusso PM Demichele A Abramson VG Courtney R Randolph SS Shaik MN Wilner KD ODwyer PJ Schwartz GK Phase I dose-escalation trial of the oral cyclin-dependent kinase 46 inhibitor PD 0332991 administered using a 21-day schedule in patients with advanced cancer Clin Cancer Res 2012 Jan 1518(2)568-76 doi 1011581078-0432CCR-11-0509 Epub 2011 Nov 16
Novartis
Kisqalireg (ribociclib)
CDK 46 Inhibitor
Premenopausal HR+ HER2- MBC
Heavily pretreatedRelapsed Met Cancer
16
132 (20 BC)
0-1 (25) 2-3 (42)4+ (32)
Ribociclib 50 mg ranging up to 1200 mg dose escalation
23 PR-included 1 BC (5 of BC pts)
27 Gr34 Neutropenia17 Gr34 Leucopenia
Peak sales est at $25B
Infante JR Cassier PA Gerecitano JF Witteveen PO Chugh R Ribrag V Chakraborty A Matano A Dobson JR Crystal AS Parasuraman S Shapiro GI A Phase I Study of the Cyclin-Dependent Kinase 46 Inhibitor Ribociclib (LEE011) in Patients with Advanced Solid Tumors and Lymphomas Clin Cancer Res 2016 Dec 122(23)5696-5705 Epub 2016 Aug 19
Eli Lilly
Verzenioreg (abemaciclib)
CDK 46 Inhibitor
HR+HER2minusMBC
Heavily pretreatedRelapsed Met Cancer
16
12 (1 BC)
1 (312) 2 (212) 3+(7)
Abemaciclib 100 mg ranging up to 200 mg dose escalation
17 PR (included 1 BC)
17 Gr34 Neutropenia33 Gr34 Leucopenia
Peak sales est at $2B
Fujiwara Y Tamura K Kondo S Tanabe Y Iwasa S Shimomura A Kitano S Ogasawara K Turner PK Mori J Asou H Chan EM Yamamoto N Phase 1 study of abemaciclib an inhibitor of CDK 4 and 6 as a single agent for Japanese patients with advanced cancer Cancer Chemother Pharmacol 2016 Aug78(2)281-8 doi 101007s00280-016-3085-8 Epub 2016 Jun 16
Mukai H Saeki T Shimada K Naito Y Matsubara N Nakanishi T Obaishi H Namiki M Sasaki Y Phase 1 combination study of eribulin mesylate with trastuzumab for advanced or recurrent human epidermal growth factor receptor 2 positive breast cancer Invest New Drugs 2015 Feb33(1)119-27
AstraZeneca
Lynparza (Olaparib) + Cediranib
PARP inhibitor + inhibitor of VEGF receptor tyrosine kinases
HR+ HER2- MBC
BC amp OC
2013
28 (8 BC)
3 for BC
Olaparib (a poly (ADP-ribose) polymerase (PARP) inhibitor) amp Cediranib (Vascular endothelial growth factor receptor (VEGFR) 1 2 and 3 tyrosine kinase inhibitor)3 at dose level (DL) 0 (cediranib 20mg olaparib 100mg) 3 at DL1 (cediranib 20mg olaparib 200mg) 7 at DL2 (cediranib 30mg olaparib 200mg) 6 at DL3 (cediranib 30mg olaparib 400mg)
Liu JF Tolaney SM Birrer M Fleming GF Buss MK Dahlberg SE Lee H Whalen C Tyburski K Winer E Ivy P Matulonis UA A Phase 1 trial of the poly(ADP-ribose) polymerase inhibitor olaparib (AZD2281) in combination with the anti-angiogenic cediranib (AZD2171) in recurrent epithelial ovarian or triple-negative breast cancer Eur J Cancer 2013 Sep49(14)2972-8
Reyon Pharmaceutical
VM206RY
Heterologous prime-boost with a truncated HER2 sequence
HER2+ Stage IIIampIV BC
2015
9
2 chemo
Plasmid DNA (pHM-GM-CSF expressing truncated HER2 amp GM-CSF) amp adenoviral vector (Ad-HM containing modified HER2) (2 4 and 8 mgpatientvisit) of pHM-GM-CSF 3x IM weeks 0 2 and 4 Ad-HM 3 times 109 virus particles at week 6
11 PR
4 pts showed 7 minor AEs
Unclear
Kim SB Ahn JH Kim J Jung KH A phase 1 study of a heterologous prime-boost vaccination involving a truncated HER2 sequence in patients with HER2-expressing breast cancer Mol Ther Methods Clin Dev 2015 Sep 30215031 doi 101038mtm201531 eCollection 2015
Rodon J Peacuterez-Fidalgo A Krop IE Burris H Guerrero-Zotano A Britten CD Becerra C Schellens J Richards DA Schuler M Abu-Khalaf M Johnson FM Ranson M Edenfield J Silva AP Hackl W Quadt C Demanse D Duval V Baselga J Phase 11b dose escalation and expansion study of BEZ235 a dual PI3KmTOR inhibitor in patients with advanced solid tumors including patients with advanced breast cancer Cancer Chemother Pharmacol 2018 Jun 7 doi 101007s00280-018-3610-z [Epub ahead of print]
Celgene (Abraxane)
Gemcitabine + Abraxane (nab-paclitaxel)
Chemo + Chemo
OC BC NSCLC amp Panc cancer + Lung OC BC Kaposi sarcoma
MBC
2016
9
Adjuvant chemo (100)chemo post-adjuvant (33)
Gem (nucleoside metabolic inhibitor 1250 mgm2) on days 1 and 8 nab-Pac (microtubule inhibitor) starting dose of 180 mgm2 (cohort 1) 220 mgm2 (cohort 2) and 260 mgm2 (cohort 3) on day 1 of the 21-day cycle using a 3 + 3 design
0
MTD not reached29 Gr3 Neutropenia59 Gr1 Peripheralneuropathy
Yoshitomi S Taira N Doihara H Mizoo T Nogami T Iwamoto T Motoki T Shien T Ogasawara Y Matsuoka J Tsuji H Mitsuhashi T A phase 1 dose-finding and pharmacokinetic study of gemcitabine with nab-paclitaxel in patients with metastatic breast cancer Cancer Chemother Pharmacol 2016 Aug78(2)289-94
Eli Lilly
Erbituxreg (cetuximab) + Taxane
EGFR inhibitor antineoplastic agent + Chemo
Headamp Neck Colorectal Cancer
TNBC
2007-2010
18
1 chemo
Cetuximab (epidermal growth factor receptor (EGFR) antagonist ) an initial loading dose of cetuximab 400 mgm2 followed by a weekly dose of 250 mgm2Paclitaxel (microtubule inhibitor) 80 mgm2 or Docetaxel at an initial dose of 30 mgm2 was administered weekly
56 CR 22 PR
83 Dermatologic toxicity11 Grade3+
Nechushtan H Vainer G Stainberg H Salmon AY Hamburger T Peretz T A phase 12 of a combination of cetuximab and taxane for triple negative breast cancer patients Breast 2014 Aug23(4)435-8
Polyphor
Balixafortide (POL6326) + eribulin
CXCR4 antagonist + tubulin-based antimitotic
Heavily pretreated Relapsed MBC
2014-2016
56
3rd line 3 chemo
3+3 dose escalation The highest dose was established as eribulin 14 mgmsup2 on days 2 and 9 and balixafortide 55 mgkg on days 1minus3 and 8minus10 of the 21-day cycle
30 PR
41 Gr34 Neutropenia11 Gr34 Leucopenia11 Gr34 Febrileneutropenia2 Related mortalities
Apr 2018 Fast Track for HER2-MBC who have failed 2prior regimens
Pernas S Martin M Kaufman PA Gil-Martin M Gomez Pardo P Lopez-Tarruella S Manso L Ciruelos E Perez-Fidalgo JA Hernando C Ademuyiwa FO Weilbaecher K Mayer I Pluard TJ Martinez Garcia M Vahdat L Perez-Garcia J Wach A Barker D Fung S Romagnoli B Cortes J Balixafortide plus eribulin in HER2-negative metastatic breast cancer a phase 1 single-arm dose-escalation trial Lancet Oncol 2018 Jun19(6)812-824
11 PRndashbut only + letrozole (No Resp on monotherapy)
61 Gr34 Neutropenia39 Gr34 Leucopenia
$933M in 1Q2018 $31B in 2017
Tamura K Mukai H Naito Y Yonemori K Kodaira M Tanabe Y Yamamoto N Osera S Sasaki M Mori Y Hashigaki S Nagasawa T Umeyama Y Yoshino T Phase I study of palbociclib a cyclin-dependent kinase 46 inhibitor in Japanese patients Cancer Sci 2016 Jun107(6)755-63 doi 101111cas12932 Epub 2016 May 11
Pfizer
Ibrancereg (palbociclib)
CDK 46 Inhibitor
HR+ HER2- MBC
Heavily pretreated Relapsed Metastatic Cancer
2004-2008
41 (5 BC)
chemo naiumlve (17) 1-2 (51)3 (29) 3+ (2)
Palbociclib 25-150 mg dose ranging
0
20 Gr34 Neutropenia23 Gr34 Leucopenia
$933M in 1Q2018 $31B in 2017
Flaherty KT Lorusso PM Demichele A Abramson VG Courtney R Randolph SS Shaik MN Wilner KD ODwyer PJ Schwartz GK Phase I dose-escalation trial of the oral cyclin-dependent kinase 46 inhibitor PD 0332991 administered using a 21-day schedule in patients with advanced cancer Clin Cancer Res 2012 Jan 1518(2)568-76 doi 1011581078-0432CCR-11-0509 Epub 2011 Nov 16
Novartis
Kisqalireg (ribociclib)
CDK 46 Inhibitors
Premenopausal HR+ HER2- MBC
Heavily pretreated Relapsed Metastatic Cancer
2016
132 (20 BC)
0-1 (25) 2-3 (42) 4+ (32)
Ribociclib 50 mg ranging up to 1200 mg dose escalation
23 PRndashincluded 1 in BC (5 of BC pts)
27 Gr34 Neutropenia17 Gr34 Leucopenia
Peak sales projected at $25B
Infante JR Cassier PA Gerecitano JF Witteveen PO Chugh R Ribrag V Chakraborty A Matano A Dobson JR Crystal AS Parasuraman S Shapiro GI A Phase I Study of the Cyclin-Dependent Kinase 46 Inhibitor Ribociclib (LEE011) in Patients with Advanced Solid Tumors and Lymphomas Clin Cancer Res 2016 Dec 122(23)5696-5705 Epub 2016 Aug 19
Eli Lilly
Verzenioreg (abemaciclib)
CDK 46 Inhibitors
HR+HER2minusMBC
Heavily pretreated Relapsed Metastatic Cancer
2016
12 (1 BC)
1 (312) 2 (212) 3+ (7)
Abemaciclib 100 mg ranging up to 200 mg dose escalation
17 PR (included 1 in BC)
17 Gr34 Neutropenia33 Gr34 Leucopenia
Peak sales projected at $2B
Fujiwara Y Tamura K Kondo S Tanabe Y Iwasa S Shimomura A Kitano S Ogasawara K Turner PK Mori J Asou H Chan EM Yamamoto N Phase 1 study of abemaciclib an inhibitor of CDK 4 and 6 as a single agent for Japanese patients with advanced cancer Cancer Chemother Pharmacol 2016 Aug78(2)281-8 doi 101007s00280-016-3085-8 Epub 2016 Jun 16
Mukai H Saeki T Shimada K Naito Y Matsubara N Nakanishi T Obaishi H Namiki M Sasaki Y Phase 1 combination study of eribulin mesylate with trastuzumab for advanced or recurrent human epidermal growth factor receptor 2 positive breast cancer Invest New Drugs 2015 Feb33(1)119-27
AstraZeneca
Lynparza (Olaparib)+ Cediranib
PARP inhibitor+ inhibitor of VEGF RTK
HR+ HER2- MBC
BC amp OC
13
28 (8 BC)
3 for BC
Olaparib (a poly (ADP-ribose) polymerase (PARP) inhibitor) amp Cediranib (Vascular endothelial growth factor receptor (VEGFR) 1 2 and 3 tyrosine kinase inhibitor)3 at dose level (DL) 0 (cediranib 20mg olaparib 100mg) 3 at DL1 (cediranib 20mg olaparib 200mg) 7 at DL2 (cediranib 30mg olaparib 200mg) 6 at DL3 (cediranib 30mg olaparib 400mg)
Liu JF Tolaney SM Birrer M Fleming GF Buss MK Dahlberg SE Lee H Whalen C Tyburski K Winer E Ivy P Matulonis UA A Phase 1 trial of the poly(ADP-ribose) polymerase inhibitor olaparib (AZD2281) in combination with the anti-angiogenic cediranib (AZD2171) in recurrent epithelial ovarian or triple-negative breast cancer Eur J Cancer 2013 Sep49(14)2972-8
ReyonPharma
VM206RY
Heterologous prime-boost with a truncated HER2 sequence
HER2+ Stg IIIampIV BC
15
9
2 chemo
Plasmid DNA (pHM-GM-CSF expressing truncated HER2 amp GM-CSF) amp adenoviral vector (Ad-HM containing modified HER2) (2 4 and 8 mgpatientvisit) of pHM-GM-CSF 3x IM weeks 0 2 and 4 Ad-HM 3 times 109 virus particles at week 6
11 PR
4 pts 7 minor AEs
Unclear
Kim SB Ahn JH Kim J Jung KH A phase 1 study of a heterologous prime-boost vaccination involving a truncated HER2 sequence in patients with HER2-expressing breast cancer Mol Ther Methods Clin Dev 2015 Sep 30215031 doi 101038mtm201531 eCollection 2015
Rodon J Peacuterez-Fidalgo A Krop IE Burris H Guerrero-Zotano A Britten CD Becerra C Schellens J Richards DA Schuler M Abu-Khalaf M Johnson FM Ranson M Edenfield J Silva AP Hackl W Quadt C Demanse D Duval V Baselga J Phase 11b dose escalation and expansion study of BEZ235 a dual PI3KmTOR inhibitor in patients with advanced solid tumors including patients with advanced breast cancer Cancer Chemother Pharmacol 2018 Jun 7 doi 101007s00280-018-3610-z [Epub ahead of print]
Celgene(Abraxane)
Gemcitabine + Abraxane (nab-paclitaxel)
Chemo+ Chemo
OC BC NSCLC PC + LC OC BC KS
MBC
16
9
Adjuv chemo (100)chemo post-adjuv (33)
Gem (nucleoside metabolic inhibitor 1250 mgm2) on days 1 and 8 nab-Pac (microtubule inhibitor) starting dose of 180 mgm2 (cohort 1) 220 mgm2 (cohort 2) and 260 mgm2 (cohort 3) on day 1 of the 21-day cycle using a 3 + 3 design
0
MTD not reached29 Gr3 Neutropenia59 Gr1 Peripheralneuropathy
Yoshitomi S Taira N Doihara H Mizoo T Nogami T Iwamoto T Motoki T Shien T Ogasawara Y Matsuoka J Tsuji H Mitsuhashi T A phase 1 dose-finding and pharmacokinetic study of gemcitabine with nab-paclitaxel in patients with metastatic breast cancer Cancer Chemother Pharmacol 2016 Aug78(2)289-94
Eli Lilly
Erbituxreg (cetuximab) + Taxane
EGFR inhibitor antineoplastic agent + Chemo
Head amp NeckColorectal
TNBC
07-10
18
1 chemo
Cetuximab (epidermal growth factor receptor (EGFR) antagonist ) an initial loading dose of cetuximab 400 mgm2 followed by a weekly dose of 250 mgm2Paclitaxel (microtubule inhibitor) 80 mgm2 or Docetaxel at an initial dose of 30 mgm2 was administered weekly
56 CR 22 PR
83 Dermatologic toxicity11 Grade3+
Nechushtan H Vainer G Stainberg H Salmon AY Hamburger T Peretz T A phase 12 of a combination of cetuximab and taxane for triple negative breast cancer patients Breast 2014 Aug23(4)435-8
Polyphor
Balixafortide (POL6326) + eribulin
CXCR4 antagonist + tubulin-based antimitotic
Heavily pretreatedRelapsed MBC
14-16
56
3rd line 3 chemo
3+3 dose escalation The highest dose was established as eribulin 14 mgmsup2 on days 2 and 9 and balixafortide 55 mgkg on days 1minus3 and 8minus10 of the 21-day cycle
30 PR
41 Gr34 Neutropenia11 Gr34 Leucopenia11 Gr34 Febrileneutropenia2 Related mortalities
42018 Fast Track (HER2-MBC failed 2 prior regimens)
Pernas S Martin M Kaufman PA Gil-Martin M Gomez Pardo P Lopez-Tarruella S Manso L Ciruelos E Perez-Fidalgo JA Hernando C Ademuyiwa FO Weilbaecher K Mayer I Pluard TJ Martinez Garcia M Vahdat L Perez-Garcia J Wach A Barker D Fung S Romagnoli B Cortes J Balixafortide plus eribulin in HER2-negative metastatic breast cancer a phase 1 single-arm dose-escalation trial Lancet Oncol 2018 Jun19(6)812-824
1 PRndashbut only + letrozoleNo Resp on monotherapy
61 Gr34 Neutropenia39 Gr34 Leucopenia
$933M (1Q18)$31B (2017)
Tamura K Mukai H Naito Y Yonemori K Kodaira M Tanabe Y Yamamoto N Osera S Sasaki M Mori Y Hashigaki S Nagasawa T Umeyama Y Yoshino T Phase I study of palbociclib a cyclin-dependent kinase 46 inhibitor in Japanese patients Cancer Sci 2016 Jun107(6)755-63 doi 101111cas12932 Epub 2016 May 11
Pfizer
Ibrancereg (palbociclib)
CDK 46 Inhibitor
HR+ HER2- MBC
Heavily pretreatedRelapsed Met Cancer
04-08
41 (5 BC)
chemo naiumlve (17)1-2(51) 3(29) 3+(2)
Palbociclib 25-150 mg dose ranging
0
20 Gr34 Neutropenia23 Gr34 Leucopenia
$933M (1Q18)$31B (2017)
Flaherty KT Lorusso PM Demichele A Abramson VG Courtney R Randolph SS Shaik MN Wilner KD ODwyer PJ Schwartz GK Phase I dose-escalation trial of the oral cyclin-dependent kinase 46 inhibitor PD 0332991 administered using a 21-day schedule in patients with advanced cancer Clin Cancer Res 2012 Jan 1518(2)568-76 doi 1011581078-0432CCR-11-0509 Epub 2011 Nov 16
Novartis
Kisqalireg (ribociclib)
CDK 46 Inhibitor
Premenopausal HR+ HER2- MBC
Heavily pretreatedRelapsed Met Cancer
16
132 (20 BC)
0-1 (25) 2-3 (42)4+ (32)
Ribociclib 50 mg ranging up to 1200 mg dose escalation
23 PR-included 1 BC (5 of BC pts)
27 Gr34 Neutropenia17 Gr34 Leucopenia
Peak sales est at $25B
Infante JR Cassier PA Gerecitano JF Witteveen PO Chugh R Ribrag V Chakraborty A Matano A Dobson JR Crystal AS Parasuraman S Shapiro GI A Phase I Study of the Cyclin-Dependent Kinase 46 Inhibitor Ribociclib (LEE011) in Patients with Advanced Solid Tumors and Lymphomas Clin Cancer Res 2016 Dec 122(23)5696-5705 Epub 2016 Aug 19
Eli Lilly
Verzenioreg (abemaciclib)
CDK 46 Inhibitor
HR+HER2minusMBC
Heavily pretreatedRelapsed Met Cancer
16
12 (1 BC)
1 (312) 2 (212) 3+(7)
Abemaciclib 100 mg ranging up to 200 mg dose escalation
17 PR (included 1 BC)
17 Gr34 Neutropenia33 Gr34 Leucopenia
Peak sales est at $2B
Fujiwara Y Tamura K Kondo S Tanabe Y Iwasa S Shimomura A Kitano S Ogasawara K Turner PK Mori J Asou H Chan EM Yamamoto N Phase 1 study of abemaciclib an inhibitor of CDK 4 and 6 as a single agent for Japanese patients with advanced cancer Cancer Chemother Pharmacol 2016 Aug78(2)281-8 doi 101007s00280-016-3085-8 Epub 2016 Jun 16
41 Gr34 Neutropenia11 Gr34 Leucopenia11 Gr34 Febrileneutropenia2 Related mortalities
30 PRs in combination with Halaven
Bria-IMTTM
20
Injection site reactions No related SAEs or SUSARs
Tumor vol darr ampor darr circul tumor cells)All Comers 21(419) 26(519)One or More HLA matches 27(415) 33(515)Two or More HLA matches 50 (24) 75 (34))
Drug
Technology
Approved for
Market (US)
Ibrance (palbociclib)
CDK 46 Inhibitor
HR+HER2- MBC in combination with fluvestrant or aromatase inhibitor
$933M in 1Q2018 $3126M in 2017
Kisqali (ribociclib)
CDK 46 Inhibitor
2017 HR+HER2- MBC in combination with fluvestrant or aromatase inhibitor
Peak sales projected at $25B
Verzenio (abemaciclib)
CDK 46 Inhibitor
2017 HR+HER2- MBC in combination with fluvestrant or aromatase inhibitor
Peak sales projected at $2B
Lynparza (olaparib)
Poly (ADP-ribose) polymerase (PARP) inhibitor
2017 ovarian amp breast cancer
$997M in 2017
Halaven (eribulin mesylate)
Tubulin-based antimitotic
2H2017 3rd line MBC amp liposarcoma
$181M in 2017
balixafortide
CXCR4 antagonist
Fast track designation in 2018 for HER2- MBC who have failed 2 prior regimens
Drug Approvals by BriaCell Management Team
Bexxarreg (tositumomab and Iodine I131 tositumomab) Treatment of CD20 antigen-expressing relapsed or refractory low grade follicular or transformed non-Hodgkins lymphoma
Myleranreg (busulfan) for chronic myelogenous leukemia Defense of formulation change sNDA
Hycamtinreg (topotecan) for ovarian cancer Pediatric use sNDA
Navelbinereg (vinorelbine tartrate) for non-small cell lung cancer Pediatric use sNDA
Bonivareg (ibandronate) monthly oral treatment of osteoporosis
Bonivareg (ibandronate) quarterly intraveous treatment of osteoporosis
Zofranreg (ondansetron) for prevention of nausea and vomiting Pediatric use sNDA
Jakafireg (ruxolitinib) for myelofibrosis Jakafireg (ruxolitinib) for polycythemia vera
Olumiantreg (baricitinib) for rheumatoid arthritis Approved in USA Japan and Europe
18
Share Metrics
BCTV BCTXF 19
Data as of 1092018
Ticker TSX BCTV
US Ticker OTCQBBCTXF
Share Price (CAD) as of Oct 9 2018 $012
52-Week Range (CAD) $009-019
Shares Outstanding as of Oct 9 2018 1611M
Market Cap as of Oct 9 2018 (CAD) $193M
Cash and Short Term Investments as of July 31 2018 (CAD) $23M
Total Shareholders Equity as of July 31 2018 (CAD) $12M
Number of Warrants $014-$035 (CAD) as of Oct 9 2018 601M
Number of Compensation Warrants $014-$030 (CAD) as of Oct 9 2018 45M
Number of Options $014- $026 (CAD$) as of Oct 9 2018 93M
Developing Bria-OTStrade the First Off-the-Shelf Personalized Immunotherapy
Targeting Adv Breast Cancer Unmet medical need (42000 death in the US in 2017 ) $1 Bil- $5 Bil market opportunity depending on patient treatment stage
Impressive results in 2 proof-of-concept clinical trials Rapid Response Rate Repeated following re-treatment Excellent Safety Profile
Completed enrollment in Phase IIIa clinical trial of Bria-IMTtrade with outstanding safety amp efficacy data Initiated Phase IIa Combination Study of Bria-IMTtrade with Keytrudareg (Merck amp Co Inc)
Developing Bria-OTStrade along with BriaDXtrade its companion diagnostic test Ability to match and treat ~90 of patient population with Off-the-Shelf personalized immunotherapy
Experienced Management has been involved in over 10 drug approvals
Patient B001 Breast 70 No 1101 - 3501 4001 Negative -
Bria-IMTtradeHuman Proof-of-Concept Trials in Breast Cancer (Patient A002)
24
Proof-of-Concept Results Resulted in BriaCellrsquos Immunotherapy Strategy Use BriaDXtrade diagnostic to select only those patients matching Bria-IMTtrade Use BriaDXtrade diagnostic test to select Bria-OTStrade alleles matching ~90 of all patients
Bria-IMTtradeCurrent Phase IIIa Data Supports HLA Matching Hypothesis Six patients treated in 2017 Bria-IMTtrade was safe and well tolerated
Patient 01-002 73-year-old woman with breast cancer diagnosed in 1995 Developed liver metastases in2010 and lung metastases in 2017 Previously treated with 7 rounds of chemotherapy with 8 differentchemotherapy agents Received 5 cycles of Bria-IMTtrade over 3 months then monthly cycles (6 months total)Evaluated after 3 months and 6 months After 3 months despite the extensive prior therapy her scans notedthat ldquothere has been a clear response in the multiple bilateral pulmonary nodulesrdquo The response wasmaintained after 6 months of Bria-IMTtrade treatment She matches Bria-IMTtrade at 2 HLA alleles
The liver tumors were stable to slightly increased at 3 months and then progressed after 6 months
This supports our hypothesis of heightened anti-tumor activity in patients with a matched HLA types Clear path to develop BriaDXtrade to select the patients using HLA testing
1 RLL 29 Not Detectable Not Detectable2 LUL apical pleural based 34 tiny nodule lt 1mm scar tiny nodule lt 1mm scar3 xxx 39 Not Detectable Not Detectable4 40 Not Detectable Not Detectable5 RLL 45 Not Detectable Not Detectable6 LLL 49 Not Detectable Not Detectable7 xxx 52 Not Detectable Not Detectable8 RLL 52 Not Detectable Not Detectable9 RLL 56 Not Detectable Not Detectable
10 RLL costophrenic recess 56 Not Detectable Not Detectable11 XXX 58 Not Detectable Not Detectable12 LUL 60 Not Detectable Not Detectable13 XXX 67 15 1514 RUL 72 15 1515 LLL 76 Not Detectable Not Detectable16 RUL Noncalcified Nodule 77 Not Detectable Not Detectable17 RLL costophrenic recess 79 10 1018 RUL 82 Not Detectable Not Detectable19 RLL 90 Not Detectable Not Detectable20 RLL 91 lt 01 lt 0121 xxx xxx Not Detectable Not Detectable
27
Clinical Development Update ndash Summary 2018 September 26
Completed enrollment of Adv Breast cancer patients in the Phase IIIa ldquomonotherapyrdquo study of Bria-IMTtrade
We have confirmed our mechanism of action and achieved proof of concept
Initial safety data appears superior to that of the other advanced or approved drugs for breast cancer when they were at a similar clinical stage of development
Initial efficacy data is similar or superior to those of other advanced or approved drugs for breast cancer when they were at a similar clinical stage of development
Initiated Combination Study of Bria-IMTtrade with Keytrudareg or Yervoyreg in Adv breast cancer patients expecting even better response rates than those in the ldquomonotherapyrdquo study Initial safety data is expected in 4Q2018 Initial efficacy data is expected in 1Q2019
Bria-OTStrade the first off-the-shelf personalized treatment for advanced breast cancer is expected to enter the clinic in 2019
28
Bria-IMTtrade Excellent Safety Data - To Date
To date Bria-IMTtrade has been dosed in 24 patients (4 in 2004-2005 20 in 2017-2018)
Interim Data (20 patients)-Ongoing Phase IIIa Study (2017-2018)
Bria-IMTtrade has been very well tolerated (ge60 doses given to date) The majority of adverse events (AEs) were limited to expected minor local irritation at the
injection sites No related grade gt3 or unexpected AEs No related serious AEs No serious unexpected related AEs Most patients who have dropped out did so due to worsening of their underlying disease
Based on the current study Bria-IMTtrade has an excellent safety profile
29
Bria-IMTtrade - Efficacy as Predicted
Interim Data (19 patients)-Ongoing Phase IIIa Study (2017-2018) amp Original Study (2004-2005)
PD-L1 expression on circulating cancer cells amp cancer-associated cells in 100 of patients (to date) Strong rationale for combination with checkpoint inhibitors like Keytruda
30
Bria-IMTtrade appears to be most effective in patients who match with Bria-IMT trade at 2 HLA loci (types) further supporting our ldquoHLA Matching Hypothesisrdquo and the development of Bria-OTS trade to cover 90 of the patient population
Combination with immune checkpoint inhibitors may induce a more potent anti-cancer response leading to our strategy of combination studies of Bria-IMT trade with Keytruda or Yervoy
Patients (n) HLA Match
Tumor Shrinkage
Biological Response
4 ge2 50 7515 ge1 27 334 0 0 0
Biological response includes tumor shrinkage or lower circulating cancer associated cells
The confirmatory Bria-IMTtrade monotherapy Phase IIa trial has completed enrollment Additional Support for the HLA-matching hypothesis has been obtained
Bria-IMTtrade Combination Therapy study with immune checkpoint inhibitors Keytrudareg if PD-L12 positive (ge1) Yervoyreg if PD-L12 negative (lt1) Accepting patients from the monotherapy study who develop progressive disease Also enrolling patients directly into this study to enhance experience with the combination In discussion with other pharmaceutical companies to evaluate additional combinations with other
immunotherapies
Bria-OTStrade Off-the-Shelf Personalized Targeted Immunotherapy Developing Bria-OTStrade to co-express GM-CSF and interferon-α Pre-manufacture additional HLA alleles ndash Total of 15 alleles (8 Class I and 7 Class II) Co-development of BriaDXtrade companion diagnostic for HLA typing Combination therapy clinical trial with immune checkpoint inhibitors for non-responders using
information from the Bria-IMTtrade Combination Therapy Study
33
Development Timeline ndash Breast Cancer
20192018 2020 2021
Phase IIIaBria-IMTtrade
Monotherapy
Currently Enrolling Phase IIaBria-IMTtrade + Checkpoint
Currently in discussions with potential partnersPhase II Bria-IMTtrade plus Additional Combinations (1Q19 4Q22)(eg PD-1 Inhibitor PD-L1 inhibitor anti-CTLA4 anti-GITR anti-OX40)
1Q 2Q 3Q 4Q
2023
Bria-OTStrade Off-The-Shelf Personalized ImmunotherapyMonotherapy and Potential Partnered Combo Therapy
(2H19 Ongoing)
Bria-OTStradeOff-the-Shelf Cell Line cGMP Manufacturing
and BriaDXtrade(1Q18 1Q19)
Registration Studies (1Q20 2H22)Bria-IMTtrade with Checkpoint InhibitorsBria-OTStrade +- Checkpoint Inhibitors
34
Immuno-oncology Deals
Recent deals of small biotechs with big pharma in immuno-oncology
35
Date PartnershipDevelopment stage at the time of the deal Deal size
07122018 Immatics-Genmab Preclinical Up to $28B
04042018 OSE Immunotherapeutics-Boehringer Ingelheim Preclinical Up to euro113B ($139B)
02092018 Pieris Pharmaceuticals-Seattle Genetics Preclinical Up to $123B
2142018 Nektar-BMS Ph III Up to $36B
01222018 Juno-Celgene Ph II $9B (Acquisition)
11142017 Loxo-Bayer Larotrectinib (Ph II) LOXO-195 (Ph III) Up to $155B
1032017 CytomX-Amgen Preclinical Up to $15B
03202017 CytomX--BMS Ph III Up to $36B
6282016 Xencor-Novartis Preclinical Up to $24B
Early Stage Clinical Studies (Comparison)
We compared the interim data of Ph IIIa study of Bria-IMTtrade in advanced breast cancer with thedata in the early stage clinical studies of recently approved breast cancer drugs and one fasttracked product candidate
Apples to apples comparison Early Stage Clinical Studies in oncology are typically done in patientswith no other therapeutic options Thus the patients have very advanced disease and response ratesare typically quite low
The patients in our Ph IIIa study have been heavily pre-treated (median 45 prior regimens)Some recent studies of relevance in breast cancer are noted in the following slides
36
Breast Cancer Market Opportunity
Drug Technology Approved for Market (US)Ibrance (palbociclib) CDK 46 Inhibitor HR+HER2- MBC in combination with
fluvestrant or aromatase inhibitor$933M in 1Q2018 $3126M in 2017
Kisqali (ribociclib) CDK 46 Inhibitor 2017 HR+HER2- MBC in combination with fluvestrant or aromatase inhibitor
Peak sales projected at $25B
Verzenio (abemaciclib) CDK 46 Inhibitor 2017 HR+HER2- MBC in combination with fluvestrant or aromatase inhibitor
balixafortide CXCR4 antagonist Fast track designation in 2018 for HER2- MBC who have failed 2 prior regimens
The market for breast cancer drugs is a multibillion dollar market with new drugs being approvedon an ongoing basis indicating the shortage of safe and effective treatments for this deadly disease
37
Competitors- Phase III Clinical Data Bria-IMTtrade shows superior safety and similar to superior efficacy data compared with those of the multi-billion dollar drugs when they were at a similar early stage of clinical development
Injection site reactions No related SAEs or SUSARs
Tumor vol darr ampor darr circul tumor cellsAll Comers 21(419) 26(519)One or More HLA matches 27(415) 33(515)Two or More HLA matches 50 (24) 75 (34)
Sheet1 (3)
Comp -Slides
Data
HLA (2)
HLA
Data (Ph1-2+4Pt)
Competitors (2018)-Slide
Competitors (2018)
In the Pipeline Protein Kinase C delta (PKCδ) Inhibitors
30 of all human malignancies display activating RAS mutations Another 60 showing over-activity of Ras-signaling pathways
Ras has been termed ldquoundruggablerdquo (no one has been able to make a Ras inhibitor drug)
BriaCellrsquos novel proprietary PKCδ inhibitors have shown activity against multiple RAS transformed tumors Lung cancer Melanoma Breast cancer Neuroendocrine cancer Pancreatic cancer Colorectal cancer
This target has an attractive safety profile based on in vivo studies and knock out mouse studies
PKCδ inhibitors should qualify for an accelerated clinical development plan and regulatory pathway
Could be in clinic within 24 months
Cost-Effective Additional Shot-on-Goal and additional partnership opportunities
Early-Stage Preclinical Program
39
Protein Kinase C delta (PKCδ) Inhibitors
Activated PKCδ inhibits RAS degradation which in turn stimulates tumor growth
Koo et al Oncotarget 621328 2016
30 of all human malignancies display activating RASmutations with another 60 showing over-activity of Ras-signaling pathways
BriaCellrsquos novel proprietary PKCδ inhibitors have shownactivity against multiple RAS transformed tumors
This target has an attractive safety profile based on in vivostudies and knock out mouse studies
PKCδ also has potential activity as an immunotherapeuticby blocking TGFβ signaling
PKCδ inhibitors are applicable to specific niche tumor typeswhich provide an accelerated clinical development plan
Structural aspects of first generation inhibitor rottlerin and staurosporine (pan-PKC activator) were combined to create second generation inhibitor KAM1
Third generation inhibitors such as BJE6-106 have improved potency and selectivity Fourth generation inhibitors under development to optimize drug-like characteristics PKCδ inhibitors lack endothelial cell cytotoxicity amp PKCδ deficient mice develop normally and are fertile Potentially no marked intrinsic toxicity by inhibiting PKCδ
Mukai H Saeki T Shimada K Naito Y Matsubara N Nakanishi T Obaishi H Namiki M Sasaki Y Phase 1 combination study of eribulin mesylate with trastuzumab for advanced or recurrent human epidermal growth factor receptor 2 positive breast cancer Invest New Drugs 2015 Feb33(1)119-27
AstraZeneca
Lynparza (Olaparib) + Cediranib
PARP inhibitor + inhibitor of VEGF receptor tyrosine kinases
HR+ HER2- MBC
BC amp OC
2013
28 (8 BC)
3 for BC
Olaparib (a poly (ADP-ribose) polymerase (PARP) inhibitor) amp Cediranib (Vascular endothelial growth factor receptor (VEGFR) 1 2 and 3 tyrosine kinase inhibitor)3 at dose level (DL) 0 (cediranib 20mg olaparib 100mg) 3 at DL1 (cediranib 20mg olaparib 200mg) 7 at DL2 (cediranib 30mg olaparib 200mg) 6 at DL3 (cediranib 30mg olaparib 400mg)
Liu JF Tolaney SM Birrer M Fleming GF Buss MK Dahlberg SE Lee H Whalen C Tyburski K Winer E Ivy P Matulonis UA A Phase 1 trial of the poly(ADP-ribose) polymerase inhibitor olaparib (AZD2281) in combination with the anti-angiogenic cediranib (AZD2171) in recurrent epithelial ovarian or triple-negative breast cancer Eur J Cancer 2013 Sep49(14)2972-8
Reyon Pharmaceutical
VM206RY
Heterologous prime-boost with a truncated HER2 sequence
HER2+ Stage IIIampIV BC
2015
9
2 chemo
Plasmid DNA (pHM-GM-CSF expressing truncated HER2 amp GM-CSF) amp adenoviral vector (Ad-HM containing modified HER2) (2 4 and 8 mgpatientvisit) of pHM-GM-CSF 3x IM weeks 0 2 and 4 Ad-HM 3 times 109 virus particles at week 6
11 PR
4 pts showed 7 minor AEs
Unclear
Kim SB Ahn JH Kim J Jung KH A phase 1 study of a heterologous prime-boost vaccination involving a truncated HER2 sequence in patients with HER2-expressing breast cancer Mol Ther Methods Clin Dev 2015 Sep 30215031 doi 101038mtm201531 eCollection 2015
Rodon J Peacuterez-Fidalgo A Krop IE Burris H Guerrero-Zotano A Britten CD Becerra C Schellens J Richards DA Schuler M Abu-Khalaf M Johnson FM Ranson M Edenfield J Silva AP Hackl W Quadt C Demanse D Duval V Baselga J Phase 11b dose escalation and expansion study of BEZ235 a dual PI3KmTOR inhibitor in patients with advanced solid tumors including patients with advanced breast cancer Cancer Chemother Pharmacol 2018 Jun 7 doi 101007s00280-018-3610-z [Epub ahead of print]
Celgene (Abraxane)
Gemcitabine + Abraxane (nab-paclitaxel)
Chemo + Chemo
OC BC NSCLC amp Panc cancer + Lung OC BC Kaposi sarcoma
MBC
2016
9
Adjuvant chemo (100)chemo post-adjuvant (33)
Gem (nucleoside metabolic inhibitor 1250 mgm2) on days 1 and 8 nab-Pac (microtubule inhibitor) starting dose of 180 mgm2 (cohort 1) 220 mgm2 (cohort 2) and 260 mgm2 (cohort 3) on day 1 of the 21-day cycle using a 3 + 3 design
0
MTD not reached29 Gr3 Neutropenia59 Gr1 Peripheralneuropathy
Yoshitomi S Taira N Doihara H Mizoo T Nogami T Iwamoto T Motoki T Shien T Ogasawara Y Matsuoka J Tsuji H Mitsuhashi T A phase 1 dose-finding and pharmacokinetic study of gemcitabine with nab-paclitaxel in patients with metastatic breast cancer Cancer Chemother Pharmacol 2016 Aug78(2)289-94
Eli Lilly
Erbituxreg (cetuximab) + Taxane
EGFR inhibitor antineoplastic agent + Chemo
Headamp Neck Colorectal Cancer
TNBC
2007-2010
18
1 chemo
Cetuximab (epidermal growth factor receptor (EGFR) antagonist ) an initial loading dose of cetuximab 400 mgm2 followed by a weekly dose of 250 mgm2Paclitaxel (microtubule inhibitor) 80 mgm2 or Docetaxel at an initial dose of 30 mgm2 was administered weekly
56 CR 22 PR
83 Dermatologic toxicity11 Grade3+
Nechushtan H Vainer G Stainberg H Salmon AY Hamburger T Peretz T A phase 12 of a combination of cetuximab and taxane for triple negative breast cancer patients Breast 2014 Aug23(4)435-8
Polyphor
Balixafortide (POL6326) + eribulin
CXCR4 antagonist + tubulin-based antimitotic
Heavily pretreated Relapsed MBC
2014-2016
56
3rd line 3 chemo
3+3 dose escalation The highest dose was established as eribulin 14 mgmsup2 on days 2 and 9 and balixafortide 55 mgkg on days 1minus3 and 8minus10 of the 21-day cycle
30 PR
41 Gr34 Neutropenia11 Gr34 Leucopenia11 Gr34 Febrileneutropenia2 Related mortalities
Apr 2018 Fast Track for HER2-MBC who have failed 2prior regimens
Pernas S Martin M Kaufman PA Gil-Martin M Gomez Pardo P Lopez-Tarruella S Manso L Ciruelos E Perez-Fidalgo JA Hernando C Ademuyiwa FO Weilbaecher K Mayer I Pluard TJ Martinez Garcia M Vahdat L Perez-Garcia J Wach A Barker D Fung S Romagnoli B Cortes J Balixafortide plus eribulin in HER2-negative metastatic breast cancer a phase 1 single-arm dose-escalation trial Lancet Oncol 2018 Jun19(6)812-824
11 PRndashbut only + letrozole (No Resp on monotherapy)
61 Gr34 Neutropenia39 Gr34 Leucopenia
$933M in 1Q2018 $31B in 2017
Tamura K Mukai H Naito Y Yonemori K Kodaira M Tanabe Y Yamamoto N Osera S Sasaki M Mori Y Hashigaki S Nagasawa T Umeyama Y Yoshino T Phase I study of palbociclib a cyclin-dependent kinase 46 inhibitor in Japanese patients Cancer Sci 2016 Jun107(6)755-63 doi 101111cas12932 Epub 2016 May 11
Pfizer
Ibrancereg (palbociclib)
CDK 46 Inhibitor
HR+ HER2- MBC
Heavily pretreated Relapsed Metastatic Cancer
2004-2008
41 (5 BC)
chemo naiumlve (17) 1-2 (51)3 (29) 3+ (2)
Palbociclib 25-150 mg dose ranging
0
20 Gr34 Neutropenia23 Gr34 Leucopenia
$933M in 1Q2018 $31B in 2017
Flaherty KT Lorusso PM Demichele A Abramson VG Courtney R Randolph SS Shaik MN Wilner KD ODwyer PJ Schwartz GK Phase I dose-escalation trial of the oral cyclin-dependent kinase 46 inhibitor PD 0332991 administered using a 21-day schedule in patients with advanced cancer Clin Cancer Res 2012 Jan 1518(2)568-76 doi 1011581078-0432CCR-11-0509 Epub 2011 Nov 16
Novartis
Kisqalireg (ribociclib)
CDK 46 Inhibitors
Premenopausal HR+ HER2- MBC
Heavily pretreated Relapsed Metastatic Cancer
2016
132 (20 BC)
0-1 (25) 2-3 (42) 4+ (32)
Ribociclib 50 mg ranging up to 1200 mg dose escalation
23 PRndashincluded 1 in BC (5 of BC pts)
27 Gr34 Neutropenia17 Gr34 Leucopenia
Peak sales projected at $25B
Infante JR Cassier PA Gerecitano JF Witteveen PO Chugh R Ribrag V Chakraborty A Matano A Dobson JR Crystal AS Parasuraman S Shapiro GI A Phase I Study of the Cyclin-Dependent Kinase 46 Inhibitor Ribociclib (LEE011) in Patients with Advanced Solid Tumors and Lymphomas Clin Cancer Res 2016 Dec 122(23)5696-5705 Epub 2016 Aug 19
Eli Lilly
Verzenioreg (abemaciclib)
CDK 46 Inhibitors
HR+HER2minusMBC
Heavily pretreated Relapsed Metastatic Cancer
2016
12 (1 BC)
1 (312) 2 (212) 3+ (7)
Abemaciclib 100 mg ranging up to 200 mg dose escalation
17 PR (included 1 in BC)
17 Gr34 Neutropenia33 Gr34 Leucopenia
Peak sales projected at $2B
Fujiwara Y Tamura K Kondo S Tanabe Y Iwasa S Shimomura A Kitano S Ogasawara K Turner PK Mori J Asou H Chan EM Yamamoto N Phase 1 study of abemaciclib an inhibitor of CDK 4 and 6 as a single agent for Japanese patients with advanced cancer Cancer Chemother Pharmacol 2016 Aug78(2)281-8 doi 101007s00280-016-3085-8 Epub 2016 Jun 16
Mukai H Saeki T Shimada K Naito Y Matsubara N Nakanishi T Obaishi H Namiki M Sasaki Y Phase 1 combination study of eribulin mesylate with trastuzumab for advanced or recurrent human epidermal growth factor receptor 2 positive breast cancer Invest New Drugs 2015 Feb33(1)119-27
AstraZeneca
Lynparza (Olaparib)+ Cediranib
PARP inhibitor+ inhibitor of VEGF RTK
HR+ HER2- MBC
BC amp OC
13
28 (8 BC)
3 for BC
Olaparib (a poly (ADP-ribose) polymerase (PARP) inhibitor) amp Cediranib (Vascular endothelial growth factor receptor (VEGFR) 1 2 and 3 tyrosine kinase inhibitor)3 at dose level (DL) 0 (cediranib 20mg olaparib 100mg) 3 at DL1 (cediranib 20mg olaparib 200mg) 7 at DL2 (cediranib 30mg olaparib 200mg) 6 at DL3 (cediranib 30mg olaparib 400mg)
Liu JF Tolaney SM Birrer M Fleming GF Buss MK Dahlberg SE Lee H Whalen C Tyburski K Winer E Ivy P Matulonis UA A Phase 1 trial of the poly(ADP-ribose) polymerase inhibitor olaparib (AZD2281) in combination with the anti-angiogenic cediranib (AZD2171) in recurrent epithelial ovarian or triple-negative breast cancer Eur J Cancer 2013 Sep49(14)2972-8
ReyonPharma
VM206RY
Heterologous prime-boost with a truncated HER2 sequence
HER2+ Stg IIIampIV BC
15
9
2 chemo
Plasmid DNA (pHM-GM-CSF expressing truncated HER2 amp GM-CSF) amp adenoviral vector (Ad-HM containing modified HER2) (2 4 and 8 mgpatientvisit) of pHM-GM-CSF 3x IM weeks 0 2 and 4 Ad-HM 3 times 109 virus particles at week 6
11 PR
4 pts 7 minor AEs
Unclear
Kim SB Ahn JH Kim J Jung KH A phase 1 study of a heterologous prime-boost vaccination involving a truncated HER2 sequence in patients with HER2-expressing breast cancer Mol Ther Methods Clin Dev 2015 Sep 30215031 doi 101038mtm201531 eCollection 2015
Rodon J Peacuterez-Fidalgo A Krop IE Burris H Guerrero-Zotano A Britten CD Becerra C Schellens J Richards DA Schuler M Abu-Khalaf M Johnson FM Ranson M Edenfield J Silva AP Hackl W Quadt C Demanse D Duval V Baselga J Phase 11b dose escalation and expansion study of BEZ235 a dual PI3KmTOR inhibitor in patients with advanced solid tumors including patients with advanced breast cancer Cancer Chemother Pharmacol 2018 Jun 7 doi 101007s00280-018-3610-z [Epub ahead of print]
Celgene(Abraxane)
Gemcitabine + Abraxane (nab-paclitaxel)
Chemo+ Chemo
OC BC NSCLC PC + LC OC BC KS
MBC
16
9
Adjuv chemo (100)chemo post-adjuv (33)
Gem (nucleoside metabolic inhibitor 1250 mgm2) on days 1 and 8 nab-Pac (microtubule inhibitor) starting dose of 180 mgm2 (cohort 1) 220 mgm2 (cohort 2) and 260 mgm2 (cohort 3) on day 1 of the 21-day cycle using a 3 + 3 design
0
MTD not reached29 Gr3 Neutropenia59 Gr1 Peripheralneuropathy
Yoshitomi S Taira N Doihara H Mizoo T Nogami T Iwamoto T Motoki T Shien T Ogasawara Y Matsuoka J Tsuji H Mitsuhashi T A phase 1 dose-finding and pharmacokinetic study of gemcitabine with nab-paclitaxel in patients with metastatic breast cancer Cancer Chemother Pharmacol 2016 Aug78(2)289-94
Eli Lilly
Erbituxreg (cetuximab) + Taxane
EGFR inhibitor antineoplastic agent + Chemo
Head amp NeckColorectal
TNBC
07-10
18
1 chemo
Cetuximab (epidermal growth factor receptor (EGFR) antagonist ) an initial loading dose of cetuximab 400 mgm2 followed by a weekly dose of 250 mgm2Paclitaxel (microtubule inhibitor) 80 mgm2 or Docetaxel at an initial dose of 30 mgm2 was administered weekly
56 CR 22 PR
83 Dermatologic toxicity11 Grade3+
Nechushtan H Vainer G Stainberg H Salmon AY Hamburger T Peretz T A phase 12 of a combination of cetuximab and taxane for triple negative breast cancer patients Breast 2014 Aug23(4)435-8
Polyphor
Balixafortide (POL6326) + eribulin
CXCR4 antagonist + tubulin-based antimitotic
Heavily pretreatedRelapsed MBC
14-16
56
3rd line 3 chemo
3+3 dose escalation The highest dose was established as eribulin 14 mgmsup2 on days 2 and 9 and balixafortide 55 mgkg on days 1minus3 and 8minus10 of the 21-day cycle
30 PR
41 Gr34 Neutropenia11 Gr34 Leucopenia11 Gr34 Febrileneutropenia2 Related mortalities
42018 Fast Track (HER2-MBC failed 2 prior regimens)
Pernas S Martin M Kaufman PA Gil-Martin M Gomez Pardo P Lopez-Tarruella S Manso L Ciruelos E Perez-Fidalgo JA Hernando C Ademuyiwa FO Weilbaecher K Mayer I Pluard TJ Martinez Garcia M Vahdat L Perez-Garcia J Wach A Barker D Fung S Romagnoli B Cortes J Balixafortide plus eribulin in HER2-negative metastatic breast cancer a phase 1 single-arm dose-escalation trial Lancet Oncol 2018 Jun19(6)812-824
1 PRndashbut only + letrozoleNo Resp on monotherapy
61 Gr34 Neutropenia39 Gr34 Leucopenia
$933M (1Q18)$31B (2017)
Tamura K Mukai H Naito Y Yonemori K Kodaira M Tanabe Y Yamamoto N Osera S Sasaki M Mori Y Hashigaki S Nagasawa T Umeyama Y Yoshino T Phase I study of palbociclib a cyclin-dependent kinase 46 inhibitor in Japanese patients Cancer Sci 2016 Jun107(6)755-63 doi 101111cas12932 Epub 2016 May 11
Pfizer
Ibrancereg (palbociclib)
CDK 46 Inhibitor
HR+ HER2- MBC
Heavily pretreatedRelapsed Met Cancer
04-08
41 (5 BC)
chemo naiumlve (17)1-2(51) 3(29) 3+(2)
Palbociclib 25-150 mg dose ranging
0
20 Gr34 Neutropenia23 Gr34 Leucopenia
$933M (1Q18)$31B (2017)
Flaherty KT Lorusso PM Demichele A Abramson VG Courtney R Randolph SS Shaik MN Wilner KD ODwyer PJ Schwartz GK Phase I dose-escalation trial of the oral cyclin-dependent kinase 46 inhibitor PD 0332991 administered using a 21-day schedule in patients with advanced cancer Clin Cancer Res 2012 Jan 1518(2)568-76 doi 1011581078-0432CCR-11-0509 Epub 2011 Nov 16
Novartis
Kisqalireg (ribociclib)
CDK 46 Inhibitor
Premenopausal HR+ HER2- MBC
Heavily pretreatedRelapsed Met Cancer
16
132 (20 BC)
0-1 (25) 2-3 (42)4+ (32)
Ribociclib 50 mg ranging up to 1200 mg dose escalation
23 PR-included 1 BC (5 of BC pts)
27 Gr34 Neutropenia17 Gr34 Leucopenia
Peak sales est at $25B
Infante JR Cassier PA Gerecitano JF Witteveen PO Chugh R Ribrag V Chakraborty A Matano A Dobson JR Crystal AS Parasuraman S Shapiro GI A Phase I Study of the Cyclin-Dependent Kinase 46 Inhibitor Ribociclib (LEE011) in Patients with Advanced Solid Tumors and Lymphomas Clin Cancer Res 2016 Dec 122(23)5696-5705 Epub 2016 Aug 19
Eli Lilly
Verzenioreg (abemaciclib)
CDK 46 Inhibitor
HR+HER2minusMBC
Heavily pretreatedRelapsed Met Cancer
16
12 (1 BC)
1 (312) 2 (212) 3+(7)
Abemaciclib 100 mg ranging up to 200 mg dose escalation
17 PR (included 1 BC)
17 Gr34 Neutropenia33 Gr34 Leucopenia
Peak sales est at $2B
Fujiwara Y Tamura K Kondo S Tanabe Y Iwasa S Shimomura A Kitano S Ogasawara K Turner PK Mori J Asou H Chan EM Yamamoto N Phase 1 study of abemaciclib an inhibitor of CDK 4 and 6 as a single agent for Japanese patients with advanced cancer Cancer Chemother Pharmacol 2016 Aug78(2)281-8 doi 101007s00280-016-3085-8 Epub 2016 Jun 16
Mukai H Saeki T Shimada K Naito Y Matsubara N Nakanishi T Obaishi H Namiki M Sasaki Y Phase 1 combination study of eribulin mesylate with trastuzumab for advanced or recurrent human epidermal growth factor receptor 2 positive breast cancer Invest New Drugs 2015 Feb33(1)119-27
AstraZeneca
Lynparza (Olaparib) + Cediranib
PARP inhibitor + inhibitor of VEGF receptor tyrosine kinases
HR+ HER2- MBC
BC amp OC
2013
28 (8 BC)
3 for BC
Olaparib (a poly (ADP-ribose) polymerase (PARP) inhibitor) amp Cediranib (Vascular endothelial growth factor receptor (VEGFR) 1 2 and 3 tyrosine kinase inhibitor)3 at dose level (DL) 0 (cediranib 20mg olaparib 100mg) 3 at DL1 (cediranib 20mg olaparib 200mg) 7 at DL2 (cediranib 30mg olaparib 200mg) 6 at DL3 (cediranib 30mg olaparib 400mg)
Liu JF Tolaney SM Birrer M Fleming GF Buss MK Dahlberg SE Lee H Whalen C Tyburski K Winer E Ivy P Matulonis UA A Phase 1 trial of the poly(ADP-ribose) polymerase inhibitor olaparib (AZD2281) in combination with the anti-angiogenic cediranib (AZD2171) in recurrent epithelial ovarian or triple-negative breast cancer Eur J Cancer 2013 Sep49(14)2972-8
Reyon Pharmaceutical
VM206RY
Heterologous prime-boost with a truncated HER2 sequence
HER2+ Stage IIIampIV BC
2015
9
2 chemo
Plasmid DNA (pHM-GM-CSF expressing truncated HER2 amp GM-CSF) amp adenoviral vector (Ad-HM containing modified HER2) (2 4 and 8 mgpatientvisit) of pHM-GM-CSF 3x IM weeks 0 2 and 4 Ad-HM 3 times 109 virus particles at week 6
11 PR
4 pts showed 7 minor AEs
Unclear
Kim SB Ahn JH Kim J Jung KH A phase 1 study of a heterologous prime-boost vaccination involving a truncated HER2 sequence in patients with HER2-expressing breast cancer Mol Ther Methods Clin Dev 2015 Sep 30215031 doi 101038mtm201531 eCollection 2015
Rodon J Peacuterez-Fidalgo A Krop IE Burris H Guerrero-Zotano A Britten CD Becerra C Schellens J Richards DA Schuler M Abu-Khalaf M Johnson FM Ranson M Edenfield J Silva AP Hackl W Quadt C Demanse D Duval V Baselga J Phase 11b dose escalation and expansion study of BEZ235 a dual PI3KmTOR inhibitor in patients with advanced solid tumors including patients with advanced breast cancer Cancer Chemother Pharmacol 2018 Jun 7 doi 101007s00280-018-3610-z [Epub ahead of print]
Celgene (Abraxane)
Gemcitabine + Abraxane (nab-paclitaxel)
Chemo + Chemo
OC BC NSCLC amp Panc cancer + Lung OC BC Kaposi sarcoma
MBC
2016
9
Adjuvant chemo (100)chemo post-adjuvant (33)
Gem (nucleoside metabolic inhibitor 1250 mgm2) on days 1 and 8 nab-Pac (microtubule inhibitor) starting dose of 180 mgm2 (cohort 1) 220 mgm2 (cohort 2) and 260 mgm2 (cohort 3) on day 1 of the 21-day cycle using a 3 + 3 design
0
MTD not reached29 Gr3 Neutropenia59 Gr1 Peripheralneuropathy
Yoshitomi S Taira N Doihara H Mizoo T Nogami T Iwamoto T Motoki T Shien T Ogasawara Y Matsuoka J Tsuji H Mitsuhashi T A phase 1 dose-finding and pharmacokinetic study of gemcitabine with nab-paclitaxel in patients with metastatic breast cancer Cancer Chemother Pharmacol 2016 Aug78(2)289-94
Eli Lilly
Erbituxreg (cetuximab) + Taxane
EGFR inhibitor antineoplastic agent + Chemo
Headamp Neck Colorectal Cancer
TNBC
2007-2010
18
1 chemo
Cetuximab (epidermal growth factor receptor (EGFR) antagonist ) an initial loading dose of cetuximab 400 mgm2 followed by a weekly dose of 250 mgm2Paclitaxel (microtubule inhibitor) 80 mgm2 or Docetaxel at an initial dose of 30 mgm2 was administered weekly
56 CR 22 PR
83 Dermatologic toxicity11 Grade3+
Nechushtan H Vainer G Stainberg H Salmon AY Hamburger T Peretz T A phase 12 of a combination of cetuximab and taxane for triple negative breast cancer patients Breast 2014 Aug23(4)435-8
Polyphor
Balixafortide (POL6326) + eribulin
CXCR4 antagonist + tubulin-based antimitotic
Heavily pretreated Relapsed MBC
2014-2016
56
3rd line 3 chemo
3+3 dose escalation The highest dose was established as eribulin 14 mgmsup2 on days 2 and 9 and balixafortide 55 mgkg on days 1minus3 and 8minus10 of the 21-day cycle
30 PR
41 Gr34 Neutropenia11 Gr34 Leucopenia11 Gr34 Febrileneutropenia2 Related mortalities
Apr 2018 Fast Track for HER2-MBC who have failed 2prior regimens
Pernas S Martin M Kaufman PA Gil-Martin M Gomez Pardo P Lopez-Tarruella S Manso L Ciruelos E Perez-Fidalgo JA Hernando C Ademuyiwa FO Weilbaecher K Mayer I Pluard TJ Martinez Garcia M Vahdat L Perez-Garcia J Wach A Barker D Fung S Romagnoli B Cortes J Balixafortide plus eribulin in HER2-negative metastatic breast cancer a phase 1 single-arm dose-escalation trial Lancet Oncol 2018 Jun19(6)812-824
11 PRndashbut only + letrozole (No Resp on monotherapy)
61 Gr34 Neutropenia39 Gr34 Leucopenia
$933M in 1Q2018 $31B in 2017
Tamura K Mukai H Naito Y Yonemori K Kodaira M Tanabe Y Yamamoto N Osera S Sasaki M Mori Y Hashigaki S Nagasawa T Umeyama Y Yoshino T Phase I study of palbociclib a cyclin-dependent kinase 46 inhibitor in Japanese patients Cancer Sci 2016 Jun107(6)755-63 doi 101111cas12932 Epub 2016 May 11
Pfizer
Ibrancereg (palbociclib)
CDK 46 Inhibitor
HR+ HER2- MBC
Heavily pretreated Relapsed Metastatic Cancer
2004-2008
41 (5 BC)
chemo naiumlve (17) 1-2 (51)3 (29) 3+ (2)
Palbociclib 25-150 mg dose ranging
0
20 Gr34 Neutropenia23 Gr34 Leucopenia
$933M in 1Q2018 $31B in 2017
Flaherty KT Lorusso PM Demichele A Abramson VG Courtney R Randolph SS Shaik MN Wilner KD ODwyer PJ Schwartz GK Phase I dose-escalation trial of the oral cyclin-dependent kinase 46 inhibitor PD 0332991 administered using a 21-day schedule in patients with advanced cancer Clin Cancer Res 2012 Jan 1518(2)568-76 doi 1011581078-0432CCR-11-0509 Epub 2011 Nov 16
Novartis
Kisqalireg (ribociclib)
CDK 46 Inhibitors
Premenopausal HR+ HER2- MBC
Heavily pretreated Relapsed Metastatic Cancer
2016
132 (20 BC)
0-1 (25) 2-3 (42) 4+ (32)
Ribociclib 50 mg ranging up to 1200 mg dose escalation
23 PRndashincluded 1 in BC (5 of BC pts)
27 Gr34 Neutropenia17 Gr34 Leucopenia
Peak sales projected at $25B
Infante JR Cassier PA Gerecitano JF Witteveen PO Chugh R Ribrag V Chakraborty A Matano A Dobson JR Crystal AS Parasuraman S Shapiro GI A Phase I Study of the Cyclin-Dependent Kinase 46 Inhibitor Ribociclib (LEE011) in Patients with Advanced Solid Tumors and Lymphomas Clin Cancer Res 2016 Dec 122(23)5696-5705 Epub 2016 Aug 19
Eli Lilly
Verzenioreg (abemaciclib)
CDK 46 Inhibitors
HR+HER2minusMBC
Heavily pretreated Relapsed Metastatic Cancer
2016
12 (1 BC)
1 (312) 2 (212) 3+ (7)
Abemaciclib 100 mg ranging up to 200 mg dose escalation
17 PR (included 1 in BC)
17 Gr34 Neutropenia33 Gr34 Leucopenia
Peak sales projected at $2B
Fujiwara Y Tamura K Kondo S Tanabe Y Iwasa S Shimomura A Kitano S Ogasawara K Turner PK Mori J Asou H Chan EM Yamamoto N Phase 1 study of abemaciclib an inhibitor of CDK 4 and 6 as a single agent for Japanese patients with advanced cancer Cancer Chemother Pharmacol 2016 Aug78(2)281-8 doi 101007s00280-016-3085-8 Epub 2016 Jun 16
Mukai H Saeki T Shimada K Naito Y Matsubara N Nakanishi T Obaishi H Namiki M Sasaki Y Phase 1 combination study of eribulin mesylate with trastuzumab for advanced or recurrent human epidermal growth factor receptor 2 positive breast cancer Invest New Drugs 2015 Feb33(1)119-27
AstraZeneca
Lynparza (Olaparib)+ Cediranib
PARP inhibitor+ inhibitor of VEGF RTK
HR+ HER2- MBC
BC amp OC
13
28 (8 BC)
3 for BC
Olaparib (a poly (ADP-ribose) polymerase (PARP) inhibitor) amp Cediranib (Vascular endothelial growth factor receptor (VEGFR) 1 2 and 3 tyrosine kinase inhibitor)3 at dose level (DL) 0 (cediranib 20mg olaparib 100mg) 3 at DL1 (cediranib 20mg olaparib 200mg) 7 at DL2 (cediranib 30mg olaparib 200mg) 6 at DL3 (cediranib 30mg olaparib 400mg)
Liu JF Tolaney SM Birrer M Fleming GF Buss MK Dahlberg SE Lee H Whalen C Tyburski K Winer E Ivy P Matulonis UA A Phase 1 trial of the poly(ADP-ribose) polymerase inhibitor olaparib (AZD2281) in combination with the anti-angiogenic cediranib (AZD2171) in recurrent epithelial ovarian or triple-negative breast cancer Eur J Cancer 2013 Sep49(14)2972-8
ReyonPharma
VM206RY
Heterologous prime-boost with a truncated HER2 sequence
HER2+ Stg IIIampIV BC
15
9
2 chemo
Plasmid DNA (pHM-GM-CSF expressing truncated HER2 amp GM-CSF) amp adenoviral vector (Ad-HM containing modified HER2) (2 4 and 8 mgpatientvisit) of pHM-GM-CSF 3x IM weeks 0 2 and 4 Ad-HM 3 times 109 virus particles at week 6
11 PR
4 pts 7 minor AEs
Unclear
Kim SB Ahn JH Kim J Jung KH A phase 1 study of a heterologous prime-boost vaccination involving a truncated HER2 sequence in patients with HER2-expressing breast cancer Mol Ther Methods Clin Dev 2015 Sep 30215031 doi 101038mtm201531 eCollection 2015
Rodon J Peacuterez-Fidalgo A Krop IE Burris H Guerrero-Zotano A Britten CD Becerra C Schellens J Richards DA Schuler M Abu-Khalaf M Johnson FM Ranson M Edenfield J Silva AP Hackl W Quadt C Demanse D Duval V Baselga J Phase 11b dose escalation and expansion study of BEZ235 a dual PI3KmTOR inhibitor in patients with advanced solid tumors including patients with advanced breast cancer Cancer Chemother Pharmacol 2018 Jun 7 doi 101007s00280-018-3610-z [Epub ahead of print]
Celgene(Abraxane)
Gemcitabine + Abraxane (nab-paclitaxel)
Chemo+ Chemo
OC BC NSCLC PC + LC OC BC KS
MBC
16
9
Adjuv chemo (100)chemo post-adjuv (33)
Gem (nucleoside metabolic inhibitor 1250 mgm2) on days 1 and 8 nab-Pac (microtubule inhibitor) starting dose of 180 mgm2 (cohort 1) 220 mgm2 (cohort 2) and 260 mgm2 (cohort 3) on day 1 of the 21-day cycle using a 3 + 3 design
0
MTD not reached29 Gr3 Neutropenia59 Gr1 Peripheralneuropathy
Yoshitomi S Taira N Doihara H Mizoo T Nogami T Iwamoto T Motoki T Shien T Ogasawara Y Matsuoka J Tsuji H Mitsuhashi T A phase 1 dose-finding and pharmacokinetic study of gemcitabine with nab-paclitaxel in patients with metastatic breast cancer Cancer Chemother Pharmacol 2016 Aug78(2)289-94
Eli Lilly
Erbituxreg (cetuximab) + Taxane
EGFR inhibitor antineoplastic agent + Chemo
Head amp NeckColorectal
TNBC
07-10
18
1 chemo
Cetuximab (epidermal growth factor receptor (EGFR) antagonist ) an initial loading dose of cetuximab 400 mgm2 followed by a weekly dose of 250 mgm2Paclitaxel (microtubule inhibitor) 80 mgm2 or Docetaxel at an initial dose of 30 mgm2 was administered weekly
56 CR 22 PR
83 Dermatologic toxicity11 Grade3+
Nechushtan H Vainer G Stainberg H Salmon AY Hamburger T Peretz T A phase 12 of a combination of cetuximab and taxane for triple negative breast cancer patients Breast 2014 Aug23(4)435-8
Polyphor
Balixafortide (POL6326) + eribulin
CXCR4 antagonist + tubulin-based antimitotic
Heavily pretreatedRelapsed MBC
14-16
56
3rd line 3 chemo
3+3 dose escalation The highest dose was established as eribulin 14 mgmsup2 on days 2 and 9 and balixafortide 55 mgkg on days 1minus3 and 8minus10 of the 21-day cycle
30 PR
41 Gr34 Neutropenia11 Gr34 Leucopenia11 Gr34 Febrileneutropenia2 Related mortalities
42018 Fast Track (HER2-MBC failed 2 prior regimens)
Pernas S Martin M Kaufman PA Gil-Martin M Gomez Pardo P Lopez-Tarruella S Manso L Ciruelos E Perez-Fidalgo JA Hernando C Ademuyiwa FO Weilbaecher K Mayer I Pluard TJ Martinez Garcia M Vahdat L Perez-Garcia J Wach A Barker D Fung S Romagnoli B Cortes J Balixafortide plus eribulin in HER2-negative metastatic breast cancer a phase 1 single-arm dose-escalation trial Lancet Oncol 2018 Jun19(6)812-824
1 PRndashbut only + letrozoleNo Resp on monotherapy
61 Gr34 Neutropenia39 Gr34 Leucopenia
$933M (1Q18)$31B (2017)
Tamura K Mukai H Naito Y Yonemori K Kodaira M Tanabe Y Yamamoto N Osera S Sasaki M Mori Y Hashigaki S Nagasawa T Umeyama Y Yoshino T Phase I study of palbociclib a cyclin-dependent kinase 46 inhibitor in Japanese patients Cancer Sci 2016 Jun107(6)755-63 doi 101111cas12932 Epub 2016 May 11
Pfizer
Ibrancereg (palbociclib)
CDK 46 Inhibitor
HR+ HER2- MBC
Heavily pretreatedRelapsed Met Cancer
04-08
41 (5 BC)
chemo naiumlve (17)1-2(51) 3(29) 3+(2)
Palbociclib 25-150 mg dose ranging
0
20 Gr34 Neutropenia23 Gr34 Leucopenia
$933M (1Q18)$31B (2017)
Flaherty KT Lorusso PM Demichele A Abramson VG Courtney R Randolph SS Shaik MN Wilner KD ODwyer PJ Schwartz GK Phase I dose-escalation trial of the oral cyclin-dependent kinase 46 inhibitor PD 0332991 administered using a 21-day schedule in patients with advanced cancer Clin Cancer Res 2012 Jan 1518(2)568-76 doi 1011581078-0432CCR-11-0509 Epub 2011 Nov 16
Novartis
Kisqalireg (ribociclib)
CDK 46 Inhibitor
Premenopausal HR+ HER2- MBC
Heavily pretreatedRelapsed Met Cancer
16
132 (20 BC)
0-1 (25) 2-3 (42)4+ (32)
Ribociclib 50 mg ranging up to 1200 mg dose escalation
23 PR-included 1 BC (5 of BC pts)
27 Gr34 Neutropenia17 Gr34 Leucopenia
Peak sales est at $25B
Infante JR Cassier PA Gerecitano JF Witteveen PO Chugh R Ribrag V Chakraborty A Matano A Dobson JR Crystal AS Parasuraman S Shapiro GI A Phase I Study of the Cyclin-Dependent Kinase 46 Inhibitor Ribociclib (LEE011) in Patients with Advanced Solid Tumors and Lymphomas Clin Cancer Res 2016 Dec 122(23)5696-5705 Epub 2016 Aug 19
Eli Lilly
Verzenioreg (abemaciclib)
CDK 46 Inhibitor
HR+HER2minusMBC
Heavily pretreatedRelapsed Met Cancer
16
12 (1 BC)
1 (312) 2 (212) 3+(7)
Abemaciclib 100 mg ranging up to 200 mg dose escalation
17 PR (included 1 BC)
17 Gr34 Neutropenia33 Gr34 Leucopenia
Peak sales est at $2B
Fujiwara Y Tamura K Kondo S Tanabe Y Iwasa S Shimomura A Kitano S Ogasawara K Turner PK Mori J Asou H Chan EM Yamamoto N Phase 1 study of abemaciclib an inhibitor of CDK 4 and 6 as a single agent for Japanese patients with advanced cancer Cancer Chemother Pharmacol 2016 Aug78(2)281-8 doi 101007s00280-016-3085-8 Epub 2016 Jun 16
Developing Bria-OTStrade the First Off-the-Shelf Personalized Immunotherapy
Targeting Adv Breast Cancer Unmet medical need (42000 death in the US in 2017 ) $1 Bil- $5 Bil market opportunity depending on patient treatment stage
Impressive results in 2 proof-of-concept clinical trials Rapid Response Rate Repeated following re-treatment Excellent Safety Profile
Completed enrollment in Phase IIIa clinical trial of Bria-IMTtrade with outstanding safety amp efficacy data Initiated Phase IIa Combination Study of Bria-IMTtrade with Keytrudareg (Merck amp Co Inc)
Developing Bria-OTStrade along with BriaDXtrade its companion diagnostic test Ability to match and treat ~90 of patient population with Off-the-Shelf personalized immunotherapy
Experienced Management has been involved in over 10 drug approvals
Patient B001 Breast 70 No 1101 - 3501 4001 Negative -
Bria-IMTtradeHuman Proof-of-Concept Trials in Breast Cancer (Patient A002)
24
Proof-of-Concept Results Resulted in BriaCellrsquos Immunotherapy Strategy Use BriaDXtrade diagnostic to select only those patients matching Bria-IMTtrade Use BriaDXtrade diagnostic test to select Bria-OTStrade alleles matching ~90 of all patients
Bria-IMTtradeCurrent Phase IIIa Data Supports HLA Matching Hypothesis Six patients treated in 2017 Bria-IMTtrade was safe and well tolerated
Patient 01-002 73-year-old woman with breast cancer diagnosed in 1995 Developed liver metastases in2010 and lung metastases in 2017 Previously treated with 7 rounds of chemotherapy with 8 differentchemotherapy agents Received 5 cycles of Bria-IMTtrade over 3 months then monthly cycles (6 months total)Evaluated after 3 months and 6 months After 3 months despite the extensive prior therapy her scans notedthat ldquothere has been a clear response in the multiple bilateral pulmonary nodulesrdquo The response wasmaintained after 6 months of Bria-IMTtrade treatment She matches Bria-IMTtrade at 2 HLA alleles
The liver tumors were stable to slightly increased at 3 months and then progressed after 6 months
This supports our hypothesis of heightened anti-tumor activity in patients with a matched HLA types Clear path to develop BriaDXtrade to select the patients using HLA testing
1 RLL 29 Not Detectable Not Detectable2 LUL apical pleural based 34 tiny nodule lt 1mm scar tiny nodule lt 1mm scar3 xxx 39 Not Detectable Not Detectable4 40 Not Detectable Not Detectable5 RLL 45 Not Detectable Not Detectable6 LLL 49 Not Detectable Not Detectable7 xxx 52 Not Detectable Not Detectable8 RLL 52 Not Detectable Not Detectable9 RLL 56 Not Detectable Not Detectable
10 RLL costophrenic recess 56 Not Detectable Not Detectable11 XXX 58 Not Detectable Not Detectable12 LUL 60 Not Detectable Not Detectable13 XXX 67 15 1514 RUL 72 15 1515 LLL 76 Not Detectable Not Detectable16 RUL Noncalcified Nodule 77 Not Detectable Not Detectable17 RLL costophrenic recess 79 10 1018 RUL 82 Not Detectable Not Detectable19 RLL 90 Not Detectable Not Detectable20 RLL 91 lt 01 lt 0121 xxx xxx Not Detectable Not Detectable
27
Clinical Development Update ndash Summary 2018 September 26
Completed enrollment of Adv Breast cancer patients in the Phase IIIa ldquomonotherapyrdquo study of Bria-IMTtrade
We have confirmed our mechanism of action and achieved proof of concept
Initial safety data appears superior to that of the other advanced or approved drugs for breast cancer when they were at a similar clinical stage of development
Initial efficacy data is similar or superior to those of other advanced or approved drugs for breast cancer when they were at a similar clinical stage of development
Initiated Combination Study of Bria-IMTtrade with Keytrudareg or Yervoyreg in Adv breast cancer patients expecting even better response rates than those in the ldquomonotherapyrdquo study Initial safety data is expected in 4Q2018 Initial efficacy data is expected in 1Q2019
Bria-OTStrade the first off-the-shelf personalized treatment for advanced breast cancer is expected to enter the clinic in 2019
28
Bria-IMTtrade Excellent Safety Data - To Date
To date Bria-IMTtrade has been dosed in 24 patients (4 in 2004-2005 20 in 2017-2018)
Interim Data (20 patients)-Ongoing Phase IIIa Study (2017-2018)
Bria-IMTtrade has been very well tolerated (ge60 doses given to date) The majority of adverse events (AEs) were limited to expected minor local irritation at the
injection sites No related grade gt3 or unexpected AEs No related serious AEs No serious unexpected related AEs Most patients who have dropped out did so due to worsening of their underlying disease
Based on the current study Bria-IMTtrade has an excellent safety profile
29
Bria-IMTtrade - Efficacy as Predicted
Interim Data (19 patients)-Ongoing Phase IIIa Study (2017-2018) amp Original Study (2004-2005)
PD-L1 expression on circulating cancer cells amp cancer-associated cells in 100 of patients (to date) Strong rationale for combination with checkpoint inhibitors like Keytruda
30
Bria-IMTtrade appears to be most effective in patients who match with Bria-IMT trade at 2 HLA loci (types) further supporting our ldquoHLA Matching Hypothesisrdquo and the development of Bria-OTS trade to cover 90 of the patient population
Combination with immune checkpoint inhibitors may induce a more potent anti-cancer response leading to our strategy of combination studies of Bria-IMT trade with Keytruda or Yervoy
Patients (n) HLA Match
Tumor Shrinkage
Biological Response
4 ge2 50 7515 ge1 27 334 0 0 0
Biological response includes tumor shrinkage or lower circulating cancer associated cells
The confirmatory Bria-IMTtrade monotherapy Phase IIa trial has completed enrollment Additional Support for the HLA-matching hypothesis has been obtained
Bria-IMTtrade Combination Therapy study with immune checkpoint inhibitors Keytrudareg if PD-L12 positive (ge1) Yervoyreg if PD-L12 negative (lt1) Accepting patients from the monotherapy study who develop progressive disease Also enrolling patients directly into this study to enhance experience with the combination In discussion with other pharmaceutical companies to evaluate additional combinations with other
immunotherapies
Bria-OTStrade Off-the-Shelf Personalized Targeted Immunotherapy Developing Bria-OTStrade to co-express GM-CSF and interferon-α Pre-manufacture additional HLA alleles ndash Total of 15 alleles (8 Class I and 7 Class II) Co-development of BriaDXtrade companion diagnostic for HLA typing Combination therapy clinical trial with immune checkpoint inhibitors for non-responders using
information from the Bria-IMTtrade Combination Therapy Study
33
Development Timeline ndash Breast Cancer
20192018 2020 2021
Phase IIIaBria-IMTtrade
Monotherapy
Currently Enrolling Phase IIaBria-IMTtrade + Checkpoint
Currently in discussions with potential partnersPhase II Bria-IMTtrade plus Additional Combinations (1Q19 4Q22)(eg PD-1 Inhibitor PD-L1 inhibitor anti-CTLA4 anti-GITR anti-OX40)
1Q 2Q 3Q 4Q
2023
Bria-OTStrade Off-The-Shelf Personalized ImmunotherapyMonotherapy and Potential Partnered Combo Therapy
(2H19 Ongoing)
Bria-OTStradeOff-the-Shelf Cell Line cGMP Manufacturing
and BriaDXtrade(1Q18 1Q19)
Registration Studies (1Q20 2H22)Bria-IMTtrade with Checkpoint InhibitorsBria-OTStrade +- Checkpoint Inhibitors
34
Immuno-oncology Deals
Recent deals of small biotechs with big pharma in immuno-oncology
35
Date PartnershipDevelopment stage at the time of the deal Deal size
07122018 Immatics-Genmab Preclinical Up to $28B
04042018 OSE Immunotherapeutics-Boehringer Ingelheim Preclinical Up to euro113B ($139B)
02092018 Pieris Pharmaceuticals-Seattle Genetics Preclinical Up to $123B
2142018 Nektar-BMS Ph III Up to $36B
01222018 Juno-Celgene Ph II $9B (Acquisition)
11142017 Loxo-Bayer Larotrectinib (Ph II) LOXO-195 (Ph III) Up to $155B
1032017 CytomX-Amgen Preclinical Up to $15B
03202017 CytomX--BMS Ph III Up to $36B
6282016 Xencor-Novartis Preclinical Up to $24B
Early Stage Clinical Studies (Comparison)
We compared the interim data of Ph IIIa study of Bria-IMTtrade in advanced breast cancer with thedata in the early stage clinical studies of recently approved breast cancer drugs and one fasttracked product candidate
Apples to apples comparison Early Stage Clinical Studies in oncology are typically done in patientswith no other therapeutic options Thus the patients have very advanced disease and response ratesare typically quite low
The patients in our Ph IIIa study have been heavily pre-treated (median 45 prior regimens)Some recent studies of relevance in breast cancer are noted in the following slides
36
Breast Cancer Market Opportunity
Drug Technology Approved for Market (US)Ibrance (palbociclib) CDK 46 Inhibitor HR+HER2- MBC in combination with
fluvestrant or aromatase inhibitor$933M in 1Q2018 $3126M in 2017
Kisqali (ribociclib) CDK 46 Inhibitor 2017 HR+HER2- MBC in combination with fluvestrant or aromatase inhibitor
Peak sales projected at $25B
Verzenio (abemaciclib) CDK 46 Inhibitor 2017 HR+HER2- MBC in combination with fluvestrant or aromatase inhibitor
balixafortide CXCR4 antagonist Fast track designation in 2018 for HER2- MBC who have failed 2 prior regimens
The market for breast cancer drugs is a multibillion dollar market with new drugs being approvedon an ongoing basis indicating the shortage of safe and effective treatments for this deadly disease
37
Competitors- Phase III Clinical Data Bria-IMTtrade shows superior safety and similar to superior efficacy data compared with those of the multi-billion dollar drugs when they were at a similar early stage of clinical development
Injection site reactions No related SAEs or SUSARs
Tumor vol darr ampor darr circul tumor cellsAll Comers 21(419) 26(519)One or More HLA matches 27(415) 33(515)Two or More HLA matches 50 (24) 75 (34)
Sheet1 (3)
Comp -Slides
Data
HLA (2)
HLA
Data (Ph1-2+4Pt)
Competitors (2018)-Slide
Competitors (2018)
In the Pipeline Protein Kinase C delta (PKCδ) Inhibitors
30 of all human malignancies display activating RAS mutations Another 60 showing over-activity of Ras-signaling pathways
Ras has been termed ldquoundruggablerdquo (no one has been able to make a Ras inhibitor drug)
BriaCellrsquos novel proprietary PKCδ inhibitors have shown activity against multiple RAS transformed tumors Lung cancer Melanoma Breast cancer Neuroendocrine cancer Pancreatic cancer Colorectal cancer
This target has an attractive safety profile based on in vivo studies and knock out mouse studies
PKCδ inhibitors should qualify for an accelerated clinical development plan and regulatory pathway
Could be in clinic within 24 months
Cost-Effective Additional Shot-on-Goal and additional partnership opportunities
Early-Stage Preclinical Program
39
Protein Kinase C delta (PKCδ) Inhibitors
Activated PKCδ inhibits RAS degradation which in turn stimulates tumor growth
Koo et al Oncotarget 621328 2016
30 of all human malignancies display activating RASmutations with another 60 showing over-activity of Ras-signaling pathways
BriaCellrsquos novel proprietary PKCδ inhibitors have shownactivity against multiple RAS transformed tumors
This target has an attractive safety profile based on in vivostudies and knock out mouse studies
PKCδ also has potential activity as an immunotherapeuticby blocking TGFβ signaling
PKCδ inhibitors are applicable to specific niche tumor typeswhich provide an accelerated clinical development plan
Structural aspects of first generation inhibitor rottlerin and staurosporine (pan-PKC activator) were combined to create second generation inhibitor KAM1
Third generation inhibitors such as BJE6-106 have improved potency and selectivity Fourth generation inhibitors under development to optimize drug-like characteristics PKCδ inhibitors lack endothelial cell cytotoxicity amp PKCδ deficient mice develop normally and are fertile Potentially no marked intrinsic toxicity by inhibiting PKCδ
Mukai H Saeki T Shimada K Naito Y Matsubara N Nakanishi T Obaishi H Namiki M Sasaki Y Phase 1 combination study of eribulin mesylate with trastuzumab for advanced or recurrent human epidermal growth factor receptor 2 positive breast cancer Invest New Drugs 2015 Feb33(1)119-27
AstraZeneca
Lynparza (Olaparib) + Cediranib
PARP inhibitor + inhibitor of VEGF receptor tyrosine kinases
HR+ HER2- MBC
BC amp OC
2013
28 (8 BC)
3 for BC
Olaparib (a poly (ADP-ribose) polymerase (PARP) inhibitor) amp Cediranib (Vascular endothelial growth factor receptor (VEGFR) 1 2 and 3 tyrosine kinase inhibitor)3 at dose level (DL) 0 (cediranib 20mg olaparib 100mg) 3 at DL1 (cediranib 20mg olaparib 200mg) 7 at DL2 (cediranib 30mg olaparib 200mg) 6 at DL3 (cediranib 30mg olaparib 400mg)
Liu JF Tolaney SM Birrer M Fleming GF Buss MK Dahlberg SE Lee H Whalen C Tyburski K Winer E Ivy P Matulonis UA A Phase 1 trial of the poly(ADP-ribose) polymerase inhibitor olaparib (AZD2281) in combination with the anti-angiogenic cediranib (AZD2171) in recurrent epithelial ovarian or triple-negative breast cancer Eur J Cancer 2013 Sep49(14)2972-8
Reyon Pharmaceutical
VM206RY
Heterologous prime-boost with a truncated HER2 sequence
HER2+ Stage IIIampIV BC
2015
9
2 chemo
Plasmid DNA (pHM-GM-CSF expressing truncated HER2 amp GM-CSF) amp adenoviral vector (Ad-HM containing modified HER2) (2 4 and 8 mgpatientvisit) of pHM-GM-CSF 3x IM weeks 0 2 and 4 Ad-HM 3 times 109 virus particles at week 6
11 PR
4 pts showed 7 minor AEs
Unclear
Kim SB Ahn JH Kim J Jung KH A phase 1 study of a heterologous prime-boost vaccination involving a truncated HER2 sequence in patients with HER2-expressing breast cancer Mol Ther Methods Clin Dev 2015 Sep 30215031 doi 101038mtm201531 eCollection 2015
Rodon J Peacuterez-Fidalgo A Krop IE Burris H Guerrero-Zotano A Britten CD Becerra C Schellens J Richards DA Schuler M Abu-Khalaf M Johnson FM Ranson M Edenfield J Silva AP Hackl W Quadt C Demanse D Duval V Baselga J Phase 11b dose escalation and expansion study of BEZ235 a dual PI3KmTOR inhibitor in patients with advanced solid tumors including patients with advanced breast cancer Cancer Chemother Pharmacol 2018 Jun 7 doi 101007s00280-018-3610-z [Epub ahead of print]
Celgene (Abraxane)
Gemcitabine + Abraxane (nab-paclitaxel)
Chemo + Chemo
OC BC NSCLC amp Panc cancer + Lung OC BC Kaposi sarcoma
MBC
2016
9
Adjuvant chemo (100)chemo post-adjuvant (33)
Gem (nucleoside metabolic inhibitor 1250 mgm2) on days 1 and 8 nab-Pac (microtubule inhibitor) starting dose of 180 mgm2 (cohort 1) 220 mgm2 (cohort 2) and 260 mgm2 (cohort 3) on day 1 of the 21-day cycle using a 3 + 3 design
0
MTD not reached29 Gr3 Neutropenia59 Gr1 Peripheralneuropathy
Yoshitomi S Taira N Doihara H Mizoo T Nogami T Iwamoto T Motoki T Shien T Ogasawara Y Matsuoka J Tsuji H Mitsuhashi T A phase 1 dose-finding and pharmacokinetic study of gemcitabine with nab-paclitaxel in patients with metastatic breast cancer Cancer Chemother Pharmacol 2016 Aug78(2)289-94
Eli Lilly
Erbituxreg (cetuximab) + Taxane
EGFR inhibitor antineoplastic agent + Chemo
Headamp Neck Colorectal Cancer
TNBC
2007-2010
18
1 chemo
Cetuximab (epidermal growth factor receptor (EGFR) antagonist ) an initial loading dose of cetuximab 400 mgm2 followed by a weekly dose of 250 mgm2Paclitaxel (microtubule inhibitor) 80 mgm2 or Docetaxel at an initial dose of 30 mgm2 was administered weekly
56 CR 22 PR
83 Dermatologic toxicity11 Grade3+
Nechushtan H Vainer G Stainberg H Salmon AY Hamburger T Peretz T A phase 12 of a combination of cetuximab and taxane for triple negative breast cancer patients Breast 2014 Aug23(4)435-8
Polyphor
Balixafortide (POL6326) + eribulin
CXCR4 antagonist + tubulin-based antimitotic
Heavily pretreated Relapsed MBC
2014-2016
56
3rd line 3 chemo
3+3 dose escalation The highest dose was established as eribulin 14 mgmsup2 on days 2 and 9 and balixafortide 55 mgkg on days 1minus3 and 8minus10 of the 21-day cycle
30 PR
41 Gr34 Neutropenia11 Gr34 Leucopenia11 Gr34 Febrileneutropenia2 Related mortalities
Apr 2018 Fast Track for HER2-MBC who have failed 2prior regimens
Pernas S Martin M Kaufman PA Gil-Martin M Gomez Pardo P Lopez-Tarruella S Manso L Ciruelos E Perez-Fidalgo JA Hernando C Ademuyiwa FO Weilbaecher K Mayer I Pluard TJ Martinez Garcia M Vahdat L Perez-Garcia J Wach A Barker D Fung S Romagnoli B Cortes J Balixafortide plus eribulin in HER2-negative metastatic breast cancer a phase 1 single-arm dose-escalation trial Lancet Oncol 2018 Jun19(6)812-824
11 PRndashbut only + letrozole (No Resp on monotherapy)
61 Gr34 Neutropenia39 Gr34 Leucopenia
$933M in 1Q2018 $31B in 2017
Tamura K Mukai H Naito Y Yonemori K Kodaira M Tanabe Y Yamamoto N Osera S Sasaki M Mori Y Hashigaki S Nagasawa T Umeyama Y Yoshino T Phase I study of palbociclib a cyclin-dependent kinase 46 inhibitor in Japanese patients Cancer Sci 2016 Jun107(6)755-63 doi 101111cas12932 Epub 2016 May 11
Pfizer
Ibrancereg (palbociclib)
CDK 46 Inhibitor
HR+ HER2- MBC
Heavily pretreated Relapsed Metastatic Cancer
2004-2008
41 (5 BC)
chemo naiumlve (17) 1-2 (51)3 (29) 3+ (2)
Palbociclib 25-150 mg dose ranging
0
20 Gr34 Neutropenia23 Gr34 Leucopenia
$933M in 1Q2018 $31B in 2017
Flaherty KT Lorusso PM Demichele A Abramson VG Courtney R Randolph SS Shaik MN Wilner KD ODwyer PJ Schwartz GK Phase I dose-escalation trial of the oral cyclin-dependent kinase 46 inhibitor PD 0332991 administered using a 21-day schedule in patients with advanced cancer Clin Cancer Res 2012 Jan 1518(2)568-76 doi 1011581078-0432CCR-11-0509 Epub 2011 Nov 16
Novartis
Kisqalireg (ribociclib)
CDK 46 Inhibitors
Premenopausal HR+ HER2- MBC
Heavily pretreated Relapsed Metastatic Cancer
2016
132 (20 BC)
0-1 (25) 2-3 (42) 4+ (32)
Ribociclib 50 mg ranging up to 1200 mg dose escalation
23 PRndashincluded 1 in BC (5 of BC pts)
27 Gr34 Neutropenia17 Gr34 Leucopenia
Peak sales projected at $25B
Infante JR Cassier PA Gerecitano JF Witteveen PO Chugh R Ribrag V Chakraborty A Matano A Dobson JR Crystal AS Parasuraman S Shapiro GI A Phase I Study of the Cyclin-Dependent Kinase 46 Inhibitor Ribociclib (LEE011) in Patients with Advanced Solid Tumors and Lymphomas Clin Cancer Res 2016 Dec 122(23)5696-5705 Epub 2016 Aug 19
Eli Lilly
Verzenioreg (abemaciclib)
CDK 46 Inhibitors
HR+HER2minusMBC
Heavily pretreated Relapsed Metastatic Cancer
2016
12 (1 BC)
1 (312) 2 (212) 3+ (7)
Abemaciclib 100 mg ranging up to 200 mg dose escalation
17 PR (included 1 in BC)
17 Gr34 Neutropenia33 Gr34 Leucopenia
Peak sales projected at $2B
Fujiwara Y Tamura K Kondo S Tanabe Y Iwasa S Shimomura A Kitano S Ogasawara K Turner PK Mori J Asou H Chan EM Yamamoto N Phase 1 study of abemaciclib an inhibitor of CDK 4 and 6 as a single agent for Japanese patients with advanced cancer Cancer Chemother Pharmacol 2016 Aug78(2)281-8 doi 101007s00280-016-3085-8 Epub 2016 Jun 16
Mukai H Saeki T Shimada K Naito Y Matsubara N Nakanishi T Obaishi H Namiki M Sasaki Y Phase 1 combination study of eribulin mesylate with trastuzumab for advanced or recurrent human epidermal growth factor receptor 2 positive breast cancer Invest New Drugs 2015 Feb33(1)119-27
AstraZeneca
Lynparza (Olaparib)+ Cediranib
PARP inhibitor+ inhibitor of VEGF RTK
HR+ HER2- MBC
BC amp OC
13
28 (8 BC)
3 for BC
Olaparib (a poly (ADP-ribose) polymerase (PARP) inhibitor) amp Cediranib (Vascular endothelial growth factor receptor (VEGFR) 1 2 and 3 tyrosine kinase inhibitor)3 at dose level (DL) 0 (cediranib 20mg olaparib 100mg) 3 at DL1 (cediranib 20mg olaparib 200mg) 7 at DL2 (cediranib 30mg olaparib 200mg) 6 at DL3 (cediranib 30mg olaparib 400mg)
Liu JF Tolaney SM Birrer M Fleming GF Buss MK Dahlberg SE Lee H Whalen C Tyburski K Winer E Ivy P Matulonis UA A Phase 1 trial of the poly(ADP-ribose) polymerase inhibitor olaparib (AZD2281) in combination with the anti-angiogenic cediranib (AZD2171) in recurrent epithelial ovarian or triple-negative breast cancer Eur J Cancer 2013 Sep49(14)2972-8
ReyonPharma
VM206RY
Heterologous prime-boost with a truncated HER2 sequence
HER2+ Stg IIIampIV BC
15
9
2 chemo
Plasmid DNA (pHM-GM-CSF expressing truncated HER2 amp GM-CSF) amp adenoviral vector (Ad-HM containing modified HER2) (2 4 and 8 mgpatientvisit) of pHM-GM-CSF 3x IM weeks 0 2 and 4 Ad-HM 3 times 109 virus particles at week 6
11 PR
4 pts 7 minor AEs
Unclear
Kim SB Ahn JH Kim J Jung KH A phase 1 study of a heterologous prime-boost vaccination involving a truncated HER2 sequence in patients with HER2-expressing breast cancer Mol Ther Methods Clin Dev 2015 Sep 30215031 doi 101038mtm201531 eCollection 2015
Rodon J Peacuterez-Fidalgo A Krop IE Burris H Guerrero-Zotano A Britten CD Becerra C Schellens J Richards DA Schuler M Abu-Khalaf M Johnson FM Ranson M Edenfield J Silva AP Hackl W Quadt C Demanse D Duval V Baselga J Phase 11b dose escalation and expansion study of BEZ235 a dual PI3KmTOR inhibitor in patients with advanced solid tumors including patients with advanced breast cancer Cancer Chemother Pharmacol 2018 Jun 7 doi 101007s00280-018-3610-z [Epub ahead of print]
Celgene(Abraxane)
Gemcitabine + Abraxane (nab-paclitaxel)
Chemo+ Chemo
OC BC NSCLC PC + LC OC BC KS
MBC
16
9
Adjuv chemo (100)chemo post-adjuv (33)
Gem (nucleoside metabolic inhibitor 1250 mgm2) on days 1 and 8 nab-Pac (microtubule inhibitor) starting dose of 180 mgm2 (cohort 1) 220 mgm2 (cohort 2) and 260 mgm2 (cohort 3) on day 1 of the 21-day cycle using a 3 + 3 design
0
MTD not reached29 Gr3 Neutropenia59 Gr1 Peripheralneuropathy
Yoshitomi S Taira N Doihara H Mizoo T Nogami T Iwamoto T Motoki T Shien T Ogasawara Y Matsuoka J Tsuji H Mitsuhashi T A phase 1 dose-finding and pharmacokinetic study of gemcitabine with nab-paclitaxel in patients with metastatic breast cancer Cancer Chemother Pharmacol 2016 Aug78(2)289-94
Eli Lilly
Erbituxreg (cetuximab) + Taxane
EGFR inhibitor antineoplastic agent + Chemo
Head amp NeckColorectal
TNBC
07-10
18
1 chemo
Cetuximab (epidermal growth factor receptor (EGFR) antagonist ) an initial loading dose of cetuximab 400 mgm2 followed by a weekly dose of 250 mgm2Paclitaxel (microtubule inhibitor) 80 mgm2 or Docetaxel at an initial dose of 30 mgm2 was administered weekly
56 CR 22 PR
83 Dermatologic toxicity11 Grade3+
Nechushtan H Vainer G Stainberg H Salmon AY Hamburger T Peretz T A phase 12 of a combination of cetuximab and taxane for triple negative breast cancer patients Breast 2014 Aug23(4)435-8
Polyphor
Balixafortide (POL6326) + eribulin
CXCR4 antagonist + tubulin-based antimitotic
Heavily pretreatedRelapsed MBC
14-16
56
3rd line 3 chemo
3+3 dose escalation The highest dose was established as eribulin 14 mgmsup2 on days 2 and 9 and balixafortide 55 mgkg on days 1minus3 and 8minus10 of the 21-day cycle
30 PR
41 Gr34 Neutropenia11 Gr34 Leucopenia11 Gr34 Febrileneutropenia2 Related mortalities
42018 Fast Track (HER2-MBC failed 2 prior regimens)
Pernas S Martin M Kaufman PA Gil-Martin M Gomez Pardo P Lopez-Tarruella S Manso L Ciruelos E Perez-Fidalgo JA Hernando C Ademuyiwa FO Weilbaecher K Mayer I Pluard TJ Martinez Garcia M Vahdat L Perez-Garcia J Wach A Barker D Fung S Romagnoli B Cortes J Balixafortide plus eribulin in HER2-negative metastatic breast cancer a phase 1 single-arm dose-escalation trial Lancet Oncol 2018 Jun19(6)812-824
1 PRndashbut only + letrozoleNo Resp on monotherapy
61 Gr34 Neutropenia39 Gr34 Leucopenia
$933M (1Q18)$31B (2017)
Tamura K Mukai H Naito Y Yonemori K Kodaira M Tanabe Y Yamamoto N Osera S Sasaki M Mori Y Hashigaki S Nagasawa T Umeyama Y Yoshino T Phase I study of palbociclib a cyclin-dependent kinase 46 inhibitor in Japanese patients Cancer Sci 2016 Jun107(6)755-63 doi 101111cas12932 Epub 2016 May 11
Pfizer
Ibrancereg (palbociclib)
CDK 46 Inhibitor
HR+ HER2- MBC
Heavily pretreatedRelapsed Met Cancer
04-08
41 (5 BC)
chemo naiumlve (17)1-2(51) 3(29) 3+(2)
Palbociclib 25-150 mg dose ranging
0
20 Gr34 Neutropenia23 Gr34 Leucopenia
$933M (1Q18)$31B (2017)
Flaherty KT Lorusso PM Demichele A Abramson VG Courtney R Randolph SS Shaik MN Wilner KD ODwyer PJ Schwartz GK Phase I dose-escalation trial of the oral cyclin-dependent kinase 46 inhibitor PD 0332991 administered using a 21-day schedule in patients with advanced cancer Clin Cancer Res 2012 Jan 1518(2)568-76 doi 1011581078-0432CCR-11-0509 Epub 2011 Nov 16
Novartis
Kisqalireg (ribociclib)
CDK 46 Inhibitor
Premenopausal HR+ HER2- MBC
Heavily pretreatedRelapsed Met Cancer
16
132 (20 BC)
0-1 (25) 2-3 (42)4+ (32)
Ribociclib 50 mg ranging up to 1200 mg dose escalation
23 PR-included 1 BC (5 of BC pts)
27 Gr34 Neutropenia17 Gr34 Leucopenia
Peak sales est at $25B
Infante JR Cassier PA Gerecitano JF Witteveen PO Chugh R Ribrag V Chakraborty A Matano A Dobson JR Crystal AS Parasuraman S Shapiro GI A Phase I Study of the Cyclin-Dependent Kinase 46 Inhibitor Ribociclib (LEE011) in Patients with Advanced Solid Tumors and Lymphomas Clin Cancer Res 2016 Dec 122(23)5696-5705 Epub 2016 Aug 19
Eli Lilly
Verzenioreg (abemaciclib)
CDK 46 Inhibitor
HR+HER2minusMBC
Heavily pretreatedRelapsed Met Cancer
16
12 (1 BC)
1 (312) 2 (212) 3+(7)
Abemaciclib 100 mg ranging up to 200 mg dose escalation
17 PR (included 1 BC)
17 Gr34 Neutropenia33 Gr34 Leucopenia
Peak sales est at $2B
Fujiwara Y Tamura K Kondo S Tanabe Y Iwasa S Shimomura A Kitano S Ogasawara K Turner PK Mori J Asou H Chan EM Yamamoto N Phase 1 study of abemaciclib an inhibitor of CDK 4 and 6 as a single agent for Japanese patients with advanced cancer Cancer Chemother Pharmacol 2016 Aug78(2)281-8 doi 101007s00280-016-3085-8 Epub 2016 Jun 16
Mukai H Saeki T Shimada K Naito Y Matsubara N Nakanishi T Obaishi H Namiki M Sasaki Y Phase 1 combination study of eribulin mesylate with trastuzumab for advanced or recurrent human epidermal growth factor receptor 2 positive breast cancer Invest New Drugs 2015 Feb33(1)119-27
AstraZeneca
Lynparza (Olaparib) + Cediranib
PARP inhibitor + inhibitor of VEGF receptor tyrosine kinases
HR+ HER2- MBC
BC amp OC
2013
28 (8 BC)
3 for BC
Olaparib (a poly (ADP-ribose) polymerase (PARP) inhibitor) amp Cediranib (Vascular endothelial growth factor receptor (VEGFR) 1 2 and 3 tyrosine kinase inhibitor)3 at dose level (DL) 0 (cediranib 20mg olaparib 100mg) 3 at DL1 (cediranib 20mg olaparib 200mg) 7 at DL2 (cediranib 30mg olaparib 200mg) 6 at DL3 (cediranib 30mg olaparib 400mg)
Liu JF Tolaney SM Birrer M Fleming GF Buss MK Dahlberg SE Lee H Whalen C Tyburski K Winer E Ivy P Matulonis UA A Phase 1 trial of the poly(ADP-ribose) polymerase inhibitor olaparib (AZD2281) in combination with the anti-angiogenic cediranib (AZD2171) in recurrent epithelial ovarian or triple-negative breast cancer Eur J Cancer 2013 Sep49(14)2972-8
Reyon Pharmaceutical
VM206RY
Heterologous prime-boost with a truncated HER2 sequence
HER2+ Stage IIIampIV BC
2015
9
2 chemo
Plasmid DNA (pHM-GM-CSF expressing truncated HER2 amp GM-CSF) amp adenoviral vector (Ad-HM containing modified HER2) (2 4 and 8 mgpatientvisit) of pHM-GM-CSF 3x IM weeks 0 2 and 4 Ad-HM 3 times 109 virus particles at week 6
11 PR
4 pts showed 7 minor AEs
Unclear
Kim SB Ahn JH Kim J Jung KH A phase 1 study of a heterologous prime-boost vaccination involving a truncated HER2 sequence in patients with HER2-expressing breast cancer Mol Ther Methods Clin Dev 2015 Sep 30215031 doi 101038mtm201531 eCollection 2015
Rodon J Peacuterez-Fidalgo A Krop IE Burris H Guerrero-Zotano A Britten CD Becerra C Schellens J Richards DA Schuler M Abu-Khalaf M Johnson FM Ranson M Edenfield J Silva AP Hackl W Quadt C Demanse D Duval V Baselga J Phase 11b dose escalation and expansion study of BEZ235 a dual PI3KmTOR inhibitor in patients with advanced solid tumors including patients with advanced breast cancer Cancer Chemother Pharmacol 2018 Jun 7 doi 101007s00280-018-3610-z [Epub ahead of print]
Celgene (Abraxane)
Gemcitabine + Abraxane (nab-paclitaxel)
Chemo + Chemo
OC BC NSCLC amp Panc cancer + Lung OC BC Kaposi sarcoma
MBC
2016
9
Adjuvant chemo (100)chemo post-adjuvant (33)
Gem (nucleoside metabolic inhibitor 1250 mgm2) on days 1 and 8 nab-Pac (microtubule inhibitor) starting dose of 180 mgm2 (cohort 1) 220 mgm2 (cohort 2) and 260 mgm2 (cohort 3) on day 1 of the 21-day cycle using a 3 + 3 design
0
MTD not reached29 Gr3 Neutropenia59 Gr1 Peripheralneuropathy
Yoshitomi S Taira N Doihara H Mizoo T Nogami T Iwamoto T Motoki T Shien T Ogasawara Y Matsuoka J Tsuji H Mitsuhashi T A phase 1 dose-finding and pharmacokinetic study of gemcitabine with nab-paclitaxel in patients with metastatic breast cancer Cancer Chemother Pharmacol 2016 Aug78(2)289-94
Eli Lilly
Erbituxreg (cetuximab) + Taxane
EGFR inhibitor antineoplastic agent + Chemo
Headamp Neck Colorectal Cancer
TNBC
2007-2010
18
1 chemo
Cetuximab (epidermal growth factor receptor (EGFR) antagonist ) an initial loading dose of cetuximab 400 mgm2 followed by a weekly dose of 250 mgm2Paclitaxel (microtubule inhibitor) 80 mgm2 or Docetaxel at an initial dose of 30 mgm2 was administered weekly
56 CR 22 PR
83 Dermatologic toxicity11 Grade3+
Nechushtan H Vainer G Stainberg H Salmon AY Hamburger T Peretz T A phase 12 of a combination of cetuximab and taxane for triple negative breast cancer patients Breast 2014 Aug23(4)435-8
Polyphor
Balixafortide (POL6326) + eribulin
CXCR4 antagonist + tubulin-based antimitotic
Heavily pretreated Relapsed MBC
2014-2016
56
3rd line 3 chemo
3+3 dose escalation The highest dose was established as eribulin 14 mgmsup2 on days 2 and 9 and balixafortide 55 mgkg on days 1minus3 and 8minus10 of the 21-day cycle
30 PR
41 Gr34 Neutropenia11 Gr34 Leucopenia11 Gr34 Febrileneutropenia2 Related mortalities
Apr 2018 Fast Track for HER2-MBC who have failed 2prior regimens
Pernas S Martin M Kaufman PA Gil-Martin M Gomez Pardo P Lopez-Tarruella S Manso L Ciruelos E Perez-Fidalgo JA Hernando C Ademuyiwa FO Weilbaecher K Mayer I Pluard TJ Martinez Garcia M Vahdat L Perez-Garcia J Wach A Barker D Fung S Romagnoli B Cortes J Balixafortide plus eribulin in HER2-negative metastatic breast cancer a phase 1 single-arm dose-escalation trial Lancet Oncol 2018 Jun19(6)812-824
11 PRndashbut only + letrozole (No Resp on monotherapy)
61 Gr34 Neutropenia39 Gr34 Leucopenia
$933M in 1Q2018 $31B in 2017
Tamura K Mukai H Naito Y Yonemori K Kodaira M Tanabe Y Yamamoto N Osera S Sasaki M Mori Y Hashigaki S Nagasawa T Umeyama Y Yoshino T Phase I study of palbociclib a cyclin-dependent kinase 46 inhibitor in Japanese patients Cancer Sci 2016 Jun107(6)755-63 doi 101111cas12932 Epub 2016 May 11
Pfizer
Ibrancereg (palbociclib)
CDK 46 Inhibitor
HR+ HER2- MBC
Heavily pretreated Relapsed Metastatic Cancer
2004-2008
41 (5 BC)
chemo naiumlve (17) 1-2 (51)3 (29) 3+ (2)
Palbociclib 25-150 mg dose ranging
0
20 Gr34 Neutropenia23 Gr34 Leucopenia
$933M in 1Q2018 $31B in 2017
Flaherty KT Lorusso PM Demichele A Abramson VG Courtney R Randolph SS Shaik MN Wilner KD ODwyer PJ Schwartz GK Phase I dose-escalation trial of the oral cyclin-dependent kinase 46 inhibitor PD 0332991 administered using a 21-day schedule in patients with advanced cancer Clin Cancer Res 2012 Jan 1518(2)568-76 doi 1011581078-0432CCR-11-0509 Epub 2011 Nov 16
Novartis
Kisqalireg (ribociclib)
CDK 46 Inhibitors
Premenopausal HR+ HER2- MBC
Heavily pretreated Relapsed Metastatic Cancer
2016
132 (20 BC)
0-1 (25) 2-3 (42) 4+ (32)
Ribociclib 50 mg ranging up to 1200 mg dose escalation
23 PRndashincluded 1 in BC (5 of BC pts)
27 Gr34 Neutropenia17 Gr34 Leucopenia
Peak sales projected at $25B
Infante JR Cassier PA Gerecitano JF Witteveen PO Chugh R Ribrag V Chakraborty A Matano A Dobson JR Crystal AS Parasuraman S Shapiro GI A Phase I Study of the Cyclin-Dependent Kinase 46 Inhibitor Ribociclib (LEE011) in Patients with Advanced Solid Tumors and Lymphomas Clin Cancer Res 2016 Dec 122(23)5696-5705 Epub 2016 Aug 19
Eli Lilly
Verzenioreg (abemaciclib)
CDK 46 Inhibitors
HR+HER2minusMBC
Heavily pretreated Relapsed Metastatic Cancer
2016
12 (1 BC)
1 (312) 2 (212) 3+ (7)
Abemaciclib 100 mg ranging up to 200 mg dose escalation
17 PR (included 1 in BC)
17 Gr34 Neutropenia33 Gr34 Leucopenia
Peak sales projected at $2B
Fujiwara Y Tamura K Kondo S Tanabe Y Iwasa S Shimomura A Kitano S Ogasawara K Turner PK Mori J Asou H Chan EM Yamamoto N Phase 1 study of abemaciclib an inhibitor of CDK 4 and 6 as a single agent for Japanese patients with advanced cancer Cancer Chemother Pharmacol 2016 Aug78(2)281-8 doi 101007s00280-016-3085-8 Epub 2016 Jun 16
Mukai H Saeki T Shimada K Naito Y Matsubara N Nakanishi T Obaishi H Namiki M Sasaki Y Phase 1 combination study of eribulin mesylate with trastuzumab for advanced or recurrent human epidermal growth factor receptor 2 positive breast cancer Invest New Drugs 2015 Feb33(1)119-27
AstraZeneca
Lynparza (Olaparib)+ Cediranib
PARP inhibitor+ inhibitor of VEGF RTK
HR+ HER2- MBC
BC amp OC
13
28 (8 BC)
3 for BC
Olaparib (a poly (ADP-ribose) polymerase (PARP) inhibitor) amp Cediranib (Vascular endothelial growth factor receptor (VEGFR) 1 2 and 3 tyrosine kinase inhibitor)3 at dose level (DL) 0 (cediranib 20mg olaparib 100mg) 3 at DL1 (cediranib 20mg olaparib 200mg) 7 at DL2 (cediranib 30mg olaparib 200mg) 6 at DL3 (cediranib 30mg olaparib 400mg)
Liu JF Tolaney SM Birrer M Fleming GF Buss MK Dahlberg SE Lee H Whalen C Tyburski K Winer E Ivy P Matulonis UA A Phase 1 trial of the poly(ADP-ribose) polymerase inhibitor olaparib (AZD2281) in combination with the anti-angiogenic cediranib (AZD2171) in recurrent epithelial ovarian or triple-negative breast cancer Eur J Cancer 2013 Sep49(14)2972-8
ReyonPharma
VM206RY
Heterologous prime-boost with a truncated HER2 sequence
HER2+ Stg IIIampIV BC
15
9
2 chemo
Plasmid DNA (pHM-GM-CSF expressing truncated HER2 amp GM-CSF) amp adenoviral vector (Ad-HM containing modified HER2) (2 4 and 8 mgpatientvisit) of pHM-GM-CSF 3x IM weeks 0 2 and 4 Ad-HM 3 times 109 virus particles at week 6
11 PR
4 pts 7 minor AEs
Unclear
Kim SB Ahn JH Kim J Jung KH A phase 1 study of a heterologous prime-boost vaccination involving a truncated HER2 sequence in patients with HER2-expressing breast cancer Mol Ther Methods Clin Dev 2015 Sep 30215031 doi 101038mtm201531 eCollection 2015
Rodon J Peacuterez-Fidalgo A Krop IE Burris H Guerrero-Zotano A Britten CD Becerra C Schellens J Richards DA Schuler M Abu-Khalaf M Johnson FM Ranson M Edenfield J Silva AP Hackl W Quadt C Demanse D Duval V Baselga J Phase 11b dose escalation and expansion study of BEZ235 a dual PI3KmTOR inhibitor in patients with advanced solid tumors including patients with advanced breast cancer Cancer Chemother Pharmacol 2018 Jun 7 doi 101007s00280-018-3610-z [Epub ahead of print]
Celgene(Abraxane)
Gemcitabine + Abraxane (nab-paclitaxel)
Chemo+ Chemo
OC BC NSCLC PC + LC OC BC KS
MBC
16
9
Adjuv chemo (100)chemo post-adjuv (33)
Gem (nucleoside metabolic inhibitor 1250 mgm2) on days 1 and 8 nab-Pac (microtubule inhibitor) starting dose of 180 mgm2 (cohort 1) 220 mgm2 (cohort 2) and 260 mgm2 (cohort 3) on day 1 of the 21-day cycle using a 3 + 3 design
0
MTD not reached29 Gr3 Neutropenia59 Gr1 Peripheralneuropathy
Yoshitomi S Taira N Doihara H Mizoo T Nogami T Iwamoto T Motoki T Shien T Ogasawara Y Matsuoka J Tsuji H Mitsuhashi T A phase 1 dose-finding and pharmacokinetic study of gemcitabine with nab-paclitaxel in patients with metastatic breast cancer Cancer Chemother Pharmacol 2016 Aug78(2)289-94
Eli Lilly
Erbituxreg (cetuximab) + Taxane
EGFR inhibitor antineoplastic agent + Chemo
Head amp NeckColorectal
TNBC
07-10
18
1 chemo
Cetuximab (epidermal growth factor receptor (EGFR) antagonist ) an initial loading dose of cetuximab 400 mgm2 followed by a weekly dose of 250 mgm2Paclitaxel (microtubule inhibitor) 80 mgm2 or Docetaxel at an initial dose of 30 mgm2 was administered weekly
56 CR 22 PR
83 Dermatologic toxicity11 Grade3+
Nechushtan H Vainer G Stainberg H Salmon AY Hamburger T Peretz T A phase 12 of a combination of cetuximab and taxane for triple negative breast cancer patients Breast 2014 Aug23(4)435-8
Polyphor
Balixafortide (POL6326) + eribulin
CXCR4 antagonist + tubulin-based antimitotic
Heavily pretreatedRelapsed MBC
14-16
56
3rd line 3 chemo
3+3 dose escalation The highest dose was established as eribulin 14 mgmsup2 on days 2 and 9 and balixafortide 55 mgkg on days 1minus3 and 8minus10 of the 21-day cycle
30 PR
41 Gr34 Neutropenia11 Gr34 Leucopenia11 Gr34 Febrileneutropenia2 Related mortalities
42018 Fast Track (HER2-MBC failed 2 prior regimens)
Pernas S Martin M Kaufman PA Gil-Martin M Gomez Pardo P Lopez-Tarruella S Manso L Ciruelos E Perez-Fidalgo JA Hernando C Ademuyiwa FO Weilbaecher K Mayer I Pluard TJ Martinez Garcia M Vahdat L Perez-Garcia J Wach A Barker D Fung S Romagnoli B Cortes J Balixafortide plus eribulin in HER2-negative metastatic breast cancer a phase 1 single-arm dose-escalation trial Lancet Oncol 2018 Jun19(6)812-824
1 PRndashbut only + letrozoleNo Resp on monotherapy
61 Gr34 Neutropenia39 Gr34 Leucopenia
$933M (1Q18)$31B (2017)
Tamura K Mukai H Naito Y Yonemori K Kodaira M Tanabe Y Yamamoto N Osera S Sasaki M Mori Y Hashigaki S Nagasawa T Umeyama Y Yoshino T Phase I study of palbociclib a cyclin-dependent kinase 46 inhibitor in Japanese patients Cancer Sci 2016 Jun107(6)755-63 doi 101111cas12932 Epub 2016 May 11
Pfizer
Ibrancereg (palbociclib)
CDK 46 Inhibitor
HR+ HER2- MBC
Heavily pretreatedRelapsed Met Cancer
04-08
41 (5 BC)
chemo naiumlve (17)1-2(51) 3(29) 3+(2)
Palbociclib 25-150 mg dose ranging
0
20 Gr34 Neutropenia23 Gr34 Leucopenia
$933M (1Q18)$31B (2017)
Flaherty KT Lorusso PM Demichele A Abramson VG Courtney R Randolph SS Shaik MN Wilner KD ODwyer PJ Schwartz GK Phase I dose-escalation trial of the oral cyclin-dependent kinase 46 inhibitor PD 0332991 administered using a 21-day schedule in patients with advanced cancer Clin Cancer Res 2012 Jan 1518(2)568-76 doi 1011581078-0432CCR-11-0509 Epub 2011 Nov 16
Novartis
Kisqalireg (ribociclib)
CDK 46 Inhibitor
Premenopausal HR+ HER2- MBC
Heavily pretreatedRelapsed Met Cancer
16
132 (20 BC)
0-1 (25) 2-3 (42)4+ (32)
Ribociclib 50 mg ranging up to 1200 mg dose escalation
23 PR-included 1 BC (5 of BC pts)
27 Gr34 Neutropenia17 Gr34 Leucopenia
Peak sales est at $25B
Infante JR Cassier PA Gerecitano JF Witteveen PO Chugh R Ribrag V Chakraborty A Matano A Dobson JR Crystal AS Parasuraman S Shapiro GI A Phase I Study of the Cyclin-Dependent Kinase 46 Inhibitor Ribociclib (LEE011) in Patients with Advanced Solid Tumors and Lymphomas Clin Cancer Res 2016 Dec 122(23)5696-5705 Epub 2016 Aug 19
Eli Lilly
Verzenioreg (abemaciclib)
CDK 46 Inhibitor
HR+HER2minusMBC
Heavily pretreatedRelapsed Met Cancer
16
12 (1 BC)
1 (312) 2 (212) 3+(7)
Abemaciclib 100 mg ranging up to 200 mg dose escalation
17 PR (included 1 BC)
17 Gr34 Neutropenia33 Gr34 Leucopenia
Peak sales est at $2B
Fujiwara Y Tamura K Kondo S Tanabe Y Iwasa S Shimomura A Kitano S Ogasawara K Turner PK Mori J Asou H Chan EM Yamamoto N Phase 1 study of abemaciclib an inhibitor of CDK 4 and 6 as a single agent for Japanese patients with advanced cancer Cancer Chemother Pharmacol 2016 Aug78(2)281-8 doi 101007s00280-016-3085-8 Epub 2016 Jun 16
Developing Bria-OTStrade the First Off-the-Shelf Personalized Immunotherapy
Targeting Adv Breast Cancer Unmet medical need (42000 death in the US in 2017 ) $1 Bil- $5 Bil market opportunity depending on patient treatment stage
Impressive results in 2 proof-of-concept clinical trials Rapid Response Rate Repeated following re-treatment Excellent Safety Profile
Completed enrollment in Phase IIIa clinical trial of Bria-IMTtrade with outstanding safety amp efficacy data Initiated Phase IIa Combination Study of Bria-IMTtrade with Keytrudareg (Merck amp Co Inc)
Developing Bria-OTStrade along with BriaDXtrade its companion diagnostic test Ability to match and treat ~90 of patient population with Off-the-Shelf personalized immunotherapy
Experienced Management has been involved in over 10 drug approvals
Patient B001 Breast 70 No 1101 - 3501 4001 Negative -
Bria-IMTtradeHuman Proof-of-Concept Trials in Breast Cancer (Patient A002)
24
Proof-of-Concept Results Resulted in BriaCellrsquos Immunotherapy Strategy Use BriaDXtrade diagnostic to select only those patients matching Bria-IMTtrade Use BriaDXtrade diagnostic test to select Bria-OTStrade alleles matching ~90 of all patients
Bria-IMTtradeCurrent Phase IIIa Data Supports HLA Matching Hypothesis Six patients treated in 2017 Bria-IMTtrade was safe and well tolerated
Patient 01-002 73-year-old woman with breast cancer diagnosed in 1995 Developed liver metastases in2010 and lung metastases in 2017 Previously treated with 7 rounds of chemotherapy with 8 differentchemotherapy agents Received 5 cycles of Bria-IMTtrade over 3 months then monthly cycles (6 months total)Evaluated after 3 months and 6 months After 3 months despite the extensive prior therapy her scans notedthat ldquothere has been a clear response in the multiple bilateral pulmonary nodulesrdquo The response wasmaintained after 6 months of Bria-IMTtrade treatment She matches Bria-IMTtrade at 2 HLA alleles
The liver tumors were stable to slightly increased at 3 months and then progressed after 6 months
This supports our hypothesis of heightened anti-tumor activity in patients with a matched HLA types Clear path to develop BriaDXtrade to select the patients using HLA testing
1 RLL 29 Not Detectable Not Detectable2 LUL apical pleural based 34 tiny nodule lt 1mm scar tiny nodule lt 1mm scar3 xxx 39 Not Detectable Not Detectable4 40 Not Detectable Not Detectable5 RLL 45 Not Detectable Not Detectable6 LLL 49 Not Detectable Not Detectable7 xxx 52 Not Detectable Not Detectable8 RLL 52 Not Detectable Not Detectable9 RLL 56 Not Detectable Not Detectable
10 RLL costophrenic recess 56 Not Detectable Not Detectable11 XXX 58 Not Detectable Not Detectable12 LUL 60 Not Detectable Not Detectable13 XXX 67 15 1514 RUL 72 15 1515 LLL 76 Not Detectable Not Detectable16 RUL Noncalcified Nodule 77 Not Detectable Not Detectable17 RLL costophrenic recess 79 10 1018 RUL 82 Not Detectable Not Detectable19 RLL 90 Not Detectable Not Detectable20 RLL 91 lt 01 lt 0121 xxx xxx Not Detectable Not Detectable
27
Clinical Development Update ndash Summary 2018 September 26
Completed enrollment of Adv Breast cancer patients in the Phase IIIa ldquomonotherapyrdquo study of Bria-IMTtrade
We have confirmed our mechanism of action and achieved proof of concept
Initial safety data appears superior to that of the other advanced or approved drugs for breast cancer when they were at a similar clinical stage of development
Initial efficacy data is similar or superior to those of other advanced or approved drugs for breast cancer when they were at a similar clinical stage of development
Initiated Combination Study of Bria-IMTtrade with Keytrudareg or Yervoyreg in Adv breast cancer patients expecting even better response rates than those in the ldquomonotherapyrdquo study Initial safety data is expected in 4Q2018 Initial efficacy data is expected in 1Q2019
Bria-OTStrade the first off-the-shelf personalized treatment for advanced breast cancer is expected to enter the clinic in 2019
28
Bria-IMTtrade Excellent Safety Data - To Date
To date Bria-IMTtrade has been dosed in 24 patients (4 in 2004-2005 20 in 2017-2018)
Interim Data (20 patients)-Ongoing Phase IIIa Study (2017-2018)
Bria-IMTtrade has been very well tolerated (ge60 doses given to date) The majority of adverse events (AEs) were limited to expected minor local irritation at the
injection sites No related grade gt3 or unexpected AEs No related serious AEs No serious unexpected related AEs Most patients who have dropped out did so due to worsening of their underlying disease
Based on the current study Bria-IMTtrade has an excellent safety profile
29
Bria-IMTtrade - Efficacy as Predicted
Interim Data (19 patients)-Ongoing Phase IIIa Study (2017-2018) amp Original Study (2004-2005)
PD-L1 expression on circulating cancer cells amp cancer-associated cells in 100 of patients (to date) Strong rationale for combination with checkpoint inhibitors like Keytruda
30
Bria-IMTtrade appears to be most effective in patients who match with Bria-IMT trade at 2 HLA loci (types) further supporting our ldquoHLA Matching Hypothesisrdquo and the development of Bria-OTS trade to cover 90 of the patient population
Combination with immune checkpoint inhibitors may induce a more potent anti-cancer response leading to our strategy of combination studies of Bria-IMT trade with Keytruda or Yervoy
Patients (n) HLA Match
Tumor Shrinkage
Biological Response
4 ge2 50 7515 ge1 27 334 0 0 0
Biological response includes tumor shrinkage or lower circulating cancer associated cells
The confirmatory Bria-IMTtrade monotherapy Phase IIa trial has completed enrollment Additional Support for the HLA-matching hypothesis has been obtained
Bria-IMTtrade Combination Therapy study with immune checkpoint inhibitors Keytrudareg if PD-L12 positive (ge1) Yervoyreg if PD-L12 negative (lt1) Accepting patients from the monotherapy study who develop progressive disease Also enrolling patients directly into this study to enhance experience with the combination In discussion with other pharmaceutical companies to evaluate additional combinations with other
immunotherapies
Bria-OTStrade Off-the-Shelf Personalized Targeted Immunotherapy Developing Bria-OTStrade to co-express GM-CSF and interferon-α Pre-manufacture additional HLA alleles ndash Total of 15 alleles (8 Class I and 7 Class II) Co-development of BriaDXtrade companion diagnostic for HLA typing Combination therapy clinical trial with immune checkpoint inhibitors for non-responders using
information from the Bria-IMTtrade Combination Therapy Study
33
Development Timeline ndash Breast Cancer
20192018 2020 2021
Phase IIIaBria-IMTtrade
Monotherapy
Currently Enrolling Phase IIaBria-IMTtrade + Checkpoint
Currently in discussions with potential partnersPhase II Bria-IMTtrade plus Additional Combinations (1Q19 4Q22)(eg PD-1 Inhibitor PD-L1 inhibitor anti-CTLA4 anti-GITR anti-OX40)
1Q 2Q 3Q 4Q
2023
Bria-OTStrade Off-The-Shelf Personalized ImmunotherapyMonotherapy and Potential Partnered Combo Therapy
(2H19 Ongoing)
Bria-OTStradeOff-the-Shelf Cell Line cGMP Manufacturing
and BriaDXtrade(1Q18 1Q19)
Registration Studies (1Q20 2H22)Bria-IMTtrade with Checkpoint InhibitorsBria-OTStrade +- Checkpoint Inhibitors
34
Immuno-oncology Deals
Recent deals of small biotechs with big pharma in immuno-oncology
35
Date PartnershipDevelopment stage at the time of the deal Deal size
07122018 Immatics-Genmab Preclinical Up to $28B
04042018 OSE Immunotherapeutics-Boehringer Ingelheim Preclinical Up to euro113B ($139B)
02092018 Pieris Pharmaceuticals-Seattle Genetics Preclinical Up to $123B
2142018 Nektar-BMS Ph III Up to $36B
01222018 Juno-Celgene Ph II $9B (Acquisition)
11142017 Loxo-Bayer Larotrectinib (Ph II) LOXO-195 (Ph III) Up to $155B
1032017 CytomX-Amgen Preclinical Up to $15B
03202017 CytomX--BMS Ph III Up to $36B
6282016 Xencor-Novartis Preclinical Up to $24B
Early Stage Clinical Studies (Comparison)
We compared the interim data of Ph IIIa study of Bria-IMTtrade in advanced breast cancer with thedata in the early stage clinical studies of recently approved breast cancer drugs and one fasttracked product candidate
Apples to apples comparison Early Stage Clinical Studies in oncology are typically done in patientswith no other therapeutic options Thus the patients have very advanced disease and response ratesare typically quite low
The patients in our Ph IIIa study have been heavily pre-treated (median 45 prior regimens)Some recent studies of relevance in breast cancer are noted in the following slides
36
Breast Cancer Market Opportunity
Drug Technology Approved for Market (US)Ibrance (palbociclib) CDK 46 Inhibitor HR+HER2- MBC in combination with
fluvestrant or aromatase inhibitor$933M in 1Q2018 $3126M in 2017
Kisqali (ribociclib) CDK 46 Inhibitor 2017 HR+HER2- MBC in combination with fluvestrant or aromatase inhibitor
Peak sales projected at $25B
Verzenio (abemaciclib) CDK 46 Inhibitor 2017 HR+HER2- MBC in combination with fluvestrant or aromatase inhibitor
balixafortide CXCR4 antagonist Fast track designation in 2018 for HER2- MBC who have failed 2 prior regimens
The market for breast cancer drugs is a multibillion dollar market with new drugs being approvedon an ongoing basis indicating the shortage of safe and effective treatments for this deadly disease
37
Competitors- Phase III Clinical Data Bria-IMTtrade shows superior safety and similar to superior efficacy data compared with those of the multi-billion dollar drugs when they were at a similar early stage of clinical development
Injection site reactions No related SAEs or SUSARs
Tumor vol darr ampor darr circul tumor cellsAll Comers 21(419) 26(519)One or More HLA matches 27(415) 33(515)Two or More HLA matches 50 (24) 75 (34)
Sheet1 (3)
Comp -Slides
Data
HLA (2)
HLA
Data (Ph1-2+4Pt)
Competitors (2018)-Slide
Competitors (2018)
In the Pipeline Protein Kinase C delta (PKCδ) Inhibitors
30 of all human malignancies display activating RAS mutations Another 60 showing over-activity of Ras-signaling pathways
Ras has been termed ldquoundruggablerdquo (no one has been able to make a Ras inhibitor drug)
BriaCellrsquos novel proprietary PKCδ inhibitors have shown activity against multiple RAS transformed tumors Lung cancer Melanoma Breast cancer Neuroendocrine cancer Pancreatic cancer Colorectal cancer
This target has an attractive safety profile based on in vivo studies and knock out mouse studies
PKCδ inhibitors should qualify for an accelerated clinical development plan and regulatory pathway
Could be in clinic within 24 months
Cost-Effective Additional Shot-on-Goal and additional partnership opportunities
Early-Stage Preclinical Program
39
Protein Kinase C delta (PKCδ) Inhibitors
Activated PKCδ inhibits RAS degradation which in turn stimulates tumor growth
Koo et al Oncotarget 621328 2016
30 of all human malignancies display activating RASmutations with another 60 showing over-activity of Ras-signaling pathways
BriaCellrsquos novel proprietary PKCδ inhibitors have shownactivity against multiple RAS transformed tumors
This target has an attractive safety profile based on in vivostudies and knock out mouse studies
PKCδ also has potential activity as an immunotherapeuticby blocking TGFβ signaling
PKCδ inhibitors are applicable to specific niche tumor typeswhich provide an accelerated clinical development plan
Structural aspects of first generation inhibitor rottlerin and staurosporine (pan-PKC activator) were combined to create second generation inhibitor KAM1
Third generation inhibitors such as BJE6-106 have improved potency and selectivity Fourth generation inhibitors under development to optimize drug-like characteristics PKCδ inhibitors lack endothelial cell cytotoxicity amp PKCδ deficient mice develop normally and are fertile Potentially no marked intrinsic toxicity by inhibiting PKCδ
Mukai H Saeki T Shimada K Naito Y Matsubara N Nakanishi T Obaishi H Namiki M Sasaki Y Phase 1 combination study of eribulin mesylate with trastuzumab for advanced or recurrent human epidermal growth factor receptor 2 positive breast cancer Invest New Drugs 2015 Feb33(1)119-27
AstraZeneca
Lynparza (Olaparib) + Cediranib
PARP inhibitor + inhibitor of VEGF receptor tyrosine kinases
HR+ HER2- MBC
BC amp OC
2013
28 (8 BC)
3 for BC
Olaparib (a poly (ADP-ribose) polymerase (PARP) inhibitor) amp Cediranib (Vascular endothelial growth factor receptor (VEGFR) 1 2 and 3 tyrosine kinase inhibitor)3 at dose level (DL) 0 (cediranib 20mg olaparib 100mg) 3 at DL1 (cediranib 20mg olaparib 200mg) 7 at DL2 (cediranib 30mg olaparib 200mg) 6 at DL3 (cediranib 30mg olaparib 400mg)
Liu JF Tolaney SM Birrer M Fleming GF Buss MK Dahlberg SE Lee H Whalen C Tyburski K Winer E Ivy P Matulonis UA A Phase 1 trial of the poly(ADP-ribose) polymerase inhibitor olaparib (AZD2281) in combination with the anti-angiogenic cediranib (AZD2171) in recurrent epithelial ovarian or triple-negative breast cancer Eur J Cancer 2013 Sep49(14)2972-8
Reyon Pharmaceutical
VM206RY
Heterologous prime-boost with a truncated HER2 sequence
HER2+ Stage IIIampIV BC
2015
9
2 chemo
Plasmid DNA (pHM-GM-CSF expressing truncated HER2 amp GM-CSF) amp adenoviral vector (Ad-HM containing modified HER2) (2 4 and 8 mgpatientvisit) of pHM-GM-CSF 3x IM weeks 0 2 and 4 Ad-HM 3 times 109 virus particles at week 6
11 PR
4 pts showed 7 minor AEs
Unclear
Kim SB Ahn JH Kim J Jung KH A phase 1 study of a heterologous prime-boost vaccination involving a truncated HER2 sequence in patients with HER2-expressing breast cancer Mol Ther Methods Clin Dev 2015 Sep 30215031 doi 101038mtm201531 eCollection 2015
Rodon J Peacuterez-Fidalgo A Krop IE Burris H Guerrero-Zotano A Britten CD Becerra C Schellens J Richards DA Schuler M Abu-Khalaf M Johnson FM Ranson M Edenfield J Silva AP Hackl W Quadt C Demanse D Duval V Baselga J Phase 11b dose escalation and expansion study of BEZ235 a dual PI3KmTOR inhibitor in patients with advanced solid tumors including patients with advanced breast cancer Cancer Chemother Pharmacol 2018 Jun 7 doi 101007s00280-018-3610-z [Epub ahead of print]
Celgene (Abraxane)
Gemcitabine + Abraxane (nab-paclitaxel)
Chemo + Chemo
OC BC NSCLC amp Panc cancer + Lung OC BC Kaposi sarcoma
MBC
2016
9
Adjuvant chemo (100)chemo post-adjuvant (33)
Gem (nucleoside metabolic inhibitor 1250 mgm2) on days 1 and 8 nab-Pac (microtubule inhibitor) starting dose of 180 mgm2 (cohort 1) 220 mgm2 (cohort 2) and 260 mgm2 (cohort 3) on day 1 of the 21-day cycle using a 3 + 3 design
0
MTD not reached29 Gr3 Neutropenia59 Gr1 Peripheralneuropathy
Yoshitomi S Taira N Doihara H Mizoo T Nogami T Iwamoto T Motoki T Shien T Ogasawara Y Matsuoka J Tsuji H Mitsuhashi T A phase 1 dose-finding and pharmacokinetic study of gemcitabine with nab-paclitaxel in patients with metastatic breast cancer Cancer Chemother Pharmacol 2016 Aug78(2)289-94
Eli Lilly
Erbituxreg (cetuximab) + Taxane
EGFR inhibitor antineoplastic agent + Chemo
Headamp Neck Colorectal Cancer
TNBC
2007-2010
18
1 chemo
Cetuximab (epidermal growth factor receptor (EGFR) antagonist ) an initial loading dose of cetuximab 400 mgm2 followed by a weekly dose of 250 mgm2Paclitaxel (microtubule inhibitor) 80 mgm2 or Docetaxel at an initial dose of 30 mgm2 was administered weekly
56 CR 22 PR
83 Dermatologic toxicity11 Grade3+
Nechushtan H Vainer G Stainberg H Salmon AY Hamburger T Peretz T A phase 12 of a combination of cetuximab and taxane for triple negative breast cancer patients Breast 2014 Aug23(4)435-8
Polyphor
Balixafortide (POL6326) + eribulin
CXCR4 antagonist + tubulin-based antimitotic
Heavily pretreated Relapsed MBC
2014-2016
56
3rd line 3 chemo
3+3 dose escalation The highest dose was established as eribulin 14 mgmsup2 on days 2 and 9 and balixafortide 55 mgkg on days 1minus3 and 8minus10 of the 21-day cycle
30 PR
41 Gr34 Neutropenia11 Gr34 Leucopenia11 Gr34 Febrileneutropenia2 Related mortalities
Apr 2018 Fast Track for HER2-MBC who have failed 2prior regimens
Pernas S Martin M Kaufman PA Gil-Martin M Gomez Pardo P Lopez-Tarruella S Manso L Ciruelos E Perez-Fidalgo JA Hernando C Ademuyiwa FO Weilbaecher K Mayer I Pluard TJ Martinez Garcia M Vahdat L Perez-Garcia J Wach A Barker D Fung S Romagnoli B Cortes J Balixafortide plus eribulin in HER2-negative metastatic breast cancer a phase 1 single-arm dose-escalation trial Lancet Oncol 2018 Jun19(6)812-824
11 PRndashbut only + letrozole (No Resp on monotherapy)
61 Gr34 Neutropenia39 Gr34 Leucopenia
$933M in 1Q2018 $31B in 2017
Tamura K Mukai H Naito Y Yonemori K Kodaira M Tanabe Y Yamamoto N Osera S Sasaki M Mori Y Hashigaki S Nagasawa T Umeyama Y Yoshino T Phase I study of palbociclib a cyclin-dependent kinase 46 inhibitor in Japanese patients Cancer Sci 2016 Jun107(6)755-63 doi 101111cas12932 Epub 2016 May 11
Pfizer
Ibrancereg (palbociclib)
CDK 46 Inhibitor
HR+ HER2- MBC
Heavily pretreated Relapsed Metastatic Cancer
2004-2008
41 (5 BC)
chemo naiumlve (17) 1-2 (51)3 (29) 3+ (2)
Palbociclib 25-150 mg dose ranging
0
20 Gr34 Neutropenia23 Gr34 Leucopenia
$933M in 1Q2018 $31B in 2017
Flaherty KT Lorusso PM Demichele A Abramson VG Courtney R Randolph SS Shaik MN Wilner KD ODwyer PJ Schwartz GK Phase I dose-escalation trial of the oral cyclin-dependent kinase 46 inhibitor PD 0332991 administered using a 21-day schedule in patients with advanced cancer Clin Cancer Res 2012 Jan 1518(2)568-76 doi 1011581078-0432CCR-11-0509 Epub 2011 Nov 16
Novartis
Kisqalireg (ribociclib)
CDK 46 Inhibitors
Premenopausal HR+ HER2- MBC
Heavily pretreated Relapsed Metastatic Cancer
2016
132 (20 BC)
0-1 (25) 2-3 (42) 4+ (32)
Ribociclib 50 mg ranging up to 1200 mg dose escalation
23 PRndashincluded 1 in BC (5 of BC pts)
27 Gr34 Neutropenia17 Gr34 Leucopenia
Peak sales projected at $25B
Infante JR Cassier PA Gerecitano JF Witteveen PO Chugh R Ribrag V Chakraborty A Matano A Dobson JR Crystal AS Parasuraman S Shapiro GI A Phase I Study of the Cyclin-Dependent Kinase 46 Inhibitor Ribociclib (LEE011) in Patients with Advanced Solid Tumors and Lymphomas Clin Cancer Res 2016 Dec 122(23)5696-5705 Epub 2016 Aug 19
Eli Lilly
Verzenioreg (abemaciclib)
CDK 46 Inhibitors
HR+HER2minusMBC
Heavily pretreated Relapsed Metastatic Cancer
2016
12 (1 BC)
1 (312) 2 (212) 3+ (7)
Abemaciclib 100 mg ranging up to 200 mg dose escalation
17 PR (included 1 in BC)
17 Gr34 Neutropenia33 Gr34 Leucopenia
Peak sales projected at $2B
Fujiwara Y Tamura K Kondo S Tanabe Y Iwasa S Shimomura A Kitano S Ogasawara K Turner PK Mori J Asou H Chan EM Yamamoto N Phase 1 study of abemaciclib an inhibitor of CDK 4 and 6 as a single agent for Japanese patients with advanced cancer Cancer Chemother Pharmacol 2016 Aug78(2)281-8 doi 101007s00280-016-3085-8 Epub 2016 Jun 16
Mukai H Saeki T Shimada K Naito Y Matsubara N Nakanishi T Obaishi H Namiki M Sasaki Y Phase 1 combination study of eribulin mesylate with trastuzumab for advanced or recurrent human epidermal growth factor receptor 2 positive breast cancer Invest New Drugs 2015 Feb33(1)119-27
AstraZeneca
Lynparza (Olaparib)+ Cediranib
PARP inhibitor+ inhibitor of VEGF RTK
HR+ HER2- MBC
BC amp OC
13
28 (8 BC)
3 for BC
Olaparib (a poly (ADP-ribose) polymerase (PARP) inhibitor) amp Cediranib (Vascular endothelial growth factor receptor (VEGFR) 1 2 and 3 tyrosine kinase inhibitor)3 at dose level (DL) 0 (cediranib 20mg olaparib 100mg) 3 at DL1 (cediranib 20mg olaparib 200mg) 7 at DL2 (cediranib 30mg olaparib 200mg) 6 at DL3 (cediranib 30mg olaparib 400mg)
Liu JF Tolaney SM Birrer M Fleming GF Buss MK Dahlberg SE Lee H Whalen C Tyburski K Winer E Ivy P Matulonis UA A Phase 1 trial of the poly(ADP-ribose) polymerase inhibitor olaparib (AZD2281) in combination with the anti-angiogenic cediranib (AZD2171) in recurrent epithelial ovarian or triple-negative breast cancer Eur J Cancer 2013 Sep49(14)2972-8
ReyonPharma
VM206RY
Heterologous prime-boost with a truncated HER2 sequence
HER2+ Stg IIIampIV BC
15
9
2 chemo
Plasmid DNA (pHM-GM-CSF expressing truncated HER2 amp GM-CSF) amp adenoviral vector (Ad-HM containing modified HER2) (2 4 and 8 mgpatientvisit) of pHM-GM-CSF 3x IM weeks 0 2 and 4 Ad-HM 3 times 109 virus particles at week 6
11 PR
4 pts 7 minor AEs
Unclear
Kim SB Ahn JH Kim J Jung KH A phase 1 study of a heterologous prime-boost vaccination involving a truncated HER2 sequence in patients with HER2-expressing breast cancer Mol Ther Methods Clin Dev 2015 Sep 30215031 doi 101038mtm201531 eCollection 2015
Rodon J Peacuterez-Fidalgo A Krop IE Burris H Guerrero-Zotano A Britten CD Becerra C Schellens J Richards DA Schuler M Abu-Khalaf M Johnson FM Ranson M Edenfield J Silva AP Hackl W Quadt C Demanse D Duval V Baselga J Phase 11b dose escalation and expansion study of BEZ235 a dual PI3KmTOR inhibitor in patients with advanced solid tumors including patients with advanced breast cancer Cancer Chemother Pharmacol 2018 Jun 7 doi 101007s00280-018-3610-z [Epub ahead of print]
Celgene(Abraxane)
Gemcitabine + Abraxane (nab-paclitaxel)
Chemo+ Chemo
OC BC NSCLC PC + LC OC BC KS
MBC
16
9
Adjuv chemo (100)chemo post-adjuv (33)
Gem (nucleoside metabolic inhibitor 1250 mgm2) on days 1 and 8 nab-Pac (microtubule inhibitor) starting dose of 180 mgm2 (cohort 1) 220 mgm2 (cohort 2) and 260 mgm2 (cohort 3) on day 1 of the 21-day cycle using a 3 + 3 design
0
MTD not reached29 Gr3 Neutropenia59 Gr1 Peripheralneuropathy
Yoshitomi S Taira N Doihara H Mizoo T Nogami T Iwamoto T Motoki T Shien T Ogasawara Y Matsuoka J Tsuji H Mitsuhashi T A phase 1 dose-finding and pharmacokinetic study of gemcitabine with nab-paclitaxel in patients with metastatic breast cancer Cancer Chemother Pharmacol 2016 Aug78(2)289-94
Eli Lilly
Erbituxreg (cetuximab) + Taxane
EGFR inhibitor antineoplastic agent + Chemo
Head amp NeckColorectal
TNBC
07-10
18
1 chemo
Cetuximab (epidermal growth factor receptor (EGFR) antagonist ) an initial loading dose of cetuximab 400 mgm2 followed by a weekly dose of 250 mgm2Paclitaxel (microtubule inhibitor) 80 mgm2 or Docetaxel at an initial dose of 30 mgm2 was administered weekly
56 CR 22 PR
83 Dermatologic toxicity11 Grade3+
Nechushtan H Vainer G Stainberg H Salmon AY Hamburger T Peretz T A phase 12 of a combination of cetuximab and taxane for triple negative breast cancer patients Breast 2014 Aug23(4)435-8
Polyphor
Balixafortide (POL6326) + eribulin
CXCR4 antagonist + tubulin-based antimitotic
Heavily pretreatedRelapsed MBC
14-16
56
3rd line 3 chemo
3+3 dose escalation The highest dose was established as eribulin 14 mgmsup2 on days 2 and 9 and balixafortide 55 mgkg on days 1minus3 and 8minus10 of the 21-day cycle
30 PR
41 Gr34 Neutropenia11 Gr34 Leucopenia11 Gr34 Febrileneutropenia2 Related mortalities
42018 Fast Track (HER2-MBC failed 2 prior regimens)
Pernas S Martin M Kaufman PA Gil-Martin M Gomez Pardo P Lopez-Tarruella S Manso L Ciruelos E Perez-Fidalgo JA Hernando C Ademuyiwa FO Weilbaecher K Mayer I Pluard TJ Martinez Garcia M Vahdat L Perez-Garcia J Wach A Barker D Fung S Romagnoli B Cortes J Balixafortide plus eribulin in HER2-negative metastatic breast cancer a phase 1 single-arm dose-escalation trial Lancet Oncol 2018 Jun19(6)812-824
1 PRndashbut only + letrozoleNo Resp on monotherapy
61 Gr34 Neutropenia39 Gr34 Leucopenia
$933M (1Q18)$31B (2017)
Tamura K Mukai H Naito Y Yonemori K Kodaira M Tanabe Y Yamamoto N Osera S Sasaki M Mori Y Hashigaki S Nagasawa T Umeyama Y Yoshino T Phase I study of palbociclib a cyclin-dependent kinase 46 inhibitor in Japanese patients Cancer Sci 2016 Jun107(6)755-63 doi 101111cas12932 Epub 2016 May 11
Pfizer
Ibrancereg (palbociclib)
CDK 46 Inhibitor
HR+ HER2- MBC
Heavily pretreatedRelapsed Met Cancer
04-08
41 (5 BC)
chemo naiumlve (17)1-2(51) 3(29) 3+(2)
Palbociclib 25-150 mg dose ranging
0
20 Gr34 Neutropenia23 Gr34 Leucopenia
$933M (1Q18)$31B (2017)
Flaherty KT Lorusso PM Demichele A Abramson VG Courtney R Randolph SS Shaik MN Wilner KD ODwyer PJ Schwartz GK Phase I dose-escalation trial of the oral cyclin-dependent kinase 46 inhibitor PD 0332991 administered using a 21-day schedule in patients with advanced cancer Clin Cancer Res 2012 Jan 1518(2)568-76 doi 1011581078-0432CCR-11-0509 Epub 2011 Nov 16
Novartis
Kisqalireg (ribociclib)
CDK 46 Inhibitor
Premenopausal HR+ HER2- MBC
Heavily pretreatedRelapsed Met Cancer
16
132 (20 BC)
0-1 (25) 2-3 (42)4+ (32)
Ribociclib 50 mg ranging up to 1200 mg dose escalation
23 PR-included 1 BC (5 of BC pts)
27 Gr34 Neutropenia17 Gr34 Leucopenia
Peak sales est at $25B
Infante JR Cassier PA Gerecitano JF Witteveen PO Chugh R Ribrag V Chakraborty A Matano A Dobson JR Crystal AS Parasuraman S Shapiro GI A Phase I Study of the Cyclin-Dependent Kinase 46 Inhibitor Ribociclib (LEE011) in Patients with Advanced Solid Tumors and Lymphomas Clin Cancer Res 2016 Dec 122(23)5696-5705 Epub 2016 Aug 19
Eli Lilly
Verzenioreg (abemaciclib)
CDK 46 Inhibitor
HR+HER2minusMBC
Heavily pretreatedRelapsed Met Cancer
16
12 (1 BC)
1 (312) 2 (212) 3+(7)
Abemaciclib 100 mg ranging up to 200 mg dose escalation
17 PR (included 1 BC)
17 Gr34 Neutropenia33 Gr34 Leucopenia
Peak sales est at $2B
Fujiwara Y Tamura K Kondo S Tanabe Y Iwasa S Shimomura A Kitano S Ogasawara K Turner PK Mori J Asou H Chan EM Yamamoto N Phase 1 study of abemaciclib an inhibitor of CDK 4 and 6 as a single agent for Japanese patients with advanced cancer Cancer Chemother Pharmacol 2016 Aug78(2)281-8 doi 101007s00280-016-3085-8 Epub 2016 Jun 16
Mukai H Saeki T Shimada K Naito Y Matsubara N Nakanishi T Obaishi H Namiki M Sasaki Y Phase 1 combination study of eribulin mesylate with trastuzumab for advanced or recurrent human epidermal growth factor receptor 2 positive breast cancer Invest New Drugs 2015 Feb33(1)119-27
AstraZeneca
Lynparza (Olaparib) + Cediranib
PARP inhibitor + inhibitor of VEGF receptor tyrosine kinases
HR+ HER2- MBC
BC amp OC
2013
28 (8 BC)
3 for BC
Olaparib (a poly (ADP-ribose) polymerase (PARP) inhibitor) amp Cediranib (Vascular endothelial growth factor receptor (VEGFR) 1 2 and 3 tyrosine kinase inhibitor)3 at dose level (DL) 0 (cediranib 20mg olaparib 100mg) 3 at DL1 (cediranib 20mg olaparib 200mg) 7 at DL2 (cediranib 30mg olaparib 200mg) 6 at DL3 (cediranib 30mg olaparib 400mg)
Liu JF Tolaney SM Birrer M Fleming GF Buss MK Dahlberg SE Lee H Whalen C Tyburski K Winer E Ivy P Matulonis UA A Phase 1 trial of the poly(ADP-ribose) polymerase inhibitor olaparib (AZD2281) in combination with the anti-angiogenic cediranib (AZD2171) in recurrent epithelial ovarian or triple-negative breast cancer Eur J Cancer 2013 Sep49(14)2972-8
Reyon Pharmaceutical
VM206RY
Heterologous prime-boost with a truncated HER2 sequence
HER2+ Stage IIIampIV BC
2015
9
2 chemo
Plasmid DNA (pHM-GM-CSF expressing truncated HER2 amp GM-CSF) amp adenoviral vector (Ad-HM containing modified HER2) (2 4 and 8 mgpatientvisit) of pHM-GM-CSF 3x IM weeks 0 2 and 4 Ad-HM 3 times 109 virus particles at week 6
11 PR
4 pts showed 7 minor AEs
Unclear
Kim SB Ahn JH Kim J Jung KH A phase 1 study of a heterologous prime-boost vaccination involving a truncated HER2 sequence in patients with HER2-expressing breast cancer Mol Ther Methods Clin Dev 2015 Sep 30215031 doi 101038mtm201531 eCollection 2015
Rodon J Peacuterez-Fidalgo A Krop IE Burris H Guerrero-Zotano A Britten CD Becerra C Schellens J Richards DA Schuler M Abu-Khalaf M Johnson FM Ranson M Edenfield J Silva AP Hackl W Quadt C Demanse D Duval V Baselga J Phase 11b dose escalation and expansion study of BEZ235 a dual PI3KmTOR inhibitor in patients with advanced solid tumors including patients with advanced breast cancer Cancer Chemother Pharmacol 2018 Jun 7 doi 101007s00280-018-3610-z [Epub ahead of print]
Celgene (Abraxane)
Gemcitabine + Abraxane (nab-paclitaxel)
Chemo + Chemo
OC BC NSCLC amp Panc cancer + Lung OC BC Kaposi sarcoma
MBC
2016
9
Adjuvant chemo (100)chemo post-adjuvant (33)
Gem (nucleoside metabolic inhibitor 1250 mgm2) on days 1 and 8 nab-Pac (microtubule inhibitor) starting dose of 180 mgm2 (cohort 1) 220 mgm2 (cohort 2) and 260 mgm2 (cohort 3) on day 1 of the 21-day cycle using a 3 + 3 design
0
MTD not reached29 Gr3 Neutropenia59 Gr1 Peripheralneuropathy
Yoshitomi S Taira N Doihara H Mizoo T Nogami T Iwamoto T Motoki T Shien T Ogasawara Y Matsuoka J Tsuji H Mitsuhashi T A phase 1 dose-finding and pharmacokinetic study of gemcitabine with nab-paclitaxel in patients with metastatic breast cancer Cancer Chemother Pharmacol 2016 Aug78(2)289-94
Eli Lilly
Erbituxreg (cetuximab) + Taxane
EGFR inhibitor antineoplastic agent + Chemo
Headamp Neck Colorectal Cancer
TNBC
2007-2010
18
1 chemo
Cetuximab (epidermal growth factor receptor (EGFR) antagonist ) an initial loading dose of cetuximab 400 mgm2 followed by a weekly dose of 250 mgm2Paclitaxel (microtubule inhibitor) 80 mgm2 or Docetaxel at an initial dose of 30 mgm2 was administered weekly
56 CR 22 PR
83 Dermatologic toxicity11 Grade3+
Nechushtan H Vainer G Stainberg H Salmon AY Hamburger T Peretz T A phase 12 of a combination of cetuximab and taxane for triple negative breast cancer patients Breast 2014 Aug23(4)435-8
Polyphor
Balixafortide (POL6326) + eribulin
CXCR4 antagonist + tubulin-based antimitotic
Heavily pretreated Relapsed MBC
2014-2016
56
3rd line 3 chemo
3+3 dose escalation The highest dose was established as eribulin 14 mgmsup2 on days 2 and 9 and balixafortide 55 mgkg on days 1minus3 and 8minus10 of the 21-day cycle
30 PR
41 Gr34 Neutropenia11 Gr34 Leucopenia11 Gr34 Febrileneutropenia2 Related mortalities
Apr 2018 Fast Track for HER2-MBC who have failed 2prior regimens
Pernas S Martin M Kaufman PA Gil-Martin M Gomez Pardo P Lopez-Tarruella S Manso L Ciruelos E Perez-Fidalgo JA Hernando C Ademuyiwa FO Weilbaecher K Mayer I Pluard TJ Martinez Garcia M Vahdat L Perez-Garcia J Wach A Barker D Fung S Romagnoli B Cortes J Balixafortide plus eribulin in HER2-negative metastatic breast cancer a phase 1 single-arm dose-escalation trial Lancet Oncol 2018 Jun19(6)812-824
11 PRndashbut only + letrozole (No Resp on monotherapy)
61 Gr34 Neutropenia39 Gr34 Leucopenia
$933M in 1Q2018 $31B in 2017
Tamura K Mukai H Naito Y Yonemori K Kodaira M Tanabe Y Yamamoto N Osera S Sasaki M Mori Y Hashigaki S Nagasawa T Umeyama Y Yoshino T Phase I study of palbociclib a cyclin-dependent kinase 46 inhibitor in Japanese patients Cancer Sci 2016 Jun107(6)755-63 doi 101111cas12932 Epub 2016 May 11
Pfizer
Ibrancereg (palbociclib)
CDK 46 Inhibitor
HR+ HER2- MBC
Heavily pretreated Relapsed Metastatic Cancer
2004-2008
41 (5 BC)
chemo naiumlve (17) 1-2 (51)3 (29) 3+ (2)
Palbociclib 25-150 mg dose ranging
0
20 Gr34 Neutropenia23 Gr34 Leucopenia
$933M in 1Q2018 $31B in 2017
Flaherty KT Lorusso PM Demichele A Abramson VG Courtney R Randolph SS Shaik MN Wilner KD ODwyer PJ Schwartz GK Phase I dose-escalation trial of the oral cyclin-dependent kinase 46 inhibitor PD 0332991 administered using a 21-day schedule in patients with advanced cancer Clin Cancer Res 2012 Jan 1518(2)568-76 doi 1011581078-0432CCR-11-0509 Epub 2011 Nov 16
Novartis
Kisqalireg (ribociclib)
CDK 46 Inhibitors
Premenopausal HR+ HER2- MBC
Heavily pretreated Relapsed Metastatic Cancer
2016
132 (20 BC)
0-1 (25) 2-3 (42) 4+ (32)
Ribociclib 50 mg ranging up to 1200 mg dose escalation
23 PRndashincluded 1 in BC (5 of BC pts)
27 Gr34 Neutropenia17 Gr34 Leucopenia
Peak sales projected at $25B
Infante JR Cassier PA Gerecitano JF Witteveen PO Chugh R Ribrag V Chakraborty A Matano A Dobson JR Crystal AS Parasuraman S Shapiro GI A Phase I Study of the Cyclin-Dependent Kinase 46 Inhibitor Ribociclib (LEE011) in Patients with Advanced Solid Tumors and Lymphomas Clin Cancer Res 2016 Dec 122(23)5696-5705 Epub 2016 Aug 19
Eli Lilly
Verzenioreg (abemaciclib)
CDK 46 Inhibitors
HR+HER2minusMBC
Heavily pretreated Relapsed Metastatic Cancer
2016
12 (1 BC)
1 (312) 2 (212) 3+ (7)
Abemaciclib 100 mg ranging up to 200 mg dose escalation
17 PR (included 1 in BC)
17 Gr34 Neutropenia33 Gr34 Leucopenia
Peak sales projected at $2B
Fujiwara Y Tamura K Kondo S Tanabe Y Iwasa S Shimomura A Kitano S Ogasawara K Turner PK Mori J Asou H Chan EM Yamamoto N Phase 1 study of abemaciclib an inhibitor of CDK 4 and 6 as a single agent for Japanese patients with advanced cancer Cancer Chemother Pharmacol 2016 Aug78(2)281-8 doi 101007s00280-016-3085-8 Epub 2016 Jun 16
Mukai H Saeki T Shimada K Naito Y Matsubara N Nakanishi T Obaishi H Namiki M Sasaki Y Phase 1 combination study of eribulin mesylate with trastuzumab for advanced or recurrent human epidermal growth factor receptor 2 positive breast cancer Invest New Drugs 2015 Feb33(1)119-27
AstraZeneca
Lynparza (Olaparib)+ Cediranib
PARP inhibitor+ inhibitor of VEGF RTK
HR+ HER2- MBC
BC amp OC
13
28 (8 BC)
3 for BC
Olaparib (a poly (ADP-ribose) polymerase (PARP) inhibitor) amp Cediranib (Vascular endothelial growth factor receptor (VEGFR) 1 2 and 3 tyrosine kinase inhibitor)3 at dose level (DL) 0 (cediranib 20mg olaparib 100mg) 3 at DL1 (cediranib 20mg olaparib 200mg) 7 at DL2 (cediranib 30mg olaparib 200mg) 6 at DL3 (cediranib 30mg olaparib 400mg)
Liu JF Tolaney SM Birrer M Fleming GF Buss MK Dahlberg SE Lee H Whalen C Tyburski K Winer E Ivy P Matulonis UA A Phase 1 trial of the poly(ADP-ribose) polymerase inhibitor olaparib (AZD2281) in combination with the anti-angiogenic cediranib (AZD2171) in recurrent epithelial ovarian or triple-negative breast cancer Eur J Cancer 2013 Sep49(14)2972-8
ReyonPharma
VM206RY
Heterologous prime-boost with a truncated HER2 sequence
HER2+ Stg IIIampIV BC
15
9
2 chemo
Plasmid DNA (pHM-GM-CSF expressing truncated HER2 amp GM-CSF) amp adenoviral vector (Ad-HM containing modified HER2) (2 4 and 8 mgpatientvisit) of pHM-GM-CSF 3x IM weeks 0 2 and 4 Ad-HM 3 times 109 virus particles at week 6
11 PR
4 pts 7 minor AEs
Unclear
Kim SB Ahn JH Kim J Jung KH A phase 1 study of a heterologous prime-boost vaccination involving a truncated HER2 sequence in patients with HER2-expressing breast cancer Mol Ther Methods Clin Dev 2015 Sep 30215031 doi 101038mtm201531 eCollection 2015
Rodon J Peacuterez-Fidalgo A Krop IE Burris H Guerrero-Zotano A Britten CD Becerra C Schellens J Richards DA Schuler M Abu-Khalaf M Johnson FM Ranson M Edenfield J Silva AP Hackl W Quadt C Demanse D Duval V Baselga J Phase 11b dose escalation and expansion study of BEZ235 a dual PI3KmTOR inhibitor in patients with advanced solid tumors including patients with advanced breast cancer Cancer Chemother Pharmacol 2018 Jun 7 doi 101007s00280-018-3610-z [Epub ahead of print]
Celgene(Abraxane)
Gemcitabine + Abraxane (nab-paclitaxel)
Chemo+ Chemo
OC BC NSCLC PC + LC OC BC KS
MBC
16
9
Adjuv chemo (100)chemo post-adjuv (33)
Gem (nucleoside metabolic inhibitor 1250 mgm2) on days 1 and 8 nab-Pac (microtubule inhibitor) starting dose of 180 mgm2 (cohort 1) 220 mgm2 (cohort 2) and 260 mgm2 (cohort 3) on day 1 of the 21-day cycle using a 3 + 3 design
0
MTD not reached29 Gr3 Neutropenia59 Gr1 Peripheralneuropathy
Yoshitomi S Taira N Doihara H Mizoo T Nogami T Iwamoto T Motoki T Shien T Ogasawara Y Matsuoka J Tsuji H Mitsuhashi T A phase 1 dose-finding and pharmacokinetic study of gemcitabine with nab-paclitaxel in patients with metastatic breast cancer Cancer Chemother Pharmacol 2016 Aug78(2)289-94
Eli Lilly
Erbituxreg (cetuximab) + Taxane
EGFR inhibitor antineoplastic agent + Chemo
Head amp NeckColorectal
TNBC
07-10
18
1 chemo
Cetuximab (epidermal growth factor receptor (EGFR) antagonist ) an initial loading dose of cetuximab 400 mgm2 followed by a weekly dose of 250 mgm2Paclitaxel (microtubule inhibitor) 80 mgm2 or Docetaxel at an initial dose of 30 mgm2 was administered weekly
56 CR 22 PR
83 Dermatologic toxicity11 Grade3+
Nechushtan H Vainer G Stainberg H Salmon AY Hamburger T Peretz T A phase 12 of a combination of cetuximab and taxane for triple negative breast cancer patients Breast 2014 Aug23(4)435-8
Polyphor
Balixafortide (POL6326) + eribulin
CXCR4 antagonist + tubulin-based antimitotic
Heavily pretreatedRelapsed MBC
14-16
56
3rd line 3 chemo
3+3 dose escalation The highest dose was established as eribulin 14 mgmsup2 on days 2 and 9 and balixafortide 55 mgkg on days 1minus3 and 8minus10 of the 21-day cycle
30 PR
41 Gr34 Neutropenia11 Gr34 Leucopenia11 Gr34 Febrileneutropenia2 Related mortalities
42018 Fast Track (HER2-MBC failed 2 prior regimens)
Pernas S Martin M Kaufman PA Gil-Martin M Gomez Pardo P Lopez-Tarruella S Manso L Ciruelos E Perez-Fidalgo JA Hernando C Ademuyiwa FO Weilbaecher K Mayer I Pluard TJ Martinez Garcia M Vahdat L Perez-Garcia J Wach A Barker D Fung S Romagnoli B Cortes J Balixafortide plus eribulin in HER2-negative metastatic breast cancer a phase 1 single-arm dose-escalation trial Lancet Oncol 2018 Jun19(6)812-824
1 PRndashbut only + letrozoleNo Resp on monotherapy
61 Gr34 Neutropenia39 Gr34 Leucopenia
$933M (1Q18)$31B (2017)
Tamura K Mukai H Naito Y Yonemori K Kodaira M Tanabe Y Yamamoto N Osera S Sasaki M Mori Y Hashigaki S Nagasawa T Umeyama Y Yoshino T Phase I study of palbociclib a cyclin-dependent kinase 46 inhibitor in Japanese patients Cancer Sci 2016 Jun107(6)755-63 doi 101111cas12932 Epub 2016 May 11
Pfizer
Ibrancereg (palbociclib)
CDK 46 Inhibitor
HR+ HER2- MBC
Heavily pretreatedRelapsed Met Cancer
04-08
41 (5 BC)
chemo naiumlve (17)1-2(51) 3(29) 3+(2)
Palbociclib 25-150 mg dose ranging
0
20 Gr34 Neutropenia23 Gr34 Leucopenia
$933M (1Q18)$31B (2017)
Flaherty KT Lorusso PM Demichele A Abramson VG Courtney R Randolph SS Shaik MN Wilner KD ODwyer PJ Schwartz GK Phase I dose-escalation trial of the oral cyclin-dependent kinase 46 inhibitor PD 0332991 administered using a 21-day schedule in patients with advanced cancer Clin Cancer Res 2012 Jan 1518(2)568-76 doi 1011581078-0432CCR-11-0509 Epub 2011 Nov 16
Novartis
Kisqalireg (ribociclib)
CDK 46 Inhibitor
Premenopausal HR+ HER2- MBC
Heavily pretreatedRelapsed Met Cancer
16
132 (20 BC)
0-1 (25) 2-3 (42)4+ (32)
Ribociclib 50 mg ranging up to 1200 mg dose escalation
23 PR-included 1 BC (5 of BC pts)
27 Gr34 Neutropenia17 Gr34 Leucopenia
Peak sales est at $25B
Infante JR Cassier PA Gerecitano JF Witteveen PO Chugh R Ribrag V Chakraborty A Matano A Dobson JR Crystal AS Parasuraman S Shapiro GI A Phase I Study of the Cyclin-Dependent Kinase 46 Inhibitor Ribociclib (LEE011) in Patients with Advanced Solid Tumors and Lymphomas Clin Cancer Res 2016 Dec 122(23)5696-5705 Epub 2016 Aug 19
Eli Lilly
Verzenioreg (abemaciclib)
CDK 46 Inhibitor
HR+HER2minusMBC
Heavily pretreatedRelapsed Met Cancer
16
12 (1 BC)
1 (312) 2 (212) 3+(7)
Abemaciclib 100 mg ranging up to 200 mg dose escalation
17 PR (included 1 BC)
17 Gr34 Neutropenia33 Gr34 Leucopenia
Peak sales est at $2B
Fujiwara Y Tamura K Kondo S Tanabe Y Iwasa S Shimomura A Kitano S Ogasawara K Turner PK Mori J Asou H Chan EM Yamamoto N Phase 1 study of abemaciclib an inhibitor of CDK 4 and 6 as a single agent for Japanese patients with advanced cancer Cancer Chemother Pharmacol 2016 Aug78(2)281-8 doi 101007s00280-016-3085-8 Epub 2016 Jun 16
41 Gr34 Neutropenia11 Gr34 Leucopenia11 Gr34 Febrileneutropenia2 Related mortalities
30 PRs in combination with Halaven
Bria-IMTTM
20
Injection site reactions No related SAEs or SUSARs
Tumor vol darr ampor darr circul tumor cells)All Comers 21(419) 26(519)One or More HLA matches 27(415) 33(515)Two or More HLA matches 50 (24) 75 (34))
Drug
Technology
Approved for
Market (US)
Ibrance (palbociclib)
CDK 46 Inhibitor
HR+HER2- MBC in combination with fluvestrant or aromatase inhibitor
$933M in 1Q2018 $3126M in 2017
Kisqali (ribociclib)
CDK 46 Inhibitor
2017 HR+HER2- MBC in combination with fluvestrant or aromatase inhibitor
Peak sales projected at $25B
Verzenio (abemaciclib)
CDK 46 Inhibitor
2017 HR+HER2- MBC in combination with fluvestrant or aromatase inhibitor
Peak sales projected at $2B
Lynparza (olaparib)
Poly (ADP-ribose) polymerase (PARP) inhibitor
2017 ovarian amp breast cancer
$997M in 2017
Halaven (eribulin mesylate)
Tubulin-based antimitotic
2H2017 3rd line MBC amp liposarcoma
$181M in 2017
balixafortide
CXCR4 antagonist
Fast track designation in 2018 for HER2- MBC who have failed 2 prior regimens
BriaCell Investment Highlights
Developing Bria-OTStrade the First Off-the-Shelf Personalized Immunotherapy
Targeting Adv Breast Cancer Unmet medical need (42000 death in the US in 2017 ) $1 Bil- $5 Bil market opportunity depending on patient treatment stage
Impressive results in 2 proof-of-concept clinical trials Rapid Response Rate Repeated following re-treatment Excellent Safety Profile
Completed enrollment in Phase IIIa clinical trial of Bria-IMTtrade with outstanding safety amp efficacy data Initiated Phase IIa Combination Study of Bria-IMTtrade with Keytrudareg (Merck amp Co Inc)
Developing Bria-OTStrade along with BriaDXtrade its companion diagnostic test Ability to match and treat ~90 of patient population with Off-the-Shelf personalized immunotherapy
Experienced Management has been involved in over 10 drug approvals
Patient B001 Breast 70 No 1101 - 3501 4001 Negative -
Bria-IMTtradeHuman Proof-of-Concept Trials in Breast Cancer (Patient A002)
24
Proof-of-Concept Results Resulted in BriaCellrsquos Immunotherapy Strategy Use BriaDXtrade diagnostic to select only those patients matching Bria-IMTtrade Use BriaDXtrade diagnostic test to select Bria-OTStrade alleles matching ~90 of all patients
Bria-IMTtradeCurrent Phase IIIa Data Supports HLA Matching Hypothesis Six patients treated in 2017 Bria-IMTtrade was safe and well tolerated
Patient 01-002 73-year-old woman with breast cancer diagnosed in 1995 Developed liver metastases in2010 and lung metastases in 2017 Previously treated with 7 rounds of chemotherapy with 8 differentchemotherapy agents Received 5 cycles of Bria-IMTtrade over 3 months then monthly cycles (6 months total)Evaluated after 3 months and 6 months After 3 months despite the extensive prior therapy her scans notedthat ldquothere has been a clear response in the multiple bilateral pulmonary nodulesrdquo The response wasmaintained after 6 months of Bria-IMTtrade treatment She matches Bria-IMTtrade at 2 HLA alleles
The liver tumors were stable to slightly increased at 3 months and then progressed after 6 months
This supports our hypothesis of heightened anti-tumor activity in patients with a matched HLA types Clear path to develop BriaDXtrade to select the patients using HLA testing
1 RLL 29 Not Detectable Not Detectable2 LUL apical pleural based 34 tiny nodule lt 1mm scar tiny nodule lt 1mm scar3 xxx 39 Not Detectable Not Detectable4 40 Not Detectable Not Detectable5 RLL 45 Not Detectable Not Detectable6 LLL 49 Not Detectable Not Detectable7 xxx 52 Not Detectable Not Detectable8 RLL 52 Not Detectable Not Detectable9 RLL 56 Not Detectable Not Detectable
10 RLL costophrenic recess 56 Not Detectable Not Detectable11 XXX 58 Not Detectable Not Detectable12 LUL 60 Not Detectable Not Detectable13 XXX 67 15 1514 RUL 72 15 1515 LLL 76 Not Detectable Not Detectable16 RUL Noncalcified Nodule 77 Not Detectable Not Detectable17 RLL costophrenic recess 79 10 1018 RUL 82 Not Detectable Not Detectable19 RLL 90 Not Detectable Not Detectable20 RLL 91 lt 01 lt 0121 xxx xxx Not Detectable Not Detectable
27
Clinical Development Update ndash Summary 2018 September 26
Completed enrollment of Adv Breast cancer patients in the Phase IIIa ldquomonotherapyrdquo study of Bria-IMTtrade
We have confirmed our mechanism of action and achieved proof of concept
Initial safety data appears superior to that of the other advanced or approved drugs for breast cancer when they were at a similar clinical stage of development
Initial efficacy data is similar or superior to those of other advanced or approved drugs for breast cancer when they were at a similar clinical stage of development
Initiated Combination Study of Bria-IMTtrade with Keytrudareg or Yervoyreg in Adv breast cancer patients expecting even better response rates than those in the ldquomonotherapyrdquo study Initial safety data is expected in 4Q2018 Initial efficacy data is expected in 1Q2019
Bria-OTStrade the first off-the-shelf personalized treatment for advanced breast cancer is expected to enter the clinic in 2019
28
Bria-IMTtrade Excellent Safety Data - To Date
To date Bria-IMTtrade has been dosed in 24 patients (4 in 2004-2005 20 in 2017-2018)
Interim Data (20 patients)-Ongoing Phase IIIa Study (2017-2018)
Bria-IMTtrade has been very well tolerated (ge60 doses given to date) The majority of adverse events (AEs) were limited to expected minor local irritation at the
injection sites No related grade gt3 or unexpected AEs No related serious AEs No serious unexpected related AEs Most patients who have dropped out did so due to worsening of their underlying disease
Based on the current study Bria-IMTtrade has an excellent safety profile
29
Bria-IMTtrade - Efficacy as Predicted
Interim Data (19 patients)-Ongoing Phase IIIa Study (2017-2018) amp Original Study (2004-2005)
PD-L1 expression on circulating cancer cells amp cancer-associated cells in 100 of patients (to date) Strong rationale for combination with checkpoint inhibitors like Keytruda
30
Bria-IMTtrade appears to be most effective in patients who match with Bria-IMT trade at 2 HLA loci (types) further supporting our ldquoHLA Matching Hypothesisrdquo and the development of Bria-OTS trade to cover 90 of the patient population
Combination with immune checkpoint inhibitors may induce a more potent anti-cancer response leading to our strategy of combination studies of Bria-IMT trade with Keytruda or Yervoy
Patients (n) HLA Match
Tumor Shrinkage
Biological Response
4 ge2 50 7515 ge1 27 334 0 0 0
Biological response includes tumor shrinkage or lower circulating cancer associated cells
The confirmatory Bria-IMTtrade monotherapy Phase IIa trial has completed enrollment Additional Support for the HLA-matching hypothesis has been obtained
Bria-IMTtrade Combination Therapy study with immune checkpoint inhibitors Keytrudareg if PD-L12 positive (ge1) Yervoyreg if PD-L12 negative (lt1) Accepting patients from the monotherapy study who develop progressive disease Also enrolling patients directly into this study to enhance experience with the combination In discussion with other pharmaceutical companies to evaluate additional combinations with other
immunotherapies
Bria-OTStrade Off-the-Shelf Personalized Targeted Immunotherapy Developing Bria-OTStrade to co-express GM-CSF and interferon-α Pre-manufacture additional HLA alleles ndash Total of 15 alleles (8 Class I and 7 Class II) Co-development of BriaDXtrade companion diagnostic for HLA typing Combination therapy clinical trial with immune checkpoint inhibitors for non-responders using
information from the Bria-IMTtrade Combination Therapy Study
33
Development Timeline ndash Breast Cancer
20192018 2020 2021
Phase IIIaBria-IMTtrade
Monotherapy
Currently Enrolling Phase IIaBria-IMTtrade + Checkpoint
Currently in discussions with potential partnersPhase II Bria-IMTtrade plus Additional Combinations (1Q19 4Q22)(eg PD-1 Inhibitor PD-L1 inhibitor anti-CTLA4 anti-GITR anti-OX40)
1Q 2Q 3Q 4Q
2023
Bria-OTStrade Off-The-Shelf Personalized ImmunotherapyMonotherapy and Potential Partnered Combo Therapy
(2H19 Ongoing)
Bria-OTStradeOff-the-Shelf Cell Line cGMP Manufacturing
and BriaDXtrade(1Q18 1Q19)
Registration Studies (1Q20 2H22)Bria-IMTtrade with Checkpoint InhibitorsBria-OTStrade +- Checkpoint Inhibitors
34
Immuno-oncology Deals
Recent deals of small biotechs with big pharma in immuno-oncology
35
Date PartnershipDevelopment stage at the time of the deal Deal size
07122018 Immatics-Genmab Preclinical Up to $28B
04042018 OSE Immunotherapeutics-Boehringer Ingelheim Preclinical Up to euro113B ($139B)
02092018 Pieris Pharmaceuticals-Seattle Genetics Preclinical Up to $123B
2142018 Nektar-BMS Ph III Up to $36B
01222018 Juno-Celgene Ph II $9B (Acquisition)
11142017 Loxo-Bayer Larotrectinib (Ph II) LOXO-195 (Ph III) Up to $155B
1032017 CytomX-Amgen Preclinical Up to $15B
03202017 CytomX--BMS Ph III Up to $36B
6282016 Xencor-Novartis Preclinical Up to $24B
Early Stage Clinical Studies (Comparison)
We compared the interim data of Ph IIIa study of Bria-IMTtrade in advanced breast cancer with thedata in the early stage clinical studies of recently approved breast cancer drugs and one fasttracked product candidate
Apples to apples comparison Early Stage Clinical Studies in oncology are typically done in patientswith no other therapeutic options Thus the patients have very advanced disease and response ratesare typically quite low
The patients in our Ph IIIa study have been heavily pre-treated (median 45 prior regimens)Some recent studies of relevance in breast cancer are noted in the following slides
36
Breast Cancer Market Opportunity
Drug Technology Approved for Market (US)Ibrance (palbociclib) CDK 46 Inhibitor HR+HER2- MBC in combination with
fluvestrant or aromatase inhibitor$933M in 1Q2018 $3126M in 2017
Kisqali (ribociclib) CDK 46 Inhibitor 2017 HR+HER2- MBC in combination with fluvestrant or aromatase inhibitor
Peak sales projected at $25B
Verzenio (abemaciclib) CDK 46 Inhibitor 2017 HR+HER2- MBC in combination with fluvestrant or aromatase inhibitor
balixafortide CXCR4 antagonist Fast track designation in 2018 for HER2- MBC who have failed 2 prior regimens
The market for breast cancer drugs is a multibillion dollar market with new drugs being approvedon an ongoing basis indicating the shortage of safe and effective treatments for this deadly disease
37
Competitors- Phase III Clinical Data Bria-IMTtrade shows superior safety and similar to superior efficacy data compared with those of the multi-billion dollar drugs when they were at a similar early stage of clinical development
Injection site reactions No related SAEs or SUSARs
Tumor vol darr ampor darr circul tumor cellsAll Comers 21(419) 26(519)One or More HLA matches 27(415) 33(515)Two or More HLA matches 50 (24) 75 (34)
Sheet1 (3)
Comp -Slides
Data
HLA (2)
HLA
Data (Ph1-2+4Pt)
Competitors (2018)-Slide
Competitors (2018)
In the Pipeline Protein Kinase C delta (PKCδ) Inhibitors
30 of all human malignancies display activating RAS mutations Another 60 showing over-activity of Ras-signaling pathways
Ras has been termed ldquoundruggablerdquo (no one has been able to make a Ras inhibitor drug)
BriaCellrsquos novel proprietary PKCδ inhibitors have shown activity against multiple RAS transformed tumors Lung cancer Melanoma Breast cancer Neuroendocrine cancer Pancreatic cancer Colorectal cancer
This target has an attractive safety profile based on in vivo studies and knock out mouse studies
PKCδ inhibitors should qualify for an accelerated clinical development plan and regulatory pathway
Could be in clinic within 24 months
Cost-Effective Additional Shot-on-Goal and additional partnership opportunities
Early-Stage Preclinical Program
39
Protein Kinase C delta (PKCδ) Inhibitors
Activated PKCδ inhibits RAS degradation which in turn stimulates tumor growth
Koo et al Oncotarget 621328 2016
30 of all human malignancies display activating RASmutations with another 60 showing over-activity of Ras-signaling pathways
BriaCellrsquos novel proprietary PKCδ inhibitors have shownactivity against multiple RAS transformed tumors
This target has an attractive safety profile based on in vivostudies and knock out mouse studies
PKCδ also has potential activity as an immunotherapeuticby blocking TGFβ signaling
PKCδ inhibitors are applicable to specific niche tumor typeswhich provide an accelerated clinical development plan
Structural aspects of first generation inhibitor rottlerin and staurosporine (pan-PKC activator) were combined to create second generation inhibitor KAM1
Third generation inhibitors such as BJE6-106 have improved potency and selectivity Fourth generation inhibitors under development to optimize drug-like characteristics PKCδ inhibitors lack endothelial cell cytotoxicity amp PKCδ deficient mice develop normally and are fertile Potentially no marked intrinsic toxicity by inhibiting PKCδ
Mukai H Saeki T Shimada K Naito Y Matsubara N Nakanishi T Obaishi H Namiki M Sasaki Y Phase 1 combination study of eribulin mesylate with trastuzumab for advanced or recurrent human epidermal growth factor receptor 2 positive breast cancer Invest New Drugs 2015 Feb33(1)119-27
AstraZeneca
Lynparza (Olaparib) + Cediranib
PARP inhibitor + inhibitor of VEGF receptor tyrosine kinases
HR+ HER2- MBC
BC amp OC
2013
28 (8 BC)
3 for BC
Olaparib (a poly (ADP-ribose) polymerase (PARP) inhibitor) amp Cediranib (Vascular endothelial growth factor receptor (VEGFR) 1 2 and 3 tyrosine kinase inhibitor)3 at dose level (DL) 0 (cediranib 20mg olaparib 100mg) 3 at DL1 (cediranib 20mg olaparib 200mg) 7 at DL2 (cediranib 30mg olaparib 200mg) 6 at DL3 (cediranib 30mg olaparib 400mg)
Liu JF Tolaney SM Birrer M Fleming GF Buss MK Dahlberg SE Lee H Whalen C Tyburski K Winer E Ivy P Matulonis UA A Phase 1 trial of the poly(ADP-ribose) polymerase inhibitor olaparib (AZD2281) in combination with the anti-angiogenic cediranib (AZD2171) in recurrent epithelial ovarian or triple-negative breast cancer Eur J Cancer 2013 Sep49(14)2972-8
Reyon Pharmaceutical
VM206RY
Heterologous prime-boost with a truncated HER2 sequence
HER2+ Stage IIIampIV BC
2015
9
2 chemo
Plasmid DNA (pHM-GM-CSF expressing truncated HER2 amp GM-CSF) amp adenoviral vector (Ad-HM containing modified HER2) (2 4 and 8 mgpatientvisit) of pHM-GM-CSF 3x IM weeks 0 2 and 4 Ad-HM 3 times 109 virus particles at week 6
11 PR
4 pts showed 7 minor AEs
Unclear
Kim SB Ahn JH Kim J Jung KH A phase 1 study of a heterologous prime-boost vaccination involving a truncated HER2 sequence in patients with HER2-expressing breast cancer Mol Ther Methods Clin Dev 2015 Sep 30215031 doi 101038mtm201531 eCollection 2015
Rodon J Peacuterez-Fidalgo A Krop IE Burris H Guerrero-Zotano A Britten CD Becerra C Schellens J Richards DA Schuler M Abu-Khalaf M Johnson FM Ranson M Edenfield J Silva AP Hackl W Quadt C Demanse D Duval V Baselga J Phase 11b dose escalation and expansion study of BEZ235 a dual PI3KmTOR inhibitor in patients with advanced solid tumors including patients with advanced breast cancer Cancer Chemother Pharmacol 2018 Jun 7 doi 101007s00280-018-3610-z [Epub ahead of print]
Celgene (Abraxane)
Gemcitabine + Abraxane (nab-paclitaxel)
Chemo + Chemo
OC BC NSCLC amp Panc cancer + Lung OC BC Kaposi sarcoma
MBC
2016
9
Adjuvant chemo (100)chemo post-adjuvant (33)
Gem (nucleoside metabolic inhibitor 1250 mgm2) on days 1 and 8 nab-Pac (microtubule inhibitor) starting dose of 180 mgm2 (cohort 1) 220 mgm2 (cohort 2) and 260 mgm2 (cohort 3) on day 1 of the 21-day cycle using a 3 + 3 design
0
MTD not reached29 Gr3 Neutropenia59 Gr1 Peripheralneuropathy
Yoshitomi S Taira N Doihara H Mizoo T Nogami T Iwamoto T Motoki T Shien T Ogasawara Y Matsuoka J Tsuji H Mitsuhashi T A phase 1 dose-finding and pharmacokinetic study of gemcitabine with nab-paclitaxel in patients with metastatic breast cancer Cancer Chemother Pharmacol 2016 Aug78(2)289-94
Eli Lilly
Erbituxreg (cetuximab) + Taxane
EGFR inhibitor antineoplastic agent + Chemo
Headamp Neck Colorectal Cancer
TNBC
2007-2010
18
1 chemo
Cetuximab (epidermal growth factor receptor (EGFR) antagonist ) an initial loading dose of cetuximab 400 mgm2 followed by a weekly dose of 250 mgm2Paclitaxel (microtubule inhibitor) 80 mgm2 or Docetaxel at an initial dose of 30 mgm2 was administered weekly
56 CR 22 PR
83 Dermatologic toxicity11 Grade3+
Nechushtan H Vainer G Stainberg H Salmon AY Hamburger T Peretz T A phase 12 of a combination of cetuximab and taxane for triple negative breast cancer patients Breast 2014 Aug23(4)435-8
Polyphor
Balixafortide (POL6326) + eribulin
CXCR4 antagonist + tubulin-based antimitotic
Heavily pretreated Relapsed MBC
2014-2016
56
3rd line 3 chemo
3+3 dose escalation The highest dose was established as eribulin 14 mgmsup2 on days 2 and 9 and balixafortide 55 mgkg on days 1minus3 and 8minus10 of the 21-day cycle
30 PR
41 Gr34 Neutropenia11 Gr34 Leucopenia11 Gr34 Febrileneutropenia2 Related mortalities
Apr 2018 Fast Track for HER2-MBC who have failed 2prior regimens
Pernas S Martin M Kaufman PA Gil-Martin M Gomez Pardo P Lopez-Tarruella S Manso L Ciruelos E Perez-Fidalgo JA Hernando C Ademuyiwa FO Weilbaecher K Mayer I Pluard TJ Martinez Garcia M Vahdat L Perez-Garcia J Wach A Barker D Fung S Romagnoli B Cortes J Balixafortide plus eribulin in HER2-negative metastatic breast cancer a phase 1 single-arm dose-escalation trial Lancet Oncol 2018 Jun19(6)812-824
11 PRndashbut only + letrozole (No Resp on monotherapy)
61 Gr34 Neutropenia39 Gr34 Leucopenia
$933M in 1Q2018 $31B in 2017
Tamura K Mukai H Naito Y Yonemori K Kodaira M Tanabe Y Yamamoto N Osera S Sasaki M Mori Y Hashigaki S Nagasawa T Umeyama Y Yoshino T Phase I study of palbociclib a cyclin-dependent kinase 46 inhibitor in Japanese patients Cancer Sci 2016 Jun107(6)755-63 doi 101111cas12932 Epub 2016 May 11
Pfizer
Ibrancereg (palbociclib)
CDK 46 Inhibitor
HR+ HER2- MBC
Heavily pretreated Relapsed Metastatic Cancer
2004-2008
41 (5 BC)
chemo naiumlve (17) 1-2 (51)3 (29) 3+ (2)
Palbociclib 25-150 mg dose ranging
0
20 Gr34 Neutropenia23 Gr34 Leucopenia
$933M in 1Q2018 $31B in 2017
Flaherty KT Lorusso PM Demichele A Abramson VG Courtney R Randolph SS Shaik MN Wilner KD ODwyer PJ Schwartz GK Phase I dose-escalation trial of the oral cyclin-dependent kinase 46 inhibitor PD 0332991 administered using a 21-day schedule in patients with advanced cancer Clin Cancer Res 2012 Jan 1518(2)568-76 doi 1011581078-0432CCR-11-0509 Epub 2011 Nov 16
Novartis
Kisqalireg (ribociclib)
CDK 46 Inhibitors
Premenopausal HR+ HER2- MBC
Heavily pretreated Relapsed Metastatic Cancer
2016
132 (20 BC)
0-1 (25) 2-3 (42) 4+ (32)
Ribociclib 50 mg ranging up to 1200 mg dose escalation
23 PRndashincluded 1 in BC (5 of BC pts)
27 Gr34 Neutropenia17 Gr34 Leucopenia
Peak sales projected at $25B
Infante JR Cassier PA Gerecitano JF Witteveen PO Chugh R Ribrag V Chakraborty A Matano A Dobson JR Crystal AS Parasuraman S Shapiro GI A Phase I Study of the Cyclin-Dependent Kinase 46 Inhibitor Ribociclib (LEE011) in Patients with Advanced Solid Tumors and Lymphomas Clin Cancer Res 2016 Dec 122(23)5696-5705 Epub 2016 Aug 19
Eli Lilly
Verzenioreg (abemaciclib)
CDK 46 Inhibitors
HR+HER2minusMBC
Heavily pretreated Relapsed Metastatic Cancer
2016
12 (1 BC)
1 (312) 2 (212) 3+ (7)
Abemaciclib 100 mg ranging up to 200 mg dose escalation
17 PR (included 1 in BC)
17 Gr34 Neutropenia33 Gr34 Leucopenia
Peak sales projected at $2B
Fujiwara Y Tamura K Kondo S Tanabe Y Iwasa S Shimomura A Kitano S Ogasawara K Turner PK Mori J Asou H Chan EM Yamamoto N Phase 1 study of abemaciclib an inhibitor of CDK 4 and 6 as a single agent for Japanese patients with advanced cancer Cancer Chemother Pharmacol 2016 Aug78(2)281-8 doi 101007s00280-016-3085-8 Epub 2016 Jun 16
Mukai H Saeki T Shimada K Naito Y Matsubara N Nakanishi T Obaishi H Namiki M Sasaki Y Phase 1 combination study of eribulin mesylate with trastuzumab for advanced or recurrent human epidermal growth factor receptor 2 positive breast cancer Invest New Drugs 2015 Feb33(1)119-27
AstraZeneca
Lynparza (Olaparib)+ Cediranib
PARP inhibitor+ inhibitor of VEGF RTK
HR+ HER2- MBC
BC amp OC
13
28 (8 BC)
3 for BC
Olaparib (a poly (ADP-ribose) polymerase (PARP) inhibitor) amp Cediranib (Vascular endothelial growth factor receptor (VEGFR) 1 2 and 3 tyrosine kinase inhibitor)3 at dose level (DL) 0 (cediranib 20mg olaparib 100mg) 3 at DL1 (cediranib 20mg olaparib 200mg) 7 at DL2 (cediranib 30mg olaparib 200mg) 6 at DL3 (cediranib 30mg olaparib 400mg)
Liu JF Tolaney SM Birrer M Fleming GF Buss MK Dahlberg SE Lee H Whalen C Tyburski K Winer E Ivy P Matulonis UA A Phase 1 trial of the poly(ADP-ribose) polymerase inhibitor olaparib (AZD2281) in combination with the anti-angiogenic cediranib (AZD2171) in recurrent epithelial ovarian or triple-negative breast cancer Eur J Cancer 2013 Sep49(14)2972-8
ReyonPharma
VM206RY
Heterologous prime-boost with a truncated HER2 sequence
HER2+ Stg IIIampIV BC
15
9
2 chemo
Plasmid DNA (pHM-GM-CSF expressing truncated HER2 amp GM-CSF) amp adenoviral vector (Ad-HM containing modified HER2) (2 4 and 8 mgpatientvisit) of pHM-GM-CSF 3x IM weeks 0 2 and 4 Ad-HM 3 times 109 virus particles at week 6
11 PR
4 pts 7 minor AEs
Unclear
Kim SB Ahn JH Kim J Jung KH A phase 1 study of a heterologous prime-boost vaccination involving a truncated HER2 sequence in patients with HER2-expressing breast cancer Mol Ther Methods Clin Dev 2015 Sep 30215031 doi 101038mtm201531 eCollection 2015
Rodon J Peacuterez-Fidalgo A Krop IE Burris H Guerrero-Zotano A Britten CD Becerra C Schellens J Richards DA Schuler M Abu-Khalaf M Johnson FM Ranson M Edenfield J Silva AP Hackl W Quadt C Demanse D Duval V Baselga J Phase 11b dose escalation and expansion study of BEZ235 a dual PI3KmTOR inhibitor in patients with advanced solid tumors including patients with advanced breast cancer Cancer Chemother Pharmacol 2018 Jun 7 doi 101007s00280-018-3610-z [Epub ahead of print]
Celgene(Abraxane)
Gemcitabine + Abraxane (nab-paclitaxel)
Chemo+ Chemo
OC BC NSCLC PC + LC OC BC KS
MBC
16
9
Adjuv chemo (100)chemo post-adjuv (33)
Gem (nucleoside metabolic inhibitor 1250 mgm2) on days 1 and 8 nab-Pac (microtubule inhibitor) starting dose of 180 mgm2 (cohort 1) 220 mgm2 (cohort 2) and 260 mgm2 (cohort 3) on day 1 of the 21-day cycle using a 3 + 3 design
0
MTD not reached29 Gr3 Neutropenia59 Gr1 Peripheralneuropathy
Yoshitomi S Taira N Doihara H Mizoo T Nogami T Iwamoto T Motoki T Shien T Ogasawara Y Matsuoka J Tsuji H Mitsuhashi T A phase 1 dose-finding and pharmacokinetic study of gemcitabine with nab-paclitaxel in patients with metastatic breast cancer Cancer Chemother Pharmacol 2016 Aug78(2)289-94
Eli Lilly
Erbituxreg (cetuximab) + Taxane
EGFR inhibitor antineoplastic agent + Chemo
Head amp NeckColorectal
TNBC
07-10
18
1 chemo
Cetuximab (epidermal growth factor receptor (EGFR) antagonist ) an initial loading dose of cetuximab 400 mgm2 followed by a weekly dose of 250 mgm2Paclitaxel (microtubule inhibitor) 80 mgm2 or Docetaxel at an initial dose of 30 mgm2 was administered weekly
56 CR 22 PR
83 Dermatologic toxicity11 Grade3+
Nechushtan H Vainer G Stainberg H Salmon AY Hamburger T Peretz T A phase 12 of a combination of cetuximab and taxane for triple negative breast cancer patients Breast 2014 Aug23(4)435-8
Polyphor
Balixafortide (POL6326) + eribulin
CXCR4 antagonist + tubulin-based antimitotic
Heavily pretreatedRelapsed MBC
14-16
56
3rd line 3 chemo
3+3 dose escalation The highest dose was established as eribulin 14 mgmsup2 on days 2 and 9 and balixafortide 55 mgkg on days 1minus3 and 8minus10 of the 21-day cycle
30 PR
41 Gr34 Neutropenia11 Gr34 Leucopenia11 Gr34 Febrileneutropenia2 Related mortalities
42018 Fast Track (HER2-MBC failed 2 prior regimens)
Pernas S Martin M Kaufman PA Gil-Martin M Gomez Pardo P Lopez-Tarruella S Manso L Ciruelos E Perez-Fidalgo JA Hernando C Ademuyiwa FO Weilbaecher K Mayer I Pluard TJ Martinez Garcia M Vahdat L Perez-Garcia J Wach A Barker D Fung S Romagnoli B Cortes J Balixafortide plus eribulin in HER2-negative metastatic breast cancer a phase 1 single-arm dose-escalation trial Lancet Oncol 2018 Jun19(6)812-824
1 PRndashbut only + letrozoleNo Resp on monotherapy
61 Gr34 Neutropenia39 Gr34 Leucopenia
$933M (1Q18)$31B (2017)
Tamura K Mukai H Naito Y Yonemori K Kodaira M Tanabe Y Yamamoto N Osera S Sasaki M Mori Y Hashigaki S Nagasawa T Umeyama Y Yoshino T Phase I study of palbociclib a cyclin-dependent kinase 46 inhibitor in Japanese patients Cancer Sci 2016 Jun107(6)755-63 doi 101111cas12932 Epub 2016 May 11
Pfizer
Ibrancereg (palbociclib)
CDK 46 Inhibitor
HR+ HER2- MBC
Heavily pretreatedRelapsed Met Cancer
04-08
41 (5 BC)
chemo naiumlve (17)1-2(51) 3(29) 3+(2)
Palbociclib 25-150 mg dose ranging
0
20 Gr34 Neutropenia23 Gr34 Leucopenia
$933M (1Q18)$31B (2017)
Flaherty KT Lorusso PM Demichele A Abramson VG Courtney R Randolph SS Shaik MN Wilner KD ODwyer PJ Schwartz GK Phase I dose-escalation trial of the oral cyclin-dependent kinase 46 inhibitor PD 0332991 administered using a 21-day schedule in patients with advanced cancer Clin Cancer Res 2012 Jan 1518(2)568-76 doi 1011581078-0432CCR-11-0509 Epub 2011 Nov 16
Novartis
Kisqalireg (ribociclib)
CDK 46 Inhibitor
Premenopausal HR+ HER2- MBC
Heavily pretreatedRelapsed Met Cancer
16
132 (20 BC)
0-1 (25) 2-3 (42)4+ (32)
Ribociclib 50 mg ranging up to 1200 mg dose escalation
23 PR-included 1 BC (5 of BC pts)
27 Gr34 Neutropenia17 Gr34 Leucopenia
Peak sales est at $25B
Infante JR Cassier PA Gerecitano JF Witteveen PO Chugh R Ribrag V Chakraborty A Matano A Dobson JR Crystal AS Parasuraman S Shapiro GI A Phase I Study of the Cyclin-Dependent Kinase 46 Inhibitor Ribociclib (LEE011) in Patients with Advanced Solid Tumors and Lymphomas Clin Cancer Res 2016 Dec 122(23)5696-5705 Epub 2016 Aug 19
Eli Lilly
Verzenioreg (abemaciclib)
CDK 46 Inhibitor
HR+HER2minusMBC
Heavily pretreatedRelapsed Met Cancer
16
12 (1 BC)
1 (312) 2 (212) 3+(7)
Abemaciclib 100 mg ranging up to 200 mg dose escalation
17 PR (included 1 BC)
17 Gr34 Neutropenia33 Gr34 Leucopenia
Peak sales est at $2B
Fujiwara Y Tamura K Kondo S Tanabe Y Iwasa S Shimomura A Kitano S Ogasawara K Turner PK Mori J Asou H Chan EM Yamamoto N Phase 1 study of abemaciclib an inhibitor of CDK 4 and 6 as a single agent for Japanese patients with advanced cancer Cancer Chemother Pharmacol 2016 Aug78(2)281-8 doi 101007s00280-016-3085-8 Epub 2016 Jun 16
Mukai H Saeki T Shimada K Naito Y Matsubara N Nakanishi T Obaishi H Namiki M Sasaki Y Phase 1 combination study of eribulin mesylate with trastuzumab for advanced or recurrent human epidermal growth factor receptor 2 positive breast cancer Invest New Drugs 2015 Feb33(1)119-27
AstraZeneca
Lynparza (Olaparib) + Cediranib
PARP inhibitor + inhibitor of VEGF receptor tyrosine kinases
HR+ HER2- MBC
BC amp OC
2013
28 (8 BC)
3 for BC
Olaparib (a poly (ADP-ribose) polymerase (PARP) inhibitor) amp Cediranib (Vascular endothelial growth factor receptor (VEGFR) 1 2 and 3 tyrosine kinase inhibitor)3 at dose level (DL) 0 (cediranib 20mg olaparib 100mg) 3 at DL1 (cediranib 20mg olaparib 200mg) 7 at DL2 (cediranib 30mg olaparib 200mg) 6 at DL3 (cediranib 30mg olaparib 400mg)
Liu JF Tolaney SM Birrer M Fleming GF Buss MK Dahlberg SE Lee H Whalen C Tyburski K Winer E Ivy P Matulonis UA A Phase 1 trial of the poly(ADP-ribose) polymerase inhibitor olaparib (AZD2281) in combination with the anti-angiogenic cediranib (AZD2171) in recurrent epithelial ovarian or triple-negative breast cancer Eur J Cancer 2013 Sep49(14)2972-8
Reyon Pharmaceutical
VM206RY
Heterologous prime-boost with a truncated HER2 sequence
HER2+ Stage IIIampIV BC
2015
9
2 chemo
Plasmid DNA (pHM-GM-CSF expressing truncated HER2 amp GM-CSF) amp adenoviral vector (Ad-HM containing modified HER2) (2 4 and 8 mgpatientvisit) of pHM-GM-CSF 3x IM weeks 0 2 and 4 Ad-HM 3 times 109 virus particles at week 6
11 PR
4 pts showed 7 minor AEs
Unclear
Kim SB Ahn JH Kim J Jung KH A phase 1 study of a heterologous prime-boost vaccination involving a truncated HER2 sequence in patients with HER2-expressing breast cancer Mol Ther Methods Clin Dev 2015 Sep 30215031 doi 101038mtm201531 eCollection 2015
Rodon J Peacuterez-Fidalgo A Krop IE Burris H Guerrero-Zotano A Britten CD Becerra C Schellens J Richards DA Schuler M Abu-Khalaf M Johnson FM Ranson M Edenfield J Silva AP Hackl W Quadt C Demanse D Duval V Baselga J Phase 11b dose escalation and expansion study of BEZ235 a dual PI3KmTOR inhibitor in patients with advanced solid tumors including patients with advanced breast cancer Cancer Chemother Pharmacol 2018 Jun 7 doi 101007s00280-018-3610-z [Epub ahead of print]
Celgene (Abraxane)
Gemcitabine + Abraxane (nab-paclitaxel)
Chemo + Chemo
OC BC NSCLC amp Panc cancer + Lung OC BC Kaposi sarcoma
MBC
2016
9
Adjuvant chemo (100)chemo post-adjuvant (33)
Gem (nucleoside metabolic inhibitor 1250 mgm2) on days 1 and 8 nab-Pac (microtubule inhibitor) starting dose of 180 mgm2 (cohort 1) 220 mgm2 (cohort 2) and 260 mgm2 (cohort 3) on day 1 of the 21-day cycle using a 3 + 3 design
0
MTD not reached29 Gr3 Neutropenia59 Gr1 Peripheralneuropathy
Yoshitomi S Taira N Doihara H Mizoo T Nogami T Iwamoto T Motoki T Shien T Ogasawara Y Matsuoka J Tsuji H Mitsuhashi T A phase 1 dose-finding and pharmacokinetic study of gemcitabine with nab-paclitaxel in patients with metastatic breast cancer Cancer Chemother Pharmacol 2016 Aug78(2)289-94
Eli Lilly
Erbituxreg (cetuximab) + Taxane
EGFR inhibitor antineoplastic agent + Chemo
Headamp Neck Colorectal Cancer
TNBC
2007-2010
18
1 chemo
Cetuximab (epidermal growth factor receptor (EGFR) antagonist ) an initial loading dose of cetuximab 400 mgm2 followed by a weekly dose of 250 mgm2Paclitaxel (microtubule inhibitor) 80 mgm2 or Docetaxel at an initial dose of 30 mgm2 was administered weekly
56 CR 22 PR
83 Dermatologic toxicity11 Grade3+
Nechushtan H Vainer G Stainberg H Salmon AY Hamburger T Peretz T A phase 12 of a combination of cetuximab and taxane for triple negative breast cancer patients Breast 2014 Aug23(4)435-8
Polyphor
Balixafortide (POL6326) + eribulin
CXCR4 antagonist + tubulin-based antimitotic
Heavily pretreated Relapsed MBC
2014-2016
56
3rd line 3 chemo
3+3 dose escalation The highest dose was established as eribulin 14 mgmsup2 on days 2 and 9 and balixafortide 55 mgkg on days 1minus3 and 8minus10 of the 21-day cycle
30 PR
41 Gr34 Neutropenia11 Gr34 Leucopenia11 Gr34 Febrileneutropenia2 Related mortalities
Apr 2018 Fast Track for HER2-MBC who have failed 2prior regimens
Pernas S Martin M Kaufman PA Gil-Martin M Gomez Pardo P Lopez-Tarruella S Manso L Ciruelos E Perez-Fidalgo JA Hernando C Ademuyiwa FO Weilbaecher K Mayer I Pluard TJ Martinez Garcia M Vahdat L Perez-Garcia J Wach A Barker D Fung S Romagnoli B Cortes J Balixafortide plus eribulin in HER2-negative metastatic breast cancer a phase 1 single-arm dose-escalation trial Lancet Oncol 2018 Jun19(6)812-824
11 PRndashbut only + letrozole (No Resp on monotherapy)
61 Gr34 Neutropenia39 Gr34 Leucopenia
$933M in 1Q2018 $31B in 2017
Tamura K Mukai H Naito Y Yonemori K Kodaira M Tanabe Y Yamamoto N Osera S Sasaki M Mori Y Hashigaki S Nagasawa T Umeyama Y Yoshino T Phase I study of palbociclib a cyclin-dependent kinase 46 inhibitor in Japanese patients Cancer Sci 2016 Jun107(6)755-63 doi 101111cas12932 Epub 2016 May 11
Pfizer
Ibrancereg (palbociclib)
CDK 46 Inhibitor
HR+ HER2- MBC
Heavily pretreated Relapsed Metastatic Cancer
2004-2008
41 (5 BC)
chemo naiumlve (17) 1-2 (51)3 (29) 3+ (2)
Palbociclib 25-150 mg dose ranging
0
20 Gr34 Neutropenia23 Gr34 Leucopenia
$933M in 1Q2018 $31B in 2017
Flaherty KT Lorusso PM Demichele A Abramson VG Courtney R Randolph SS Shaik MN Wilner KD ODwyer PJ Schwartz GK Phase I dose-escalation trial of the oral cyclin-dependent kinase 46 inhibitor PD 0332991 administered using a 21-day schedule in patients with advanced cancer Clin Cancer Res 2012 Jan 1518(2)568-76 doi 1011581078-0432CCR-11-0509 Epub 2011 Nov 16
Novartis
Kisqalireg (ribociclib)
CDK 46 Inhibitors
Premenopausal HR+ HER2- MBC
Heavily pretreated Relapsed Metastatic Cancer
2016
132 (20 BC)
0-1 (25) 2-3 (42) 4+ (32)
Ribociclib 50 mg ranging up to 1200 mg dose escalation
23 PRndashincluded 1 in BC (5 of BC pts)
27 Gr34 Neutropenia17 Gr34 Leucopenia
Peak sales projected at $25B
Infante JR Cassier PA Gerecitano JF Witteveen PO Chugh R Ribrag V Chakraborty A Matano A Dobson JR Crystal AS Parasuraman S Shapiro GI A Phase I Study of the Cyclin-Dependent Kinase 46 Inhibitor Ribociclib (LEE011) in Patients with Advanced Solid Tumors and Lymphomas Clin Cancer Res 2016 Dec 122(23)5696-5705 Epub 2016 Aug 19
Eli Lilly
Verzenioreg (abemaciclib)
CDK 46 Inhibitors
HR+HER2minusMBC
Heavily pretreated Relapsed Metastatic Cancer
2016
12 (1 BC)
1 (312) 2 (212) 3+ (7)
Abemaciclib 100 mg ranging up to 200 mg dose escalation
17 PR (included 1 in BC)
17 Gr34 Neutropenia33 Gr34 Leucopenia
Peak sales projected at $2B
Fujiwara Y Tamura K Kondo S Tanabe Y Iwasa S Shimomura A Kitano S Ogasawara K Turner PK Mori J Asou H Chan EM Yamamoto N Phase 1 study of abemaciclib an inhibitor of CDK 4 and 6 as a single agent for Japanese patients with advanced cancer Cancer Chemother Pharmacol 2016 Aug78(2)281-8 doi 101007s00280-016-3085-8 Epub 2016 Jun 16
Mukai H Saeki T Shimada K Naito Y Matsubara N Nakanishi T Obaishi H Namiki M Sasaki Y Phase 1 combination study of eribulin mesylate with trastuzumab for advanced or recurrent human epidermal growth factor receptor 2 positive breast cancer Invest New Drugs 2015 Feb33(1)119-27
AstraZeneca
Lynparza (Olaparib)+ Cediranib
PARP inhibitor+ inhibitor of VEGF RTK
HR+ HER2- MBC
BC amp OC
13
28 (8 BC)
3 for BC
Olaparib (a poly (ADP-ribose) polymerase (PARP) inhibitor) amp Cediranib (Vascular endothelial growth factor receptor (VEGFR) 1 2 and 3 tyrosine kinase inhibitor)3 at dose level (DL) 0 (cediranib 20mg olaparib 100mg) 3 at DL1 (cediranib 20mg olaparib 200mg) 7 at DL2 (cediranib 30mg olaparib 200mg) 6 at DL3 (cediranib 30mg olaparib 400mg)
Liu JF Tolaney SM Birrer M Fleming GF Buss MK Dahlberg SE Lee H Whalen C Tyburski K Winer E Ivy P Matulonis UA A Phase 1 trial of the poly(ADP-ribose) polymerase inhibitor olaparib (AZD2281) in combination with the anti-angiogenic cediranib (AZD2171) in recurrent epithelial ovarian or triple-negative breast cancer Eur J Cancer 2013 Sep49(14)2972-8
ReyonPharma
VM206RY
Heterologous prime-boost with a truncated HER2 sequence
HER2+ Stg IIIampIV BC
15
9
2 chemo
Plasmid DNA (pHM-GM-CSF expressing truncated HER2 amp GM-CSF) amp adenoviral vector (Ad-HM containing modified HER2) (2 4 and 8 mgpatientvisit) of pHM-GM-CSF 3x IM weeks 0 2 and 4 Ad-HM 3 times 109 virus particles at week 6
11 PR
4 pts 7 minor AEs
Unclear
Kim SB Ahn JH Kim J Jung KH A phase 1 study of a heterologous prime-boost vaccination involving a truncated HER2 sequence in patients with HER2-expressing breast cancer Mol Ther Methods Clin Dev 2015 Sep 30215031 doi 101038mtm201531 eCollection 2015
Rodon J Peacuterez-Fidalgo A Krop IE Burris H Guerrero-Zotano A Britten CD Becerra C Schellens J Richards DA Schuler M Abu-Khalaf M Johnson FM Ranson M Edenfield J Silva AP Hackl W Quadt C Demanse D Duval V Baselga J Phase 11b dose escalation and expansion study of BEZ235 a dual PI3KmTOR inhibitor in patients with advanced solid tumors including patients with advanced breast cancer Cancer Chemother Pharmacol 2018 Jun 7 doi 101007s00280-018-3610-z [Epub ahead of print]
Celgene(Abraxane)
Gemcitabine + Abraxane (nab-paclitaxel)
Chemo+ Chemo
OC BC NSCLC PC + LC OC BC KS
MBC
16
9
Adjuv chemo (100)chemo post-adjuv (33)
Gem (nucleoside metabolic inhibitor 1250 mgm2) on days 1 and 8 nab-Pac (microtubule inhibitor) starting dose of 180 mgm2 (cohort 1) 220 mgm2 (cohort 2) and 260 mgm2 (cohort 3) on day 1 of the 21-day cycle using a 3 + 3 design
0
MTD not reached29 Gr3 Neutropenia59 Gr1 Peripheralneuropathy
Yoshitomi S Taira N Doihara H Mizoo T Nogami T Iwamoto T Motoki T Shien T Ogasawara Y Matsuoka J Tsuji H Mitsuhashi T A phase 1 dose-finding and pharmacokinetic study of gemcitabine with nab-paclitaxel in patients with metastatic breast cancer Cancer Chemother Pharmacol 2016 Aug78(2)289-94
Eli Lilly
Erbituxreg (cetuximab) + Taxane
EGFR inhibitor antineoplastic agent + Chemo
Head amp NeckColorectal
TNBC
07-10
18
1 chemo
Cetuximab (epidermal growth factor receptor (EGFR) antagonist ) an initial loading dose of cetuximab 400 mgm2 followed by a weekly dose of 250 mgm2Paclitaxel (microtubule inhibitor) 80 mgm2 or Docetaxel at an initial dose of 30 mgm2 was administered weekly
56 CR 22 PR
83 Dermatologic toxicity11 Grade3+
Nechushtan H Vainer G Stainberg H Salmon AY Hamburger T Peretz T A phase 12 of a combination of cetuximab and taxane for triple negative breast cancer patients Breast 2014 Aug23(4)435-8
Polyphor
Balixafortide (POL6326) + eribulin
CXCR4 antagonist + tubulin-based antimitotic
Heavily pretreatedRelapsed MBC
14-16
56
3rd line 3 chemo
3+3 dose escalation The highest dose was established as eribulin 14 mgmsup2 on days 2 and 9 and balixafortide 55 mgkg on days 1minus3 and 8minus10 of the 21-day cycle
30 PR
41 Gr34 Neutropenia11 Gr34 Leucopenia11 Gr34 Febrileneutropenia2 Related mortalities
42018 Fast Track (HER2-MBC failed 2 prior regimens)
Pernas S Martin M Kaufman PA Gil-Martin M Gomez Pardo P Lopez-Tarruella S Manso L Ciruelos E Perez-Fidalgo JA Hernando C Ademuyiwa FO Weilbaecher K Mayer I Pluard TJ Martinez Garcia M Vahdat L Perez-Garcia J Wach A Barker D Fung S Romagnoli B Cortes J Balixafortide plus eribulin in HER2-negative metastatic breast cancer a phase 1 single-arm dose-escalation trial Lancet Oncol 2018 Jun19(6)812-824
1 PRndashbut only + letrozoleNo Resp on monotherapy
61 Gr34 Neutropenia39 Gr34 Leucopenia
$933M (1Q18)$31B (2017)
Tamura K Mukai H Naito Y Yonemori K Kodaira M Tanabe Y Yamamoto N Osera S Sasaki M Mori Y Hashigaki S Nagasawa T Umeyama Y Yoshino T Phase I study of palbociclib a cyclin-dependent kinase 46 inhibitor in Japanese patients Cancer Sci 2016 Jun107(6)755-63 doi 101111cas12932 Epub 2016 May 11
Pfizer
Ibrancereg (palbociclib)
CDK 46 Inhibitor
HR+ HER2- MBC
Heavily pretreatedRelapsed Met Cancer
04-08
41 (5 BC)
chemo naiumlve (17)1-2(51) 3(29) 3+(2)
Palbociclib 25-150 mg dose ranging
0
20 Gr34 Neutropenia23 Gr34 Leucopenia
$933M (1Q18)$31B (2017)
Flaherty KT Lorusso PM Demichele A Abramson VG Courtney R Randolph SS Shaik MN Wilner KD ODwyer PJ Schwartz GK Phase I dose-escalation trial of the oral cyclin-dependent kinase 46 inhibitor PD 0332991 administered using a 21-day schedule in patients with advanced cancer Clin Cancer Res 2012 Jan 1518(2)568-76 doi 1011581078-0432CCR-11-0509 Epub 2011 Nov 16
Novartis
Kisqalireg (ribociclib)
CDK 46 Inhibitor
Premenopausal HR+ HER2- MBC
Heavily pretreatedRelapsed Met Cancer
16
132 (20 BC)
0-1 (25) 2-3 (42)4+ (32)
Ribociclib 50 mg ranging up to 1200 mg dose escalation
23 PR-included 1 BC (5 of BC pts)
27 Gr34 Neutropenia17 Gr34 Leucopenia
Peak sales est at $25B
Infante JR Cassier PA Gerecitano JF Witteveen PO Chugh R Ribrag V Chakraborty A Matano A Dobson JR Crystal AS Parasuraman S Shapiro GI A Phase I Study of the Cyclin-Dependent Kinase 46 Inhibitor Ribociclib (LEE011) in Patients with Advanced Solid Tumors and Lymphomas Clin Cancer Res 2016 Dec 122(23)5696-5705 Epub 2016 Aug 19
Eli Lilly
Verzenioreg (abemaciclib)
CDK 46 Inhibitor
HR+HER2minusMBC
Heavily pretreatedRelapsed Met Cancer
16
12 (1 BC)
1 (312) 2 (212) 3+(7)
Abemaciclib 100 mg ranging up to 200 mg dose escalation
17 PR (included 1 BC)
17 Gr34 Neutropenia33 Gr34 Leucopenia
Peak sales est at $2B
Fujiwara Y Tamura K Kondo S Tanabe Y Iwasa S Shimomura A Kitano S Ogasawara K Turner PK Mori J Asou H Chan EM Yamamoto N Phase 1 study of abemaciclib an inhibitor of CDK 4 and 6 as a single agent for Japanese patients with advanced cancer Cancer Chemother Pharmacol 2016 Aug78(2)281-8 doi 101007s00280-016-3085-8 Epub 2016 Jun 16
Patient B001 Breast 70 No 1101 - 3501 4001 Negative -
Bria-IMTtradeHuman Proof-of-Concept Trials in Breast Cancer (Patient A002)
24
Proof-of-Concept Results Resulted in BriaCellrsquos Immunotherapy Strategy Use BriaDXtrade diagnostic to select only those patients matching Bria-IMTtrade Use BriaDXtrade diagnostic test to select Bria-OTStrade alleles matching ~90 of all patients
Bria-IMTtradeCurrent Phase IIIa Data Supports HLA Matching Hypothesis Six patients treated in 2017 Bria-IMTtrade was safe and well tolerated
Patient 01-002 73-year-old woman with breast cancer diagnosed in 1995 Developed liver metastases in2010 and lung metastases in 2017 Previously treated with 7 rounds of chemotherapy with 8 differentchemotherapy agents Received 5 cycles of Bria-IMTtrade over 3 months then monthly cycles (6 months total)Evaluated after 3 months and 6 months After 3 months despite the extensive prior therapy her scans notedthat ldquothere has been a clear response in the multiple bilateral pulmonary nodulesrdquo The response wasmaintained after 6 months of Bria-IMTtrade treatment She matches Bria-IMTtrade at 2 HLA alleles
The liver tumors were stable to slightly increased at 3 months and then progressed after 6 months
This supports our hypothesis of heightened anti-tumor activity in patients with a matched HLA types Clear path to develop BriaDXtrade to select the patients using HLA testing
1 RLL 29 Not Detectable Not Detectable2 LUL apical pleural based 34 tiny nodule lt 1mm scar tiny nodule lt 1mm scar3 xxx 39 Not Detectable Not Detectable4 40 Not Detectable Not Detectable5 RLL 45 Not Detectable Not Detectable6 LLL 49 Not Detectable Not Detectable7 xxx 52 Not Detectable Not Detectable8 RLL 52 Not Detectable Not Detectable9 RLL 56 Not Detectable Not Detectable
10 RLL costophrenic recess 56 Not Detectable Not Detectable11 XXX 58 Not Detectable Not Detectable12 LUL 60 Not Detectable Not Detectable13 XXX 67 15 1514 RUL 72 15 1515 LLL 76 Not Detectable Not Detectable16 RUL Noncalcified Nodule 77 Not Detectable Not Detectable17 RLL costophrenic recess 79 10 1018 RUL 82 Not Detectable Not Detectable19 RLL 90 Not Detectable Not Detectable20 RLL 91 lt 01 lt 0121 xxx xxx Not Detectable Not Detectable
27
Clinical Development Update ndash Summary 2018 September 26
Completed enrollment of Adv Breast cancer patients in the Phase IIIa ldquomonotherapyrdquo study of Bria-IMTtrade
We have confirmed our mechanism of action and achieved proof of concept
Initial safety data appears superior to that of the other advanced or approved drugs for breast cancer when they were at a similar clinical stage of development
Initial efficacy data is similar or superior to those of other advanced or approved drugs for breast cancer when they were at a similar clinical stage of development
Initiated Combination Study of Bria-IMTtrade with Keytrudareg or Yervoyreg in Adv breast cancer patients expecting even better response rates than those in the ldquomonotherapyrdquo study Initial safety data is expected in 4Q2018 Initial efficacy data is expected in 1Q2019
Bria-OTStrade the first off-the-shelf personalized treatment for advanced breast cancer is expected to enter the clinic in 2019
28
Bria-IMTtrade Excellent Safety Data - To Date
To date Bria-IMTtrade has been dosed in 24 patients (4 in 2004-2005 20 in 2017-2018)
Interim Data (20 patients)-Ongoing Phase IIIa Study (2017-2018)
Bria-IMTtrade has been very well tolerated (ge60 doses given to date) The majority of adverse events (AEs) were limited to expected minor local irritation at the
injection sites No related grade gt3 or unexpected AEs No related serious AEs No serious unexpected related AEs Most patients who have dropped out did so due to worsening of their underlying disease
Based on the current study Bria-IMTtrade has an excellent safety profile
29
Bria-IMTtrade - Efficacy as Predicted
Interim Data (19 patients)-Ongoing Phase IIIa Study (2017-2018) amp Original Study (2004-2005)
PD-L1 expression on circulating cancer cells amp cancer-associated cells in 100 of patients (to date) Strong rationale for combination with checkpoint inhibitors like Keytruda
30
Bria-IMTtrade appears to be most effective in patients who match with Bria-IMT trade at 2 HLA loci (types) further supporting our ldquoHLA Matching Hypothesisrdquo and the development of Bria-OTS trade to cover 90 of the patient population
Combination with immune checkpoint inhibitors may induce a more potent anti-cancer response leading to our strategy of combination studies of Bria-IMT trade with Keytruda or Yervoy
Patients (n) HLA Match
Tumor Shrinkage
Biological Response
4 ge2 50 7515 ge1 27 334 0 0 0
Biological response includes tumor shrinkage or lower circulating cancer associated cells
The confirmatory Bria-IMTtrade monotherapy Phase IIa trial has completed enrollment Additional Support for the HLA-matching hypothesis has been obtained
Bria-IMTtrade Combination Therapy study with immune checkpoint inhibitors Keytrudareg if PD-L12 positive (ge1) Yervoyreg if PD-L12 negative (lt1) Accepting patients from the monotherapy study who develop progressive disease Also enrolling patients directly into this study to enhance experience with the combination In discussion with other pharmaceutical companies to evaluate additional combinations with other
immunotherapies
Bria-OTStrade Off-the-Shelf Personalized Targeted Immunotherapy Developing Bria-OTStrade to co-express GM-CSF and interferon-α Pre-manufacture additional HLA alleles ndash Total of 15 alleles (8 Class I and 7 Class II) Co-development of BriaDXtrade companion diagnostic for HLA typing Combination therapy clinical trial with immune checkpoint inhibitors for non-responders using
information from the Bria-IMTtrade Combination Therapy Study
33
Development Timeline ndash Breast Cancer
20192018 2020 2021
Phase IIIaBria-IMTtrade
Monotherapy
Currently Enrolling Phase IIaBria-IMTtrade + Checkpoint
Currently in discussions with potential partnersPhase II Bria-IMTtrade plus Additional Combinations (1Q19 4Q22)(eg PD-1 Inhibitor PD-L1 inhibitor anti-CTLA4 anti-GITR anti-OX40)
1Q 2Q 3Q 4Q
2023
Bria-OTStrade Off-The-Shelf Personalized ImmunotherapyMonotherapy and Potential Partnered Combo Therapy
(2H19 Ongoing)
Bria-OTStradeOff-the-Shelf Cell Line cGMP Manufacturing
and BriaDXtrade(1Q18 1Q19)
Registration Studies (1Q20 2H22)Bria-IMTtrade with Checkpoint InhibitorsBria-OTStrade +- Checkpoint Inhibitors
34
Immuno-oncology Deals
Recent deals of small biotechs with big pharma in immuno-oncology
35
Date PartnershipDevelopment stage at the time of the deal Deal size
07122018 Immatics-Genmab Preclinical Up to $28B
04042018 OSE Immunotherapeutics-Boehringer Ingelheim Preclinical Up to euro113B ($139B)
02092018 Pieris Pharmaceuticals-Seattle Genetics Preclinical Up to $123B
2142018 Nektar-BMS Ph III Up to $36B
01222018 Juno-Celgene Ph II $9B (Acquisition)
11142017 Loxo-Bayer Larotrectinib (Ph II) LOXO-195 (Ph III) Up to $155B
1032017 CytomX-Amgen Preclinical Up to $15B
03202017 CytomX--BMS Ph III Up to $36B
6282016 Xencor-Novartis Preclinical Up to $24B
Early Stage Clinical Studies (Comparison)
We compared the interim data of Ph IIIa study of Bria-IMTtrade in advanced breast cancer with thedata in the early stage clinical studies of recently approved breast cancer drugs and one fasttracked product candidate
Apples to apples comparison Early Stage Clinical Studies in oncology are typically done in patientswith no other therapeutic options Thus the patients have very advanced disease and response ratesare typically quite low
The patients in our Ph IIIa study have been heavily pre-treated (median 45 prior regimens)Some recent studies of relevance in breast cancer are noted in the following slides
36
Breast Cancer Market Opportunity
Drug Technology Approved for Market (US)Ibrance (palbociclib) CDK 46 Inhibitor HR+HER2- MBC in combination with
fluvestrant or aromatase inhibitor$933M in 1Q2018 $3126M in 2017
Kisqali (ribociclib) CDK 46 Inhibitor 2017 HR+HER2- MBC in combination with fluvestrant or aromatase inhibitor
Peak sales projected at $25B
Verzenio (abemaciclib) CDK 46 Inhibitor 2017 HR+HER2- MBC in combination with fluvestrant or aromatase inhibitor
balixafortide CXCR4 antagonist Fast track designation in 2018 for HER2- MBC who have failed 2 prior regimens
The market for breast cancer drugs is a multibillion dollar market with new drugs being approvedon an ongoing basis indicating the shortage of safe and effective treatments for this deadly disease
37
Competitors- Phase III Clinical Data Bria-IMTtrade shows superior safety and similar to superior efficacy data compared with those of the multi-billion dollar drugs when they were at a similar early stage of clinical development
Injection site reactions No related SAEs or SUSARs
Tumor vol darr ampor darr circul tumor cellsAll Comers 21(419) 26(519)One or More HLA matches 27(415) 33(515)Two or More HLA matches 50 (24) 75 (34)
Sheet1 (3)
Comp -Slides
Data
HLA (2)
HLA
Data (Ph1-2+4Pt)
Competitors (2018)-Slide
Competitors (2018)
In the Pipeline Protein Kinase C delta (PKCδ) Inhibitors
30 of all human malignancies display activating RAS mutations Another 60 showing over-activity of Ras-signaling pathways
Ras has been termed ldquoundruggablerdquo (no one has been able to make a Ras inhibitor drug)
BriaCellrsquos novel proprietary PKCδ inhibitors have shown activity against multiple RAS transformed tumors Lung cancer Melanoma Breast cancer Neuroendocrine cancer Pancreatic cancer Colorectal cancer
This target has an attractive safety profile based on in vivo studies and knock out mouse studies
PKCδ inhibitors should qualify for an accelerated clinical development plan and regulatory pathway
Could be in clinic within 24 months
Cost-Effective Additional Shot-on-Goal and additional partnership opportunities
Early-Stage Preclinical Program
39
Protein Kinase C delta (PKCδ) Inhibitors
Activated PKCδ inhibits RAS degradation which in turn stimulates tumor growth
Koo et al Oncotarget 621328 2016
30 of all human malignancies display activating RASmutations with another 60 showing over-activity of Ras-signaling pathways
BriaCellrsquos novel proprietary PKCδ inhibitors have shownactivity against multiple RAS transformed tumors
This target has an attractive safety profile based on in vivostudies and knock out mouse studies
PKCδ also has potential activity as an immunotherapeuticby blocking TGFβ signaling
PKCδ inhibitors are applicable to specific niche tumor typeswhich provide an accelerated clinical development plan
Structural aspects of first generation inhibitor rottlerin and staurosporine (pan-PKC activator) were combined to create second generation inhibitor KAM1
Third generation inhibitors such as BJE6-106 have improved potency and selectivity Fourth generation inhibitors under development to optimize drug-like characteristics PKCδ inhibitors lack endothelial cell cytotoxicity amp PKCδ deficient mice develop normally and are fertile Potentially no marked intrinsic toxicity by inhibiting PKCδ
Mukai H Saeki T Shimada K Naito Y Matsubara N Nakanishi T Obaishi H Namiki M Sasaki Y Phase 1 combination study of eribulin mesylate with trastuzumab for advanced or recurrent human epidermal growth factor receptor 2 positive breast cancer Invest New Drugs 2015 Feb33(1)119-27
AstraZeneca
Lynparza (Olaparib) + Cediranib
PARP inhibitor + inhibitor of VEGF receptor tyrosine kinases
HR+ HER2- MBC
BC amp OC
2013
28 (8 BC)
3 for BC
Olaparib (a poly (ADP-ribose) polymerase (PARP) inhibitor) amp Cediranib (Vascular endothelial growth factor receptor (VEGFR) 1 2 and 3 tyrosine kinase inhibitor)3 at dose level (DL) 0 (cediranib 20mg olaparib 100mg) 3 at DL1 (cediranib 20mg olaparib 200mg) 7 at DL2 (cediranib 30mg olaparib 200mg) 6 at DL3 (cediranib 30mg olaparib 400mg)
Liu JF Tolaney SM Birrer M Fleming GF Buss MK Dahlberg SE Lee H Whalen C Tyburski K Winer E Ivy P Matulonis UA A Phase 1 trial of the poly(ADP-ribose) polymerase inhibitor olaparib (AZD2281) in combination with the anti-angiogenic cediranib (AZD2171) in recurrent epithelial ovarian or triple-negative breast cancer Eur J Cancer 2013 Sep49(14)2972-8
Reyon Pharmaceutical
VM206RY
Heterologous prime-boost with a truncated HER2 sequence
HER2+ Stage IIIampIV BC
2015
9
2 chemo
Plasmid DNA (pHM-GM-CSF expressing truncated HER2 amp GM-CSF) amp adenoviral vector (Ad-HM containing modified HER2) (2 4 and 8 mgpatientvisit) of pHM-GM-CSF 3x IM weeks 0 2 and 4 Ad-HM 3 times 109 virus particles at week 6
11 PR
4 pts showed 7 minor AEs
Unclear
Kim SB Ahn JH Kim J Jung KH A phase 1 study of a heterologous prime-boost vaccination involving a truncated HER2 sequence in patients with HER2-expressing breast cancer Mol Ther Methods Clin Dev 2015 Sep 30215031 doi 101038mtm201531 eCollection 2015
Rodon J Peacuterez-Fidalgo A Krop IE Burris H Guerrero-Zotano A Britten CD Becerra C Schellens J Richards DA Schuler M Abu-Khalaf M Johnson FM Ranson M Edenfield J Silva AP Hackl W Quadt C Demanse D Duval V Baselga J Phase 11b dose escalation and expansion study of BEZ235 a dual PI3KmTOR inhibitor in patients with advanced solid tumors including patients with advanced breast cancer Cancer Chemother Pharmacol 2018 Jun 7 doi 101007s00280-018-3610-z [Epub ahead of print]
Celgene (Abraxane)
Gemcitabine + Abraxane (nab-paclitaxel)
Chemo + Chemo
OC BC NSCLC amp Panc cancer + Lung OC BC Kaposi sarcoma
MBC
2016
9
Adjuvant chemo (100)chemo post-adjuvant (33)
Gem (nucleoside metabolic inhibitor 1250 mgm2) on days 1 and 8 nab-Pac (microtubule inhibitor) starting dose of 180 mgm2 (cohort 1) 220 mgm2 (cohort 2) and 260 mgm2 (cohort 3) on day 1 of the 21-day cycle using a 3 + 3 design
0
MTD not reached29 Gr3 Neutropenia59 Gr1 Peripheralneuropathy
Yoshitomi S Taira N Doihara H Mizoo T Nogami T Iwamoto T Motoki T Shien T Ogasawara Y Matsuoka J Tsuji H Mitsuhashi T A phase 1 dose-finding and pharmacokinetic study of gemcitabine with nab-paclitaxel in patients with metastatic breast cancer Cancer Chemother Pharmacol 2016 Aug78(2)289-94
Eli Lilly
Erbituxreg (cetuximab) + Taxane
EGFR inhibitor antineoplastic agent + Chemo
Headamp Neck Colorectal Cancer
TNBC
2007-2010
18
1 chemo
Cetuximab (epidermal growth factor receptor (EGFR) antagonist ) an initial loading dose of cetuximab 400 mgm2 followed by a weekly dose of 250 mgm2Paclitaxel (microtubule inhibitor) 80 mgm2 or Docetaxel at an initial dose of 30 mgm2 was administered weekly
56 CR 22 PR
83 Dermatologic toxicity11 Grade3+
Nechushtan H Vainer G Stainberg H Salmon AY Hamburger T Peretz T A phase 12 of a combination of cetuximab and taxane for triple negative breast cancer patients Breast 2014 Aug23(4)435-8
Polyphor
Balixafortide (POL6326) + eribulin
CXCR4 antagonist + tubulin-based antimitotic
Heavily pretreated Relapsed MBC
2014-2016
56
3rd line 3 chemo
3+3 dose escalation The highest dose was established as eribulin 14 mgmsup2 on days 2 and 9 and balixafortide 55 mgkg on days 1minus3 and 8minus10 of the 21-day cycle
30 PR
41 Gr34 Neutropenia11 Gr34 Leucopenia11 Gr34 Febrileneutropenia2 Related mortalities
Apr 2018 Fast Track for HER2-MBC who have failed 2prior regimens
Pernas S Martin M Kaufman PA Gil-Martin M Gomez Pardo P Lopez-Tarruella S Manso L Ciruelos E Perez-Fidalgo JA Hernando C Ademuyiwa FO Weilbaecher K Mayer I Pluard TJ Martinez Garcia M Vahdat L Perez-Garcia J Wach A Barker D Fung S Romagnoli B Cortes J Balixafortide plus eribulin in HER2-negative metastatic breast cancer a phase 1 single-arm dose-escalation trial Lancet Oncol 2018 Jun19(6)812-824
11 PRndashbut only + letrozole (No Resp on monotherapy)
61 Gr34 Neutropenia39 Gr34 Leucopenia
$933M in 1Q2018 $31B in 2017
Tamura K Mukai H Naito Y Yonemori K Kodaira M Tanabe Y Yamamoto N Osera S Sasaki M Mori Y Hashigaki S Nagasawa T Umeyama Y Yoshino T Phase I study of palbociclib a cyclin-dependent kinase 46 inhibitor in Japanese patients Cancer Sci 2016 Jun107(6)755-63 doi 101111cas12932 Epub 2016 May 11
Pfizer
Ibrancereg (palbociclib)
CDK 46 Inhibitor
HR+ HER2- MBC
Heavily pretreated Relapsed Metastatic Cancer
2004-2008
41 (5 BC)
chemo naiumlve (17) 1-2 (51)3 (29) 3+ (2)
Palbociclib 25-150 mg dose ranging
0
20 Gr34 Neutropenia23 Gr34 Leucopenia
$933M in 1Q2018 $31B in 2017
Flaherty KT Lorusso PM Demichele A Abramson VG Courtney R Randolph SS Shaik MN Wilner KD ODwyer PJ Schwartz GK Phase I dose-escalation trial of the oral cyclin-dependent kinase 46 inhibitor PD 0332991 administered using a 21-day schedule in patients with advanced cancer Clin Cancer Res 2012 Jan 1518(2)568-76 doi 1011581078-0432CCR-11-0509 Epub 2011 Nov 16
Novartis
Kisqalireg (ribociclib)
CDK 46 Inhibitors
Premenopausal HR+ HER2- MBC
Heavily pretreated Relapsed Metastatic Cancer
2016
132 (20 BC)
0-1 (25) 2-3 (42) 4+ (32)
Ribociclib 50 mg ranging up to 1200 mg dose escalation
23 PRndashincluded 1 in BC (5 of BC pts)
27 Gr34 Neutropenia17 Gr34 Leucopenia
Peak sales projected at $25B
Infante JR Cassier PA Gerecitano JF Witteveen PO Chugh R Ribrag V Chakraborty A Matano A Dobson JR Crystal AS Parasuraman S Shapiro GI A Phase I Study of the Cyclin-Dependent Kinase 46 Inhibitor Ribociclib (LEE011) in Patients with Advanced Solid Tumors and Lymphomas Clin Cancer Res 2016 Dec 122(23)5696-5705 Epub 2016 Aug 19
Eli Lilly
Verzenioreg (abemaciclib)
CDK 46 Inhibitors
HR+HER2minusMBC
Heavily pretreated Relapsed Metastatic Cancer
2016
12 (1 BC)
1 (312) 2 (212) 3+ (7)
Abemaciclib 100 mg ranging up to 200 mg dose escalation
17 PR (included 1 in BC)
17 Gr34 Neutropenia33 Gr34 Leucopenia
Peak sales projected at $2B
Fujiwara Y Tamura K Kondo S Tanabe Y Iwasa S Shimomura A Kitano S Ogasawara K Turner PK Mori J Asou H Chan EM Yamamoto N Phase 1 study of abemaciclib an inhibitor of CDK 4 and 6 as a single agent for Japanese patients with advanced cancer Cancer Chemother Pharmacol 2016 Aug78(2)281-8 doi 101007s00280-016-3085-8 Epub 2016 Jun 16
Mukai H Saeki T Shimada K Naito Y Matsubara N Nakanishi T Obaishi H Namiki M Sasaki Y Phase 1 combination study of eribulin mesylate with trastuzumab for advanced or recurrent human epidermal growth factor receptor 2 positive breast cancer Invest New Drugs 2015 Feb33(1)119-27
AstraZeneca
Lynparza (Olaparib)+ Cediranib
PARP inhibitor+ inhibitor of VEGF RTK
HR+ HER2- MBC
BC amp OC
13
28 (8 BC)
3 for BC
Olaparib (a poly (ADP-ribose) polymerase (PARP) inhibitor) amp Cediranib (Vascular endothelial growth factor receptor (VEGFR) 1 2 and 3 tyrosine kinase inhibitor)3 at dose level (DL) 0 (cediranib 20mg olaparib 100mg) 3 at DL1 (cediranib 20mg olaparib 200mg) 7 at DL2 (cediranib 30mg olaparib 200mg) 6 at DL3 (cediranib 30mg olaparib 400mg)
Liu JF Tolaney SM Birrer M Fleming GF Buss MK Dahlberg SE Lee H Whalen C Tyburski K Winer E Ivy P Matulonis UA A Phase 1 trial of the poly(ADP-ribose) polymerase inhibitor olaparib (AZD2281) in combination with the anti-angiogenic cediranib (AZD2171) in recurrent epithelial ovarian or triple-negative breast cancer Eur J Cancer 2013 Sep49(14)2972-8
ReyonPharma
VM206RY
Heterologous prime-boost with a truncated HER2 sequence
HER2+ Stg IIIampIV BC
15
9
2 chemo
Plasmid DNA (pHM-GM-CSF expressing truncated HER2 amp GM-CSF) amp adenoviral vector (Ad-HM containing modified HER2) (2 4 and 8 mgpatientvisit) of pHM-GM-CSF 3x IM weeks 0 2 and 4 Ad-HM 3 times 109 virus particles at week 6
11 PR
4 pts 7 minor AEs
Unclear
Kim SB Ahn JH Kim J Jung KH A phase 1 study of a heterologous prime-boost vaccination involving a truncated HER2 sequence in patients with HER2-expressing breast cancer Mol Ther Methods Clin Dev 2015 Sep 30215031 doi 101038mtm201531 eCollection 2015
Rodon J Peacuterez-Fidalgo A Krop IE Burris H Guerrero-Zotano A Britten CD Becerra C Schellens J Richards DA Schuler M Abu-Khalaf M Johnson FM Ranson M Edenfield J Silva AP Hackl W Quadt C Demanse D Duval V Baselga J Phase 11b dose escalation and expansion study of BEZ235 a dual PI3KmTOR inhibitor in patients with advanced solid tumors including patients with advanced breast cancer Cancer Chemother Pharmacol 2018 Jun 7 doi 101007s00280-018-3610-z [Epub ahead of print]
Celgene(Abraxane)
Gemcitabine + Abraxane (nab-paclitaxel)
Chemo+ Chemo
OC BC NSCLC PC + LC OC BC KS
MBC
16
9
Adjuv chemo (100)chemo post-adjuv (33)
Gem (nucleoside metabolic inhibitor 1250 mgm2) on days 1 and 8 nab-Pac (microtubule inhibitor) starting dose of 180 mgm2 (cohort 1) 220 mgm2 (cohort 2) and 260 mgm2 (cohort 3) on day 1 of the 21-day cycle using a 3 + 3 design
0
MTD not reached29 Gr3 Neutropenia59 Gr1 Peripheralneuropathy
Yoshitomi S Taira N Doihara H Mizoo T Nogami T Iwamoto T Motoki T Shien T Ogasawara Y Matsuoka J Tsuji H Mitsuhashi T A phase 1 dose-finding and pharmacokinetic study of gemcitabine with nab-paclitaxel in patients with metastatic breast cancer Cancer Chemother Pharmacol 2016 Aug78(2)289-94
Eli Lilly
Erbituxreg (cetuximab) + Taxane
EGFR inhibitor antineoplastic agent + Chemo
Head amp NeckColorectal
TNBC
07-10
18
1 chemo
Cetuximab (epidermal growth factor receptor (EGFR) antagonist ) an initial loading dose of cetuximab 400 mgm2 followed by a weekly dose of 250 mgm2Paclitaxel (microtubule inhibitor) 80 mgm2 or Docetaxel at an initial dose of 30 mgm2 was administered weekly
56 CR 22 PR
83 Dermatologic toxicity11 Grade3+
Nechushtan H Vainer G Stainberg H Salmon AY Hamburger T Peretz T A phase 12 of a combination of cetuximab and taxane for triple negative breast cancer patients Breast 2014 Aug23(4)435-8
Polyphor
Balixafortide (POL6326) + eribulin
CXCR4 antagonist + tubulin-based antimitotic
Heavily pretreatedRelapsed MBC
14-16
56
3rd line 3 chemo
3+3 dose escalation The highest dose was established as eribulin 14 mgmsup2 on days 2 and 9 and balixafortide 55 mgkg on days 1minus3 and 8minus10 of the 21-day cycle
30 PR
41 Gr34 Neutropenia11 Gr34 Leucopenia11 Gr34 Febrileneutropenia2 Related mortalities
42018 Fast Track (HER2-MBC failed 2 prior regimens)
Pernas S Martin M Kaufman PA Gil-Martin M Gomez Pardo P Lopez-Tarruella S Manso L Ciruelos E Perez-Fidalgo JA Hernando C Ademuyiwa FO Weilbaecher K Mayer I Pluard TJ Martinez Garcia M Vahdat L Perez-Garcia J Wach A Barker D Fung S Romagnoli B Cortes J Balixafortide plus eribulin in HER2-negative metastatic breast cancer a phase 1 single-arm dose-escalation trial Lancet Oncol 2018 Jun19(6)812-824
1 PRndashbut only + letrozoleNo Resp on monotherapy
61 Gr34 Neutropenia39 Gr34 Leucopenia
$933M (1Q18)$31B (2017)
Tamura K Mukai H Naito Y Yonemori K Kodaira M Tanabe Y Yamamoto N Osera S Sasaki M Mori Y Hashigaki S Nagasawa T Umeyama Y Yoshino T Phase I study of palbociclib a cyclin-dependent kinase 46 inhibitor in Japanese patients Cancer Sci 2016 Jun107(6)755-63 doi 101111cas12932 Epub 2016 May 11
Pfizer
Ibrancereg (palbociclib)
CDK 46 Inhibitor
HR+ HER2- MBC
Heavily pretreatedRelapsed Met Cancer
04-08
41 (5 BC)
chemo naiumlve (17)1-2(51) 3(29) 3+(2)
Palbociclib 25-150 mg dose ranging
0
20 Gr34 Neutropenia23 Gr34 Leucopenia
$933M (1Q18)$31B (2017)
Flaherty KT Lorusso PM Demichele A Abramson VG Courtney R Randolph SS Shaik MN Wilner KD ODwyer PJ Schwartz GK Phase I dose-escalation trial of the oral cyclin-dependent kinase 46 inhibitor PD 0332991 administered using a 21-day schedule in patients with advanced cancer Clin Cancer Res 2012 Jan 1518(2)568-76 doi 1011581078-0432CCR-11-0509 Epub 2011 Nov 16
Novartis
Kisqalireg (ribociclib)
CDK 46 Inhibitor
Premenopausal HR+ HER2- MBC
Heavily pretreatedRelapsed Met Cancer
16
132 (20 BC)
0-1 (25) 2-3 (42)4+ (32)
Ribociclib 50 mg ranging up to 1200 mg dose escalation
23 PR-included 1 BC (5 of BC pts)
27 Gr34 Neutropenia17 Gr34 Leucopenia
Peak sales est at $25B
Infante JR Cassier PA Gerecitano JF Witteveen PO Chugh R Ribrag V Chakraborty A Matano A Dobson JR Crystal AS Parasuraman S Shapiro GI A Phase I Study of the Cyclin-Dependent Kinase 46 Inhibitor Ribociclib (LEE011) in Patients with Advanced Solid Tumors and Lymphomas Clin Cancer Res 2016 Dec 122(23)5696-5705 Epub 2016 Aug 19
Eli Lilly
Verzenioreg (abemaciclib)
CDK 46 Inhibitor
HR+HER2minusMBC
Heavily pretreatedRelapsed Met Cancer
16
12 (1 BC)
1 (312) 2 (212) 3+(7)
Abemaciclib 100 mg ranging up to 200 mg dose escalation
17 PR (included 1 BC)
17 Gr34 Neutropenia33 Gr34 Leucopenia
Peak sales est at $2B
Fujiwara Y Tamura K Kondo S Tanabe Y Iwasa S Shimomura A Kitano S Ogasawara K Turner PK Mori J Asou H Chan EM Yamamoto N Phase 1 study of abemaciclib an inhibitor of CDK 4 and 6 as a single agent for Japanese patients with advanced cancer Cancer Chemother Pharmacol 2016 Aug78(2)281-8 doi 101007s00280-016-3085-8 Epub 2016 Jun 16
Mukai H Saeki T Shimada K Naito Y Matsubara N Nakanishi T Obaishi H Namiki M Sasaki Y Phase 1 combination study of eribulin mesylate with trastuzumab for advanced or recurrent human epidermal growth factor receptor 2 positive breast cancer Invest New Drugs 2015 Feb33(1)119-27
AstraZeneca
Lynparza (Olaparib) + Cediranib
PARP inhibitor + inhibitor of VEGF receptor tyrosine kinases
HR+ HER2- MBC
BC amp OC
2013
28 (8 BC)
3 for BC
Olaparib (a poly (ADP-ribose) polymerase (PARP) inhibitor) amp Cediranib (Vascular endothelial growth factor receptor (VEGFR) 1 2 and 3 tyrosine kinase inhibitor)3 at dose level (DL) 0 (cediranib 20mg olaparib 100mg) 3 at DL1 (cediranib 20mg olaparib 200mg) 7 at DL2 (cediranib 30mg olaparib 200mg) 6 at DL3 (cediranib 30mg olaparib 400mg)
Liu JF Tolaney SM Birrer M Fleming GF Buss MK Dahlberg SE Lee H Whalen C Tyburski K Winer E Ivy P Matulonis UA A Phase 1 trial of the poly(ADP-ribose) polymerase inhibitor olaparib (AZD2281) in combination with the anti-angiogenic cediranib (AZD2171) in recurrent epithelial ovarian or triple-negative breast cancer Eur J Cancer 2013 Sep49(14)2972-8
Reyon Pharmaceutical
VM206RY
Heterologous prime-boost with a truncated HER2 sequence
HER2+ Stage IIIampIV BC
2015
9
2 chemo
Plasmid DNA (pHM-GM-CSF expressing truncated HER2 amp GM-CSF) amp adenoviral vector (Ad-HM containing modified HER2) (2 4 and 8 mgpatientvisit) of pHM-GM-CSF 3x IM weeks 0 2 and 4 Ad-HM 3 times 109 virus particles at week 6
11 PR
4 pts showed 7 minor AEs
Unclear
Kim SB Ahn JH Kim J Jung KH A phase 1 study of a heterologous prime-boost vaccination involving a truncated HER2 sequence in patients with HER2-expressing breast cancer Mol Ther Methods Clin Dev 2015 Sep 30215031 doi 101038mtm201531 eCollection 2015
Rodon J Peacuterez-Fidalgo A Krop IE Burris H Guerrero-Zotano A Britten CD Becerra C Schellens J Richards DA Schuler M Abu-Khalaf M Johnson FM Ranson M Edenfield J Silva AP Hackl W Quadt C Demanse D Duval V Baselga J Phase 11b dose escalation and expansion study of BEZ235 a dual PI3KmTOR inhibitor in patients with advanced solid tumors including patients with advanced breast cancer Cancer Chemother Pharmacol 2018 Jun 7 doi 101007s00280-018-3610-z [Epub ahead of print]
Celgene (Abraxane)
Gemcitabine + Abraxane (nab-paclitaxel)
Chemo + Chemo
OC BC NSCLC amp Panc cancer + Lung OC BC Kaposi sarcoma
MBC
2016
9
Adjuvant chemo (100)chemo post-adjuvant (33)
Gem (nucleoside metabolic inhibitor 1250 mgm2) on days 1 and 8 nab-Pac (microtubule inhibitor) starting dose of 180 mgm2 (cohort 1) 220 mgm2 (cohort 2) and 260 mgm2 (cohort 3) on day 1 of the 21-day cycle using a 3 + 3 design
0
MTD not reached29 Gr3 Neutropenia59 Gr1 Peripheralneuropathy
Yoshitomi S Taira N Doihara H Mizoo T Nogami T Iwamoto T Motoki T Shien T Ogasawara Y Matsuoka J Tsuji H Mitsuhashi T A phase 1 dose-finding and pharmacokinetic study of gemcitabine with nab-paclitaxel in patients with metastatic breast cancer Cancer Chemother Pharmacol 2016 Aug78(2)289-94
Eli Lilly
Erbituxreg (cetuximab) + Taxane
EGFR inhibitor antineoplastic agent + Chemo
Headamp Neck Colorectal Cancer
TNBC
2007-2010
18
1 chemo
Cetuximab (epidermal growth factor receptor (EGFR) antagonist ) an initial loading dose of cetuximab 400 mgm2 followed by a weekly dose of 250 mgm2Paclitaxel (microtubule inhibitor) 80 mgm2 or Docetaxel at an initial dose of 30 mgm2 was administered weekly
56 CR 22 PR
83 Dermatologic toxicity11 Grade3+
Nechushtan H Vainer G Stainberg H Salmon AY Hamburger T Peretz T A phase 12 of a combination of cetuximab and taxane for triple negative breast cancer patients Breast 2014 Aug23(4)435-8
Polyphor
Balixafortide (POL6326) + eribulin
CXCR4 antagonist + tubulin-based antimitotic
Heavily pretreated Relapsed MBC
2014-2016
56
3rd line 3 chemo
3+3 dose escalation The highest dose was established as eribulin 14 mgmsup2 on days 2 and 9 and balixafortide 55 mgkg on days 1minus3 and 8minus10 of the 21-day cycle
30 PR
41 Gr34 Neutropenia11 Gr34 Leucopenia11 Gr34 Febrileneutropenia2 Related mortalities
Apr 2018 Fast Track for HER2-MBC who have failed 2prior regimens
Pernas S Martin M Kaufman PA Gil-Martin M Gomez Pardo P Lopez-Tarruella S Manso L Ciruelos E Perez-Fidalgo JA Hernando C Ademuyiwa FO Weilbaecher K Mayer I Pluard TJ Martinez Garcia M Vahdat L Perez-Garcia J Wach A Barker D Fung S Romagnoli B Cortes J Balixafortide plus eribulin in HER2-negative metastatic breast cancer a phase 1 single-arm dose-escalation trial Lancet Oncol 2018 Jun19(6)812-824
11 PRndashbut only + letrozole (No Resp on monotherapy)
61 Gr34 Neutropenia39 Gr34 Leucopenia
$933M in 1Q2018 $31B in 2017
Tamura K Mukai H Naito Y Yonemori K Kodaira M Tanabe Y Yamamoto N Osera S Sasaki M Mori Y Hashigaki S Nagasawa T Umeyama Y Yoshino T Phase I study of palbociclib a cyclin-dependent kinase 46 inhibitor in Japanese patients Cancer Sci 2016 Jun107(6)755-63 doi 101111cas12932 Epub 2016 May 11
Pfizer
Ibrancereg (palbociclib)
CDK 46 Inhibitor
HR+ HER2- MBC
Heavily pretreated Relapsed Metastatic Cancer
2004-2008
41 (5 BC)
chemo naiumlve (17) 1-2 (51)3 (29) 3+ (2)
Palbociclib 25-150 mg dose ranging
0
20 Gr34 Neutropenia23 Gr34 Leucopenia
$933M in 1Q2018 $31B in 2017
Flaherty KT Lorusso PM Demichele A Abramson VG Courtney R Randolph SS Shaik MN Wilner KD ODwyer PJ Schwartz GK Phase I dose-escalation trial of the oral cyclin-dependent kinase 46 inhibitor PD 0332991 administered using a 21-day schedule in patients with advanced cancer Clin Cancer Res 2012 Jan 1518(2)568-76 doi 1011581078-0432CCR-11-0509 Epub 2011 Nov 16
Novartis
Kisqalireg (ribociclib)
CDK 46 Inhibitors
Premenopausal HR+ HER2- MBC
Heavily pretreated Relapsed Metastatic Cancer
2016
132 (20 BC)
0-1 (25) 2-3 (42) 4+ (32)
Ribociclib 50 mg ranging up to 1200 mg dose escalation
23 PRndashincluded 1 in BC (5 of BC pts)
27 Gr34 Neutropenia17 Gr34 Leucopenia
Peak sales projected at $25B
Infante JR Cassier PA Gerecitano JF Witteveen PO Chugh R Ribrag V Chakraborty A Matano A Dobson JR Crystal AS Parasuraman S Shapiro GI A Phase I Study of the Cyclin-Dependent Kinase 46 Inhibitor Ribociclib (LEE011) in Patients with Advanced Solid Tumors and Lymphomas Clin Cancer Res 2016 Dec 122(23)5696-5705 Epub 2016 Aug 19
Eli Lilly
Verzenioreg (abemaciclib)
CDK 46 Inhibitors
HR+HER2minusMBC
Heavily pretreated Relapsed Metastatic Cancer
2016
12 (1 BC)
1 (312) 2 (212) 3+ (7)
Abemaciclib 100 mg ranging up to 200 mg dose escalation
17 PR (included 1 in BC)
17 Gr34 Neutropenia33 Gr34 Leucopenia
Peak sales projected at $2B
Fujiwara Y Tamura K Kondo S Tanabe Y Iwasa S Shimomura A Kitano S Ogasawara K Turner PK Mori J Asou H Chan EM Yamamoto N Phase 1 study of abemaciclib an inhibitor of CDK 4 and 6 as a single agent for Japanese patients with advanced cancer Cancer Chemother Pharmacol 2016 Aug78(2)281-8 doi 101007s00280-016-3085-8 Epub 2016 Jun 16
Mukai H Saeki T Shimada K Naito Y Matsubara N Nakanishi T Obaishi H Namiki M Sasaki Y Phase 1 combination study of eribulin mesylate with trastuzumab for advanced or recurrent human epidermal growth factor receptor 2 positive breast cancer Invest New Drugs 2015 Feb33(1)119-27
AstraZeneca
Lynparza (Olaparib)+ Cediranib
PARP inhibitor+ inhibitor of VEGF RTK
HR+ HER2- MBC
BC amp OC
13
28 (8 BC)
3 for BC
Olaparib (a poly (ADP-ribose) polymerase (PARP) inhibitor) amp Cediranib (Vascular endothelial growth factor receptor (VEGFR) 1 2 and 3 tyrosine kinase inhibitor)3 at dose level (DL) 0 (cediranib 20mg olaparib 100mg) 3 at DL1 (cediranib 20mg olaparib 200mg) 7 at DL2 (cediranib 30mg olaparib 200mg) 6 at DL3 (cediranib 30mg olaparib 400mg)
Liu JF Tolaney SM Birrer M Fleming GF Buss MK Dahlberg SE Lee H Whalen C Tyburski K Winer E Ivy P Matulonis UA A Phase 1 trial of the poly(ADP-ribose) polymerase inhibitor olaparib (AZD2281) in combination with the anti-angiogenic cediranib (AZD2171) in recurrent epithelial ovarian or triple-negative breast cancer Eur J Cancer 2013 Sep49(14)2972-8
ReyonPharma
VM206RY
Heterologous prime-boost with a truncated HER2 sequence
HER2+ Stg IIIampIV BC
15
9
2 chemo
Plasmid DNA (pHM-GM-CSF expressing truncated HER2 amp GM-CSF) amp adenoviral vector (Ad-HM containing modified HER2) (2 4 and 8 mgpatientvisit) of pHM-GM-CSF 3x IM weeks 0 2 and 4 Ad-HM 3 times 109 virus particles at week 6
11 PR
4 pts 7 minor AEs
Unclear
Kim SB Ahn JH Kim J Jung KH A phase 1 study of a heterologous prime-boost vaccination involving a truncated HER2 sequence in patients with HER2-expressing breast cancer Mol Ther Methods Clin Dev 2015 Sep 30215031 doi 101038mtm201531 eCollection 2015
Rodon J Peacuterez-Fidalgo A Krop IE Burris H Guerrero-Zotano A Britten CD Becerra C Schellens J Richards DA Schuler M Abu-Khalaf M Johnson FM Ranson M Edenfield J Silva AP Hackl W Quadt C Demanse D Duval V Baselga J Phase 11b dose escalation and expansion study of BEZ235 a dual PI3KmTOR inhibitor in patients with advanced solid tumors including patients with advanced breast cancer Cancer Chemother Pharmacol 2018 Jun 7 doi 101007s00280-018-3610-z [Epub ahead of print]
Celgene(Abraxane)
Gemcitabine + Abraxane (nab-paclitaxel)
Chemo+ Chemo
OC BC NSCLC PC + LC OC BC KS
MBC
16
9
Adjuv chemo (100)chemo post-adjuv (33)
Gem (nucleoside metabolic inhibitor 1250 mgm2) on days 1 and 8 nab-Pac (microtubule inhibitor) starting dose of 180 mgm2 (cohort 1) 220 mgm2 (cohort 2) and 260 mgm2 (cohort 3) on day 1 of the 21-day cycle using a 3 + 3 design
0
MTD not reached29 Gr3 Neutropenia59 Gr1 Peripheralneuropathy
Yoshitomi S Taira N Doihara H Mizoo T Nogami T Iwamoto T Motoki T Shien T Ogasawara Y Matsuoka J Tsuji H Mitsuhashi T A phase 1 dose-finding and pharmacokinetic study of gemcitabine with nab-paclitaxel in patients with metastatic breast cancer Cancer Chemother Pharmacol 2016 Aug78(2)289-94
Eli Lilly
Erbituxreg (cetuximab) + Taxane
EGFR inhibitor antineoplastic agent + Chemo
Head amp NeckColorectal
TNBC
07-10
18
1 chemo
Cetuximab (epidermal growth factor receptor (EGFR) antagonist ) an initial loading dose of cetuximab 400 mgm2 followed by a weekly dose of 250 mgm2Paclitaxel (microtubule inhibitor) 80 mgm2 or Docetaxel at an initial dose of 30 mgm2 was administered weekly
56 CR 22 PR
83 Dermatologic toxicity11 Grade3+
Nechushtan H Vainer G Stainberg H Salmon AY Hamburger T Peretz T A phase 12 of a combination of cetuximab and taxane for triple negative breast cancer patients Breast 2014 Aug23(4)435-8
Polyphor
Balixafortide (POL6326) + eribulin
CXCR4 antagonist + tubulin-based antimitotic
Heavily pretreatedRelapsed MBC
14-16
56
3rd line 3 chemo
3+3 dose escalation The highest dose was established as eribulin 14 mgmsup2 on days 2 and 9 and balixafortide 55 mgkg on days 1minus3 and 8minus10 of the 21-day cycle
30 PR
41 Gr34 Neutropenia11 Gr34 Leucopenia11 Gr34 Febrileneutropenia2 Related mortalities
42018 Fast Track (HER2-MBC failed 2 prior regimens)
Pernas S Martin M Kaufman PA Gil-Martin M Gomez Pardo P Lopez-Tarruella S Manso L Ciruelos E Perez-Fidalgo JA Hernando C Ademuyiwa FO Weilbaecher K Mayer I Pluard TJ Martinez Garcia M Vahdat L Perez-Garcia J Wach A Barker D Fung S Romagnoli B Cortes J Balixafortide plus eribulin in HER2-negative metastatic breast cancer a phase 1 single-arm dose-escalation trial Lancet Oncol 2018 Jun19(6)812-824
1 PRndashbut only + letrozoleNo Resp on monotherapy
61 Gr34 Neutropenia39 Gr34 Leucopenia
$933M (1Q18)$31B (2017)
Tamura K Mukai H Naito Y Yonemori K Kodaira M Tanabe Y Yamamoto N Osera S Sasaki M Mori Y Hashigaki S Nagasawa T Umeyama Y Yoshino T Phase I study of palbociclib a cyclin-dependent kinase 46 inhibitor in Japanese patients Cancer Sci 2016 Jun107(6)755-63 doi 101111cas12932 Epub 2016 May 11
Pfizer
Ibrancereg (palbociclib)
CDK 46 Inhibitor
HR+ HER2- MBC
Heavily pretreatedRelapsed Met Cancer
04-08
41 (5 BC)
chemo naiumlve (17)1-2(51) 3(29) 3+(2)
Palbociclib 25-150 mg dose ranging
0
20 Gr34 Neutropenia23 Gr34 Leucopenia
$933M (1Q18)$31B (2017)
Flaherty KT Lorusso PM Demichele A Abramson VG Courtney R Randolph SS Shaik MN Wilner KD ODwyer PJ Schwartz GK Phase I dose-escalation trial of the oral cyclin-dependent kinase 46 inhibitor PD 0332991 administered using a 21-day schedule in patients with advanced cancer Clin Cancer Res 2012 Jan 1518(2)568-76 doi 1011581078-0432CCR-11-0509 Epub 2011 Nov 16
Novartis
Kisqalireg (ribociclib)
CDK 46 Inhibitor
Premenopausal HR+ HER2- MBC
Heavily pretreatedRelapsed Met Cancer
16
132 (20 BC)
0-1 (25) 2-3 (42)4+ (32)
Ribociclib 50 mg ranging up to 1200 mg dose escalation
23 PR-included 1 BC (5 of BC pts)
27 Gr34 Neutropenia17 Gr34 Leucopenia
Peak sales est at $25B
Infante JR Cassier PA Gerecitano JF Witteveen PO Chugh R Ribrag V Chakraborty A Matano A Dobson JR Crystal AS Parasuraman S Shapiro GI A Phase I Study of the Cyclin-Dependent Kinase 46 Inhibitor Ribociclib (LEE011) in Patients with Advanced Solid Tumors and Lymphomas Clin Cancer Res 2016 Dec 122(23)5696-5705 Epub 2016 Aug 19
Eli Lilly
Verzenioreg (abemaciclib)
CDK 46 Inhibitor
HR+HER2minusMBC
Heavily pretreatedRelapsed Met Cancer
16
12 (1 BC)
1 (312) 2 (212) 3+(7)
Abemaciclib 100 mg ranging up to 200 mg dose escalation
17 PR (included 1 BC)
17 Gr34 Neutropenia33 Gr34 Leucopenia
Peak sales est at $2B
Fujiwara Y Tamura K Kondo S Tanabe Y Iwasa S Shimomura A Kitano S Ogasawara K Turner PK Mori J Asou H Chan EM Yamamoto N Phase 1 study of abemaciclib an inhibitor of CDK 4 and 6 as a single agent for Japanese patients with advanced cancer Cancer Chemother Pharmacol 2016 Aug78(2)281-8 doi 101007s00280-016-3085-8 Epub 2016 Jun 16
Patient B001 Breast 70 No 1101 - 3501 4001 Negative -
Bria-IMTtradeHuman Proof-of-Concept Trials in Breast Cancer (Patient A002)
24
Proof-of-Concept Results Resulted in BriaCellrsquos Immunotherapy Strategy Use BriaDXtrade diagnostic to select only those patients matching Bria-IMTtrade Use BriaDXtrade diagnostic test to select Bria-OTStrade alleles matching ~90 of all patients
Bria-IMTtradeCurrent Phase IIIa Data Supports HLA Matching Hypothesis Six patients treated in 2017 Bria-IMTtrade was safe and well tolerated
Patient 01-002 73-year-old woman with breast cancer diagnosed in 1995 Developed liver metastases in2010 and lung metastases in 2017 Previously treated with 7 rounds of chemotherapy with 8 differentchemotherapy agents Received 5 cycles of Bria-IMTtrade over 3 months then monthly cycles (6 months total)Evaluated after 3 months and 6 months After 3 months despite the extensive prior therapy her scans notedthat ldquothere has been a clear response in the multiple bilateral pulmonary nodulesrdquo The response wasmaintained after 6 months of Bria-IMTtrade treatment She matches Bria-IMTtrade at 2 HLA alleles
The liver tumors were stable to slightly increased at 3 months and then progressed after 6 months
This supports our hypothesis of heightened anti-tumor activity in patients with a matched HLA types Clear path to develop BriaDXtrade to select the patients using HLA testing
1 RLL 29 Not Detectable Not Detectable2 LUL apical pleural based 34 tiny nodule lt 1mm scar tiny nodule lt 1mm scar3 xxx 39 Not Detectable Not Detectable4 40 Not Detectable Not Detectable5 RLL 45 Not Detectable Not Detectable6 LLL 49 Not Detectable Not Detectable7 xxx 52 Not Detectable Not Detectable8 RLL 52 Not Detectable Not Detectable9 RLL 56 Not Detectable Not Detectable
10 RLL costophrenic recess 56 Not Detectable Not Detectable11 XXX 58 Not Detectable Not Detectable12 LUL 60 Not Detectable Not Detectable13 XXX 67 15 1514 RUL 72 15 1515 LLL 76 Not Detectable Not Detectable16 RUL Noncalcified Nodule 77 Not Detectable Not Detectable17 RLL costophrenic recess 79 10 1018 RUL 82 Not Detectable Not Detectable19 RLL 90 Not Detectable Not Detectable20 RLL 91 lt 01 lt 0121 xxx xxx Not Detectable Not Detectable
27
Clinical Development Update ndash Summary 2018 September 26
Completed enrollment of Adv Breast cancer patients in the Phase IIIa ldquomonotherapyrdquo study of Bria-IMTtrade
We have confirmed our mechanism of action and achieved proof of concept
Initial safety data appears superior to that of the other advanced or approved drugs for breast cancer when they were at a similar clinical stage of development
Initial efficacy data is similar or superior to those of other advanced or approved drugs for breast cancer when they were at a similar clinical stage of development
Initiated Combination Study of Bria-IMTtrade with Keytrudareg or Yervoyreg in Adv breast cancer patients expecting even better response rates than those in the ldquomonotherapyrdquo study Initial safety data is expected in 4Q2018 Initial efficacy data is expected in 1Q2019
Bria-OTStrade the first off-the-shelf personalized treatment for advanced breast cancer is expected to enter the clinic in 2019
28
Bria-IMTtrade Excellent Safety Data - To Date
To date Bria-IMTtrade has been dosed in 24 patients (4 in 2004-2005 20 in 2017-2018)
Interim Data (20 patients)-Ongoing Phase IIIa Study (2017-2018)
Bria-IMTtrade has been very well tolerated (ge60 doses given to date) The majority of adverse events (AEs) were limited to expected minor local irritation at the
injection sites No related grade gt3 or unexpected AEs No related serious AEs No serious unexpected related AEs Most patients who have dropped out did so due to worsening of their underlying disease
Based on the current study Bria-IMTtrade has an excellent safety profile
29
Bria-IMTtrade - Efficacy as Predicted
Interim Data (19 patients)-Ongoing Phase IIIa Study (2017-2018) amp Original Study (2004-2005)
PD-L1 expression on circulating cancer cells amp cancer-associated cells in 100 of patients (to date) Strong rationale for combination with checkpoint inhibitors like Keytruda
30
Bria-IMTtrade appears to be most effective in patients who match with Bria-IMT trade at 2 HLA loci (types) further supporting our ldquoHLA Matching Hypothesisrdquo and the development of Bria-OTS trade to cover 90 of the patient population
Combination with immune checkpoint inhibitors may induce a more potent anti-cancer response leading to our strategy of combination studies of Bria-IMT trade with Keytruda or Yervoy
Patients (n) HLA Match
Tumor Shrinkage
Biological Response
4 ge2 50 7515 ge1 27 334 0 0 0
Biological response includes tumor shrinkage or lower circulating cancer associated cells
The confirmatory Bria-IMTtrade monotherapy Phase IIa trial has completed enrollment Additional Support for the HLA-matching hypothesis has been obtained
Bria-IMTtrade Combination Therapy study with immune checkpoint inhibitors Keytrudareg if PD-L12 positive (ge1) Yervoyreg if PD-L12 negative (lt1) Accepting patients from the monotherapy study who develop progressive disease Also enrolling patients directly into this study to enhance experience with the combination In discussion with other pharmaceutical companies to evaluate additional combinations with other
immunotherapies
Bria-OTStrade Off-the-Shelf Personalized Targeted Immunotherapy Developing Bria-OTStrade to co-express GM-CSF and interferon-α Pre-manufacture additional HLA alleles ndash Total of 15 alleles (8 Class I and 7 Class II) Co-development of BriaDXtrade companion diagnostic for HLA typing Combination therapy clinical trial with immune checkpoint inhibitors for non-responders using
information from the Bria-IMTtrade Combination Therapy Study
33
Development Timeline ndash Breast Cancer
20192018 2020 2021
Phase IIIaBria-IMTtrade
Monotherapy
Currently Enrolling Phase IIaBria-IMTtrade + Checkpoint
Currently in discussions with potential partnersPhase II Bria-IMTtrade plus Additional Combinations (1Q19 4Q22)(eg PD-1 Inhibitor PD-L1 inhibitor anti-CTLA4 anti-GITR anti-OX40)
1Q 2Q 3Q 4Q
2023
Bria-OTStrade Off-The-Shelf Personalized ImmunotherapyMonotherapy and Potential Partnered Combo Therapy
(2H19 Ongoing)
Bria-OTStradeOff-the-Shelf Cell Line cGMP Manufacturing
and BriaDXtrade(1Q18 1Q19)
Registration Studies (1Q20 2H22)Bria-IMTtrade with Checkpoint InhibitorsBria-OTStrade +- Checkpoint Inhibitors
34
Immuno-oncology Deals
Recent deals of small biotechs with big pharma in immuno-oncology
35
Date PartnershipDevelopment stage at the time of the deal Deal size
07122018 Immatics-Genmab Preclinical Up to $28B
04042018 OSE Immunotherapeutics-Boehringer Ingelheim Preclinical Up to euro113B ($139B)
02092018 Pieris Pharmaceuticals-Seattle Genetics Preclinical Up to $123B
2142018 Nektar-BMS Ph III Up to $36B
01222018 Juno-Celgene Ph II $9B (Acquisition)
11142017 Loxo-Bayer Larotrectinib (Ph II) LOXO-195 (Ph III) Up to $155B
1032017 CytomX-Amgen Preclinical Up to $15B
03202017 CytomX--BMS Ph III Up to $36B
6282016 Xencor-Novartis Preclinical Up to $24B
Early Stage Clinical Studies (Comparison)
We compared the interim data of Ph IIIa study of Bria-IMTtrade in advanced breast cancer with thedata in the early stage clinical studies of recently approved breast cancer drugs and one fasttracked product candidate
Apples to apples comparison Early Stage Clinical Studies in oncology are typically done in patientswith no other therapeutic options Thus the patients have very advanced disease and response ratesare typically quite low
The patients in our Ph IIIa study have been heavily pre-treated (median 45 prior regimens)Some recent studies of relevance in breast cancer are noted in the following slides
36
Breast Cancer Market Opportunity
Drug Technology Approved for Market (US)Ibrance (palbociclib) CDK 46 Inhibitor HR+HER2- MBC in combination with
fluvestrant or aromatase inhibitor$933M in 1Q2018 $3126M in 2017
Kisqali (ribociclib) CDK 46 Inhibitor 2017 HR+HER2- MBC in combination with fluvestrant or aromatase inhibitor
Peak sales projected at $25B
Verzenio (abemaciclib) CDK 46 Inhibitor 2017 HR+HER2- MBC in combination with fluvestrant or aromatase inhibitor
balixafortide CXCR4 antagonist Fast track designation in 2018 for HER2- MBC who have failed 2 prior regimens
The market for breast cancer drugs is a multibillion dollar market with new drugs being approvedon an ongoing basis indicating the shortage of safe and effective treatments for this deadly disease
37
Competitors- Phase III Clinical Data Bria-IMTtrade shows superior safety and similar to superior efficacy data compared with those of the multi-billion dollar drugs when they were at a similar early stage of clinical development
Injection site reactions No related SAEs or SUSARs
Tumor vol darr ampor darr circul tumor cellsAll Comers 21(419) 26(519)One or More HLA matches 27(415) 33(515)Two or More HLA matches 50 (24) 75 (34)
Sheet1 (3)
Comp -Slides
Data
HLA (2)
HLA
Data (Ph1-2+4Pt)
Competitors (2018)-Slide
Competitors (2018)
In the Pipeline Protein Kinase C delta (PKCδ) Inhibitors
30 of all human malignancies display activating RAS mutations Another 60 showing over-activity of Ras-signaling pathways
Ras has been termed ldquoundruggablerdquo (no one has been able to make a Ras inhibitor drug)
BriaCellrsquos novel proprietary PKCδ inhibitors have shown activity against multiple RAS transformed tumors Lung cancer Melanoma Breast cancer Neuroendocrine cancer Pancreatic cancer Colorectal cancer
This target has an attractive safety profile based on in vivo studies and knock out mouse studies
PKCδ inhibitors should qualify for an accelerated clinical development plan and regulatory pathway
Could be in clinic within 24 months
Cost-Effective Additional Shot-on-Goal and additional partnership opportunities
Early-Stage Preclinical Program
39
Protein Kinase C delta (PKCδ) Inhibitors
Activated PKCδ inhibits RAS degradation which in turn stimulates tumor growth
Koo et al Oncotarget 621328 2016
30 of all human malignancies display activating RASmutations with another 60 showing over-activity of Ras-signaling pathways
BriaCellrsquos novel proprietary PKCδ inhibitors have shownactivity against multiple RAS transformed tumors
This target has an attractive safety profile based on in vivostudies and knock out mouse studies
PKCδ also has potential activity as an immunotherapeuticby blocking TGFβ signaling
PKCδ inhibitors are applicable to specific niche tumor typeswhich provide an accelerated clinical development plan
Structural aspects of first generation inhibitor rottlerin and staurosporine (pan-PKC activator) were combined to create second generation inhibitor KAM1
Third generation inhibitors such as BJE6-106 have improved potency and selectivity Fourth generation inhibitors under development to optimize drug-like characteristics PKCδ inhibitors lack endothelial cell cytotoxicity amp PKCδ deficient mice develop normally and are fertile Potentially no marked intrinsic toxicity by inhibiting PKCδ
Mukai H Saeki T Shimada K Naito Y Matsubara N Nakanishi T Obaishi H Namiki M Sasaki Y Phase 1 combination study of eribulin mesylate with trastuzumab for advanced or recurrent human epidermal growth factor receptor 2 positive breast cancer Invest New Drugs 2015 Feb33(1)119-27
AstraZeneca
Lynparza (Olaparib) + Cediranib
PARP inhibitor + inhibitor of VEGF receptor tyrosine kinases
HR+ HER2- MBC
BC amp OC
2013
28 (8 BC)
3 for BC
Olaparib (a poly (ADP-ribose) polymerase (PARP) inhibitor) amp Cediranib (Vascular endothelial growth factor receptor (VEGFR) 1 2 and 3 tyrosine kinase inhibitor)3 at dose level (DL) 0 (cediranib 20mg olaparib 100mg) 3 at DL1 (cediranib 20mg olaparib 200mg) 7 at DL2 (cediranib 30mg olaparib 200mg) 6 at DL3 (cediranib 30mg olaparib 400mg)
Liu JF Tolaney SM Birrer M Fleming GF Buss MK Dahlberg SE Lee H Whalen C Tyburski K Winer E Ivy P Matulonis UA A Phase 1 trial of the poly(ADP-ribose) polymerase inhibitor olaparib (AZD2281) in combination with the anti-angiogenic cediranib (AZD2171) in recurrent epithelial ovarian or triple-negative breast cancer Eur J Cancer 2013 Sep49(14)2972-8
Reyon Pharmaceutical
VM206RY
Heterologous prime-boost with a truncated HER2 sequence
HER2+ Stage IIIampIV BC
2015
9
2 chemo
Plasmid DNA (pHM-GM-CSF expressing truncated HER2 amp GM-CSF) amp adenoviral vector (Ad-HM containing modified HER2) (2 4 and 8 mgpatientvisit) of pHM-GM-CSF 3x IM weeks 0 2 and 4 Ad-HM 3 times 109 virus particles at week 6
11 PR
4 pts showed 7 minor AEs
Unclear
Kim SB Ahn JH Kim J Jung KH A phase 1 study of a heterologous prime-boost vaccination involving a truncated HER2 sequence in patients with HER2-expressing breast cancer Mol Ther Methods Clin Dev 2015 Sep 30215031 doi 101038mtm201531 eCollection 2015
Rodon J Peacuterez-Fidalgo A Krop IE Burris H Guerrero-Zotano A Britten CD Becerra C Schellens J Richards DA Schuler M Abu-Khalaf M Johnson FM Ranson M Edenfield J Silva AP Hackl W Quadt C Demanse D Duval V Baselga J Phase 11b dose escalation and expansion study of BEZ235 a dual PI3KmTOR inhibitor in patients with advanced solid tumors including patients with advanced breast cancer Cancer Chemother Pharmacol 2018 Jun 7 doi 101007s00280-018-3610-z [Epub ahead of print]
Celgene (Abraxane)
Gemcitabine + Abraxane (nab-paclitaxel)
Chemo + Chemo
OC BC NSCLC amp Panc cancer + Lung OC BC Kaposi sarcoma
MBC
2016
9
Adjuvant chemo (100)chemo post-adjuvant (33)
Gem (nucleoside metabolic inhibitor 1250 mgm2) on days 1 and 8 nab-Pac (microtubule inhibitor) starting dose of 180 mgm2 (cohort 1) 220 mgm2 (cohort 2) and 260 mgm2 (cohort 3) on day 1 of the 21-day cycle using a 3 + 3 design
0
MTD not reached29 Gr3 Neutropenia59 Gr1 Peripheralneuropathy
Yoshitomi S Taira N Doihara H Mizoo T Nogami T Iwamoto T Motoki T Shien T Ogasawara Y Matsuoka J Tsuji H Mitsuhashi T A phase 1 dose-finding and pharmacokinetic study of gemcitabine with nab-paclitaxel in patients with metastatic breast cancer Cancer Chemother Pharmacol 2016 Aug78(2)289-94
Eli Lilly
Erbituxreg (cetuximab) + Taxane
EGFR inhibitor antineoplastic agent + Chemo
Headamp Neck Colorectal Cancer
TNBC
2007-2010
18
1 chemo
Cetuximab (epidermal growth factor receptor (EGFR) antagonist ) an initial loading dose of cetuximab 400 mgm2 followed by a weekly dose of 250 mgm2Paclitaxel (microtubule inhibitor) 80 mgm2 or Docetaxel at an initial dose of 30 mgm2 was administered weekly
56 CR 22 PR
83 Dermatologic toxicity11 Grade3+
Nechushtan H Vainer G Stainberg H Salmon AY Hamburger T Peretz T A phase 12 of a combination of cetuximab and taxane for triple negative breast cancer patients Breast 2014 Aug23(4)435-8
Polyphor
Balixafortide (POL6326) + eribulin
CXCR4 antagonist + tubulin-based antimitotic
Heavily pretreated Relapsed MBC
2014-2016
56
3rd line 3 chemo
3+3 dose escalation The highest dose was established as eribulin 14 mgmsup2 on days 2 and 9 and balixafortide 55 mgkg on days 1minus3 and 8minus10 of the 21-day cycle
30 PR
41 Gr34 Neutropenia11 Gr34 Leucopenia11 Gr34 Febrileneutropenia2 Related mortalities
Apr 2018 Fast Track for HER2-MBC who have failed 2prior regimens
Pernas S Martin M Kaufman PA Gil-Martin M Gomez Pardo P Lopez-Tarruella S Manso L Ciruelos E Perez-Fidalgo JA Hernando C Ademuyiwa FO Weilbaecher K Mayer I Pluard TJ Martinez Garcia M Vahdat L Perez-Garcia J Wach A Barker D Fung S Romagnoli B Cortes J Balixafortide plus eribulin in HER2-negative metastatic breast cancer a phase 1 single-arm dose-escalation trial Lancet Oncol 2018 Jun19(6)812-824
11 PRndashbut only + letrozole (No Resp on monotherapy)
61 Gr34 Neutropenia39 Gr34 Leucopenia
$933M in 1Q2018 $31B in 2017
Tamura K Mukai H Naito Y Yonemori K Kodaira M Tanabe Y Yamamoto N Osera S Sasaki M Mori Y Hashigaki S Nagasawa T Umeyama Y Yoshino T Phase I study of palbociclib a cyclin-dependent kinase 46 inhibitor in Japanese patients Cancer Sci 2016 Jun107(6)755-63 doi 101111cas12932 Epub 2016 May 11
Pfizer
Ibrancereg (palbociclib)
CDK 46 Inhibitor
HR+ HER2- MBC
Heavily pretreated Relapsed Metastatic Cancer
2004-2008
41 (5 BC)
chemo naiumlve (17) 1-2 (51)3 (29) 3+ (2)
Palbociclib 25-150 mg dose ranging
0
20 Gr34 Neutropenia23 Gr34 Leucopenia
$933M in 1Q2018 $31B in 2017
Flaherty KT Lorusso PM Demichele A Abramson VG Courtney R Randolph SS Shaik MN Wilner KD ODwyer PJ Schwartz GK Phase I dose-escalation trial of the oral cyclin-dependent kinase 46 inhibitor PD 0332991 administered using a 21-day schedule in patients with advanced cancer Clin Cancer Res 2012 Jan 1518(2)568-76 doi 1011581078-0432CCR-11-0509 Epub 2011 Nov 16
Novartis
Kisqalireg (ribociclib)
CDK 46 Inhibitors
Premenopausal HR+ HER2- MBC
Heavily pretreated Relapsed Metastatic Cancer
2016
132 (20 BC)
0-1 (25) 2-3 (42) 4+ (32)
Ribociclib 50 mg ranging up to 1200 mg dose escalation
23 PRndashincluded 1 in BC (5 of BC pts)
27 Gr34 Neutropenia17 Gr34 Leucopenia
Peak sales projected at $25B
Infante JR Cassier PA Gerecitano JF Witteveen PO Chugh R Ribrag V Chakraborty A Matano A Dobson JR Crystal AS Parasuraman S Shapiro GI A Phase I Study of the Cyclin-Dependent Kinase 46 Inhibitor Ribociclib (LEE011) in Patients with Advanced Solid Tumors and Lymphomas Clin Cancer Res 2016 Dec 122(23)5696-5705 Epub 2016 Aug 19
Eli Lilly
Verzenioreg (abemaciclib)
CDK 46 Inhibitors
HR+HER2minusMBC
Heavily pretreated Relapsed Metastatic Cancer
2016
12 (1 BC)
1 (312) 2 (212) 3+ (7)
Abemaciclib 100 mg ranging up to 200 mg dose escalation
17 PR (included 1 in BC)
17 Gr34 Neutropenia33 Gr34 Leucopenia
Peak sales projected at $2B
Fujiwara Y Tamura K Kondo S Tanabe Y Iwasa S Shimomura A Kitano S Ogasawara K Turner PK Mori J Asou H Chan EM Yamamoto N Phase 1 study of abemaciclib an inhibitor of CDK 4 and 6 as a single agent for Japanese patients with advanced cancer Cancer Chemother Pharmacol 2016 Aug78(2)281-8 doi 101007s00280-016-3085-8 Epub 2016 Jun 16
Mukai H Saeki T Shimada K Naito Y Matsubara N Nakanishi T Obaishi H Namiki M Sasaki Y Phase 1 combination study of eribulin mesylate with trastuzumab for advanced or recurrent human epidermal growth factor receptor 2 positive breast cancer Invest New Drugs 2015 Feb33(1)119-27
AstraZeneca
Lynparza (Olaparib)+ Cediranib
PARP inhibitor+ inhibitor of VEGF RTK
HR+ HER2- MBC
BC amp OC
13
28 (8 BC)
3 for BC
Olaparib (a poly (ADP-ribose) polymerase (PARP) inhibitor) amp Cediranib (Vascular endothelial growth factor receptor (VEGFR) 1 2 and 3 tyrosine kinase inhibitor)3 at dose level (DL) 0 (cediranib 20mg olaparib 100mg) 3 at DL1 (cediranib 20mg olaparib 200mg) 7 at DL2 (cediranib 30mg olaparib 200mg) 6 at DL3 (cediranib 30mg olaparib 400mg)
Liu JF Tolaney SM Birrer M Fleming GF Buss MK Dahlberg SE Lee H Whalen C Tyburski K Winer E Ivy P Matulonis UA A Phase 1 trial of the poly(ADP-ribose) polymerase inhibitor olaparib (AZD2281) in combination with the anti-angiogenic cediranib (AZD2171) in recurrent epithelial ovarian or triple-negative breast cancer Eur J Cancer 2013 Sep49(14)2972-8
ReyonPharma
VM206RY
Heterologous prime-boost with a truncated HER2 sequence
HER2+ Stg IIIampIV BC
15
9
2 chemo
Plasmid DNA (pHM-GM-CSF expressing truncated HER2 amp GM-CSF) amp adenoviral vector (Ad-HM containing modified HER2) (2 4 and 8 mgpatientvisit) of pHM-GM-CSF 3x IM weeks 0 2 and 4 Ad-HM 3 times 109 virus particles at week 6
11 PR
4 pts 7 minor AEs
Unclear
Kim SB Ahn JH Kim J Jung KH A phase 1 study of a heterologous prime-boost vaccination involving a truncated HER2 sequence in patients with HER2-expressing breast cancer Mol Ther Methods Clin Dev 2015 Sep 30215031 doi 101038mtm201531 eCollection 2015
Rodon J Peacuterez-Fidalgo A Krop IE Burris H Guerrero-Zotano A Britten CD Becerra C Schellens J Richards DA Schuler M Abu-Khalaf M Johnson FM Ranson M Edenfield J Silva AP Hackl W Quadt C Demanse D Duval V Baselga J Phase 11b dose escalation and expansion study of BEZ235 a dual PI3KmTOR inhibitor in patients with advanced solid tumors including patients with advanced breast cancer Cancer Chemother Pharmacol 2018 Jun 7 doi 101007s00280-018-3610-z [Epub ahead of print]
Celgene(Abraxane)
Gemcitabine + Abraxane (nab-paclitaxel)
Chemo+ Chemo
OC BC NSCLC PC + LC OC BC KS
MBC
16
9
Adjuv chemo (100)chemo post-adjuv (33)
Gem (nucleoside metabolic inhibitor 1250 mgm2) on days 1 and 8 nab-Pac (microtubule inhibitor) starting dose of 180 mgm2 (cohort 1) 220 mgm2 (cohort 2) and 260 mgm2 (cohort 3) on day 1 of the 21-day cycle using a 3 + 3 design
0
MTD not reached29 Gr3 Neutropenia59 Gr1 Peripheralneuropathy
Yoshitomi S Taira N Doihara H Mizoo T Nogami T Iwamoto T Motoki T Shien T Ogasawara Y Matsuoka J Tsuji H Mitsuhashi T A phase 1 dose-finding and pharmacokinetic study of gemcitabine with nab-paclitaxel in patients with metastatic breast cancer Cancer Chemother Pharmacol 2016 Aug78(2)289-94
Eli Lilly
Erbituxreg (cetuximab) + Taxane
EGFR inhibitor antineoplastic agent + Chemo
Head amp NeckColorectal
TNBC
07-10
18
1 chemo
Cetuximab (epidermal growth factor receptor (EGFR) antagonist ) an initial loading dose of cetuximab 400 mgm2 followed by a weekly dose of 250 mgm2Paclitaxel (microtubule inhibitor) 80 mgm2 or Docetaxel at an initial dose of 30 mgm2 was administered weekly
56 CR 22 PR
83 Dermatologic toxicity11 Grade3+
Nechushtan H Vainer G Stainberg H Salmon AY Hamburger T Peretz T A phase 12 of a combination of cetuximab and taxane for triple negative breast cancer patients Breast 2014 Aug23(4)435-8
Polyphor
Balixafortide (POL6326) + eribulin
CXCR4 antagonist + tubulin-based antimitotic
Heavily pretreatedRelapsed MBC
14-16
56
3rd line 3 chemo
3+3 dose escalation The highest dose was established as eribulin 14 mgmsup2 on days 2 and 9 and balixafortide 55 mgkg on days 1minus3 and 8minus10 of the 21-day cycle
30 PR
41 Gr34 Neutropenia11 Gr34 Leucopenia11 Gr34 Febrileneutropenia2 Related mortalities
42018 Fast Track (HER2-MBC failed 2 prior regimens)
Pernas S Martin M Kaufman PA Gil-Martin M Gomez Pardo P Lopez-Tarruella S Manso L Ciruelos E Perez-Fidalgo JA Hernando C Ademuyiwa FO Weilbaecher K Mayer I Pluard TJ Martinez Garcia M Vahdat L Perez-Garcia J Wach A Barker D Fung S Romagnoli B Cortes J Balixafortide plus eribulin in HER2-negative metastatic breast cancer a phase 1 single-arm dose-escalation trial Lancet Oncol 2018 Jun19(6)812-824
1 PRndashbut only + letrozoleNo Resp on monotherapy
61 Gr34 Neutropenia39 Gr34 Leucopenia
$933M (1Q18)$31B (2017)
Tamura K Mukai H Naito Y Yonemori K Kodaira M Tanabe Y Yamamoto N Osera S Sasaki M Mori Y Hashigaki S Nagasawa T Umeyama Y Yoshino T Phase I study of palbociclib a cyclin-dependent kinase 46 inhibitor in Japanese patients Cancer Sci 2016 Jun107(6)755-63 doi 101111cas12932 Epub 2016 May 11
Pfizer
Ibrancereg (palbociclib)
CDK 46 Inhibitor
HR+ HER2- MBC
Heavily pretreatedRelapsed Met Cancer
04-08
41 (5 BC)
chemo naiumlve (17)1-2(51) 3(29) 3+(2)
Palbociclib 25-150 mg dose ranging
0
20 Gr34 Neutropenia23 Gr34 Leucopenia
$933M (1Q18)$31B (2017)
Flaherty KT Lorusso PM Demichele A Abramson VG Courtney R Randolph SS Shaik MN Wilner KD ODwyer PJ Schwartz GK Phase I dose-escalation trial of the oral cyclin-dependent kinase 46 inhibitor PD 0332991 administered using a 21-day schedule in patients with advanced cancer Clin Cancer Res 2012 Jan 1518(2)568-76 doi 1011581078-0432CCR-11-0509 Epub 2011 Nov 16
Novartis
Kisqalireg (ribociclib)
CDK 46 Inhibitor
Premenopausal HR+ HER2- MBC
Heavily pretreatedRelapsed Met Cancer
16
132 (20 BC)
0-1 (25) 2-3 (42)4+ (32)
Ribociclib 50 mg ranging up to 1200 mg dose escalation
23 PR-included 1 BC (5 of BC pts)
27 Gr34 Neutropenia17 Gr34 Leucopenia
Peak sales est at $25B
Infante JR Cassier PA Gerecitano JF Witteveen PO Chugh R Ribrag V Chakraborty A Matano A Dobson JR Crystal AS Parasuraman S Shapiro GI A Phase I Study of the Cyclin-Dependent Kinase 46 Inhibitor Ribociclib (LEE011) in Patients with Advanced Solid Tumors and Lymphomas Clin Cancer Res 2016 Dec 122(23)5696-5705 Epub 2016 Aug 19
Eli Lilly
Verzenioreg (abemaciclib)
CDK 46 Inhibitor
HR+HER2minusMBC
Heavily pretreatedRelapsed Met Cancer
16
12 (1 BC)
1 (312) 2 (212) 3+(7)
Abemaciclib 100 mg ranging up to 200 mg dose escalation
17 PR (included 1 BC)
17 Gr34 Neutropenia33 Gr34 Leucopenia
Peak sales est at $2B
Fujiwara Y Tamura K Kondo S Tanabe Y Iwasa S Shimomura A Kitano S Ogasawara K Turner PK Mori J Asou H Chan EM Yamamoto N Phase 1 study of abemaciclib an inhibitor of CDK 4 and 6 as a single agent for Japanese patients with advanced cancer Cancer Chemother Pharmacol 2016 Aug78(2)281-8 doi 101007s00280-016-3085-8 Epub 2016 Jun 16
Mukai H Saeki T Shimada K Naito Y Matsubara N Nakanishi T Obaishi H Namiki M Sasaki Y Phase 1 combination study of eribulin mesylate with trastuzumab for advanced or recurrent human epidermal growth factor receptor 2 positive breast cancer Invest New Drugs 2015 Feb33(1)119-27
AstraZeneca
Lynparza (Olaparib) + Cediranib
PARP inhibitor + inhibitor of VEGF receptor tyrosine kinases
HR+ HER2- MBC
BC amp OC
2013
28 (8 BC)
3 for BC
Olaparib (a poly (ADP-ribose) polymerase (PARP) inhibitor) amp Cediranib (Vascular endothelial growth factor receptor (VEGFR) 1 2 and 3 tyrosine kinase inhibitor)3 at dose level (DL) 0 (cediranib 20mg olaparib 100mg) 3 at DL1 (cediranib 20mg olaparib 200mg) 7 at DL2 (cediranib 30mg olaparib 200mg) 6 at DL3 (cediranib 30mg olaparib 400mg)
Liu JF Tolaney SM Birrer M Fleming GF Buss MK Dahlberg SE Lee H Whalen C Tyburski K Winer E Ivy P Matulonis UA A Phase 1 trial of the poly(ADP-ribose) polymerase inhibitor olaparib (AZD2281) in combination with the anti-angiogenic cediranib (AZD2171) in recurrent epithelial ovarian or triple-negative breast cancer Eur J Cancer 2013 Sep49(14)2972-8
Reyon Pharmaceutical
VM206RY
Heterologous prime-boost with a truncated HER2 sequence
HER2+ Stage IIIampIV BC
2015
9
2 chemo
Plasmid DNA (pHM-GM-CSF expressing truncated HER2 amp GM-CSF) amp adenoviral vector (Ad-HM containing modified HER2) (2 4 and 8 mgpatientvisit) of pHM-GM-CSF 3x IM weeks 0 2 and 4 Ad-HM 3 times 109 virus particles at week 6
11 PR
4 pts showed 7 minor AEs
Unclear
Kim SB Ahn JH Kim J Jung KH A phase 1 study of a heterologous prime-boost vaccination involving a truncated HER2 sequence in patients with HER2-expressing breast cancer Mol Ther Methods Clin Dev 2015 Sep 30215031 doi 101038mtm201531 eCollection 2015
Rodon J Peacuterez-Fidalgo A Krop IE Burris H Guerrero-Zotano A Britten CD Becerra C Schellens J Richards DA Schuler M Abu-Khalaf M Johnson FM Ranson M Edenfield J Silva AP Hackl W Quadt C Demanse D Duval V Baselga J Phase 11b dose escalation and expansion study of BEZ235 a dual PI3KmTOR inhibitor in patients with advanced solid tumors including patients with advanced breast cancer Cancer Chemother Pharmacol 2018 Jun 7 doi 101007s00280-018-3610-z [Epub ahead of print]
Celgene (Abraxane)
Gemcitabine + Abraxane (nab-paclitaxel)
Chemo + Chemo
OC BC NSCLC amp Panc cancer + Lung OC BC Kaposi sarcoma
MBC
2016
9
Adjuvant chemo (100)chemo post-adjuvant (33)
Gem (nucleoside metabolic inhibitor 1250 mgm2) on days 1 and 8 nab-Pac (microtubule inhibitor) starting dose of 180 mgm2 (cohort 1) 220 mgm2 (cohort 2) and 260 mgm2 (cohort 3) on day 1 of the 21-day cycle using a 3 + 3 design
0
MTD not reached29 Gr3 Neutropenia59 Gr1 Peripheralneuropathy
Yoshitomi S Taira N Doihara H Mizoo T Nogami T Iwamoto T Motoki T Shien T Ogasawara Y Matsuoka J Tsuji H Mitsuhashi T A phase 1 dose-finding and pharmacokinetic study of gemcitabine with nab-paclitaxel in patients with metastatic breast cancer Cancer Chemother Pharmacol 2016 Aug78(2)289-94
Eli Lilly
Erbituxreg (cetuximab) + Taxane
EGFR inhibitor antineoplastic agent + Chemo
Headamp Neck Colorectal Cancer
TNBC
2007-2010
18
1 chemo
Cetuximab (epidermal growth factor receptor (EGFR) antagonist ) an initial loading dose of cetuximab 400 mgm2 followed by a weekly dose of 250 mgm2Paclitaxel (microtubule inhibitor) 80 mgm2 or Docetaxel at an initial dose of 30 mgm2 was administered weekly
56 CR 22 PR
83 Dermatologic toxicity11 Grade3+
Nechushtan H Vainer G Stainberg H Salmon AY Hamburger T Peretz T A phase 12 of a combination of cetuximab and taxane for triple negative breast cancer patients Breast 2014 Aug23(4)435-8
Polyphor
Balixafortide (POL6326) + eribulin
CXCR4 antagonist + tubulin-based antimitotic
Heavily pretreated Relapsed MBC
2014-2016
56
3rd line 3 chemo
3+3 dose escalation The highest dose was established as eribulin 14 mgmsup2 on days 2 and 9 and balixafortide 55 mgkg on days 1minus3 and 8minus10 of the 21-day cycle
30 PR
41 Gr34 Neutropenia11 Gr34 Leucopenia11 Gr34 Febrileneutropenia2 Related mortalities
Apr 2018 Fast Track for HER2-MBC who have failed 2prior regimens
Pernas S Martin M Kaufman PA Gil-Martin M Gomez Pardo P Lopez-Tarruella S Manso L Ciruelos E Perez-Fidalgo JA Hernando C Ademuyiwa FO Weilbaecher K Mayer I Pluard TJ Martinez Garcia M Vahdat L Perez-Garcia J Wach A Barker D Fung S Romagnoli B Cortes J Balixafortide plus eribulin in HER2-negative metastatic breast cancer a phase 1 single-arm dose-escalation trial Lancet Oncol 2018 Jun19(6)812-824
11 PRndashbut only + letrozole (No Resp on monotherapy)
61 Gr34 Neutropenia39 Gr34 Leucopenia
$933M in 1Q2018 $31B in 2017
Tamura K Mukai H Naito Y Yonemori K Kodaira M Tanabe Y Yamamoto N Osera S Sasaki M Mori Y Hashigaki S Nagasawa T Umeyama Y Yoshino T Phase I study of palbociclib a cyclin-dependent kinase 46 inhibitor in Japanese patients Cancer Sci 2016 Jun107(6)755-63 doi 101111cas12932 Epub 2016 May 11
Pfizer
Ibrancereg (palbociclib)
CDK 46 Inhibitor
HR+ HER2- MBC
Heavily pretreated Relapsed Metastatic Cancer
2004-2008
41 (5 BC)
chemo naiumlve (17) 1-2 (51)3 (29) 3+ (2)
Palbociclib 25-150 mg dose ranging
0
20 Gr34 Neutropenia23 Gr34 Leucopenia
$933M in 1Q2018 $31B in 2017
Flaherty KT Lorusso PM Demichele A Abramson VG Courtney R Randolph SS Shaik MN Wilner KD ODwyer PJ Schwartz GK Phase I dose-escalation trial of the oral cyclin-dependent kinase 46 inhibitor PD 0332991 administered using a 21-day schedule in patients with advanced cancer Clin Cancer Res 2012 Jan 1518(2)568-76 doi 1011581078-0432CCR-11-0509 Epub 2011 Nov 16
Novartis
Kisqalireg (ribociclib)
CDK 46 Inhibitors
Premenopausal HR+ HER2- MBC
Heavily pretreated Relapsed Metastatic Cancer
2016
132 (20 BC)
0-1 (25) 2-3 (42) 4+ (32)
Ribociclib 50 mg ranging up to 1200 mg dose escalation
23 PRndashincluded 1 in BC (5 of BC pts)
27 Gr34 Neutropenia17 Gr34 Leucopenia
Peak sales projected at $25B
Infante JR Cassier PA Gerecitano JF Witteveen PO Chugh R Ribrag V Chakraborty A Matano A Dobson JR Crystal AS Parasuraman S Shapiro GI A Phase I Study of the Cyclin-Dependent Kinase 46 Inhibitor Ribociclib (LEE011) in Patients with Advanced Solid Tumors and Lymphomas Clin Cancer Res 2016 Dec 122(23)5696-5705 Epub 2016 Aug 19
Eli Lilly
Verzenioreg (abemaciclib)
CDK 46 Inhibitors
HR+HER2minusMBC
Heavily pretreated Relapsed Metastatic Cancer
2016
12 (1 BC)
1 (312) 2 (212) 3+ (7)
Abemaciclib 100 mg ranging up to 200 mg dose escalation
17 PR (included 1 in BC)
17 Gr34 Neutropenia33 Gr34 Leucopenia
Peak sales projected at $2B
Fujiwara Y Tamura K Kondo S Tanabe Y Iwasa S Shimomura A Kitano S Ogasawara K Turner PK Mori J Asou H Chan EM Yamamoto N Phase 1 study of abemaciclib an inhibitor of CDK 4 and 6 as a single agent for Japanese patients with advanced cancer Cancer Chemother Pharmacol 2016 Aug78(2)281-8 doi 101007s00280-016-3085-8 Epub 2016 Jun 16
Mukai H Saeki T Shimada K Naito Y Matsubara N Nakanishi T Obaishi H Namiki M Sasaki Y Phase 1 combination study of eribulin mesylate with trastuzumab for advanced or recurrent human epidermal growth factor receptor 2 positive breast cancer Invest New Drugs 2015 Feb33(1)119-27
AstraZeneca
Lynparza (Olaparib)+ Cediranib
PARP inhibitor+ inhibitor of VEGF RTK
HR+ HER2- MBC
BC amp OC
13
28 (8 BC)
3 for BC
Olaparib (a poly (ADP-ribose) polymerase (PARP) inhibitor) amp Cediranib (Vascular endothelial growth factor receptor (VEGFR) 1 2 and 3 tyrosine kinase inhibitor)3 at dose level (DL) 0 (cediranib 20mg olaparib 100mg) 3 at DL1 (cediranib 20mg olaparib 200mg) 7 at DL2 (cediranib 30mg olaparib 200mg) 6 at DL3 (cediranib 30mg olaparib 400mg)
Liu JF Tolaney SM Birrer M Fleming GF Buss MK Dahlberg SE Lee H Whalen C Tyburski K Winer E Ivy P Matulonis UA A Phase 1 trial of the poly(ADP-ribose) polymerase inhibitor olaparib (AZD2281) in combination with the anti-angiogenic cediranib (AZD2171) in recurrent epithelial ovarian or triple-negative breast cancer Eur J Cancer 2013 Sep49(14)2972-8
ReyonPharma
VM206RY
Heterologous prime-boost with a truncated HER2 sequence
HER2+ Stg IIIampIV BC
15
9
2 chemo
Plasmid DNA (pHM-GM-CSF expressing truncated HER2 amp GM-CSF) amp adenoviral vector (Ad-HM containing modified HER2) (2 4 and 8 mgpatientvisit) of pHM-GM-CSF 3x IM weeks 0 2 and 4 Ad-HM 3 times 109 virus particles at week 6
11 PR
4 pts 7 minor AEs
Unclear
Kim SB Ahn JH Kim J Jung KH A phase 1 study of a heterologous prime-boost vaccination involving a truncated HER2 sequence in patients with HER2-expressing breast cancer Mol Ther Methods Clin Dev 2015 Sep 30215031 doi 101038mtm201531 eCollection 2015
Rodon J Peacuterez-Fidalgo A Krop IE Burris H Guerrero-Zotano A Britten CD Becerra C Schellens J Richards DA Schuler M Abu-Khalaf M Johnson FM Ranson M Edenfield J Silva AP Hackl W Quadt C Demanse D Duval V Baselga J Phase 11b dose escalation and expansion study of BEZ235 a dual PI3KmTOR inhibitor in patients with advanced solid tumors including patients with advanced breast cancer Cancer Chemother Pharmacol 2018 Jun 7 doi 101007s00280-018-3610-z [Epub ahead of print]
Celgene(Abraxane)
Gemcitabine + Abraxane (nab-paclitaxel)
Chemo+ Chemo
OC BC NSCLC PC + LC OC BC KS
MBC
16
9
Adjuv chemo (100)chemo post-adjuv (33)
Gem (nucleoside metabolic inhibitor 1250 mgm2) on days 1 and 8 nab-Pac (microtubule inhibitor) starting dose of 180 mgm2 (cohort 1) 220 mgm2 (cohort 2) and 260 mgm2 (cohort 3) on day 1 of the 21-day cycle using a 3 + 3 design
0
MTD not reached29 Gr3 Neutropenia59 Gr1 Peripheralneuropathy
Yoshitomi S Taira N Doihara H Mizoo T Nogami T Iwamoto T Motoki T Shien T Ogasawara Y Matsuoka J Tsuji H Mitsuhashi T A phase 1 dose-finding and pharmacokinetic study of gemcitabine with nab-paclitaxel in patients with metastatic breast cancer Cancer Chemother Pharmacol 2016 Aug78(2)289-94
Eli Lilly
Erbituxreg (cetuximab) + Taxane
EGFR inhibitor antineoplastic agent + Chemo
Head amp NeckColorectal
TNBC
07-10
18
1 chemo
Cetuximab (epidermal growth factor receptor (EGFR) antagonist ) an initial loading dose of cetuximab 400 mgm2 followed by a weekly dose of 250 mgm2Paclitaxel (microtubule inhibitor) 80 mgm2 or Docetaxel at an initial dose of 30 mgm2 was administered weekly
56 CR 22 PR
83 Dermatologic toxicity11 Grade3+
Nechushtan H Vainer G Stainberg H Salmon AY Hamburger T Peretz T A phase 12 of a combination of cetuximab and taxane for triple negative breast cancer patients Breast 2014 Aug23(4)435-8
Polyphor
Balixafortide (POL6326) + eribulin
CXCR4 antagonist + tubulin-based antimitotic
Heavily pretreatedRelapsed MBC
14-16
56
3rd line 3 chemo
3+3 dose escalation The highest dose was established as eribulin 14 mgmsup2 on days 2 and 9 and balixafortide 55 mgkg on days 1minus3 and 8minus10 of the 21-day cycle
30 PR
41 Gr34 Neutropenia11 Gr34 Leucopenia11 Gr34 Febrileneutropenia2 Related mortalities
42018 Fast Track (HER2-MBC failed 2 prior regimens)
Pernas S Martin M Kaufman PA Gil-Martin M Gomez Pardo P Lopez-Tarruella S Manso L Ciruelos E Perez-Fidalgo JA Hernando C Ademuyiwa FO Weilbaecher K Mayer I Pluard TJ Martinez Garcia M Vahdat L Perez-Garcia J Wach A Barker D Fung S Romagnoli B Cortes J Balixafortide plus eribulin in HER2-negative metastatic breast cancer a phase 1 single-arm dose-escalation trial Lancet Oncol 2018 Jun19(6)812-824
1 PRndashbut only + letrozoleNo Resp on monotherapy
61 Gr34 Neutropenia39 Gr34 Leucopenia
$933M (1Q18)$31B (2017)
Tamura K Mukai H Naito Y Yonemori K Kodaira M Tanabe Y Yamamoto N Osera S Sasaki M Mori Y Hashigaki S Nagasawa T Umeyama Y Yoshino T Phase I study of palbociclib a cyclin-dependent kinase 46 inhibitor in Japanese patients Cancer Sci 2016 Jun107(6)755-63 doi 101111cas12932 Epub 2016 May 11
Pfizer
Ibrancereg (palbociclib)
CDK 46 Inhibitor
HR+ HER2- MBC
Heavily pretreatedRelapsed Met Cancer
04-08
41 (5 BC)
chemo naiumlve (17)1-2(51) 3(29) 3+(2)
Palbociclib 25-150 mg dose ranging
0
20 Gr34 Neutropenia23 Gr34 Leucopenia
$933M (1Q18)$31B (2017)
Flaherty KT Lorusso PM Demichele A Abramson VG Courtney R Randolph SS Shaik MN Wilner KD ODwyer PJ Schwartz GK Phase I dose-escalation trial of the oral cyclin-dependent kinase 46 inhibitor PD 0332991 administered using a 21-day schedule in patients with advanced cancer Clin Cancer Res 2012 Jan 1518(2)568-76 doi 1011581078-0432CCR-11-0509 Epub 2011 Nov 16
Novartis
Kisqalireg (ribociclib)
CDK 46 Inhibitor
Premenopausal HR+ HER2- MBC
Heavily pretreatedRelapsed Met Cancer
16
132 (20 BC)
0-1 (25) 2-3 (42)4+ (32)
Ribociclib 50 mg ranging up to 1200 mg dose escalation
23 PR-included 1 BC (5 of BC pts)
27 Gr34 Neutropenia17 Gr34 Leucopenia
Peak sales est at $25B
Infante JR Cassier PA Gerecitano JF Witteveen PO Chugh R Ribrag V Chakraborty A Matano A Dobson JR Crystal AS Parasuraman S Shapiro GI A Phase I Study of the Cyclin-Dependent Kinase 46 Inhibitor Ribociclib (LEE011) in Patients with Advanced Solid Tumors and Lymphomas Clin Cancer Res 2016 Dec 122(23)5696-5705 Epub 2016 Aug 19
Eli Lilly
Verzenioreg (abemaciclib)
CDK 46 Inhibitor
HR+HER2minusMBC
Heavily pretreatedRelapsed Met Cancer
16
12 (1 BC)
1 (312) 2 (212) 3+(7)
Abemaciclib 100 mg ranging up to 200 mg dose escalation
17 PR (included 1 BC)
17 Gr34 Neutropenia33 Gr34 Leucopenia
Peak sales est at $2B
Fujiwara Y Tamura K Kondo S Tanabe Y Iwasa S Shimomura A Kitano S Ogasawara K Turner PK Mori J Asou H Chan EM Yamamoto N Phase 1 study of abemaciclib an inhibitor of CDK 4 and 6 as a single agent for Japanese patients with advanced cancer Cancer Chemother Pharmacol 2016 Aug78(2)281-8 doi 101007s00280-016-3085-8 Epub 2016 Jun 16
Patient B001 Breast 70 No 1101 - 3501 4001 Negative -
Bria-IMTtradeHuman Proof-of-Concept Trials in Breast Cancer (Patient A002)
24
Proof-of-Concept Results Resulted in BriaCellrsquos Immunotherapy Strategy Use BriaDXtrade diagnostic to select only those patients matching Bria-IMTtrade Use BriaDXtrade diagnostic test to select Bria-OTStrade alleles matching ~90 of all patients
Bria-IMTtradeCurrent Phase IIIa Data Supports HLA Matching Hypothesis Six patients treated in 2017 Bria-IMTtrade was safe and well tolerated
Patient 01-002 73-year-old woman with breast cancer diagnosed in 1995 Developed liver metastases in2010 and lung metastases in 2017 Previously treated with 7 rounds of chemotherapy with 8 differentchemotherapy agents Received 5 cycles of Bria-IMTtrade over 3 months then monthly cycles (6 months total)Evaluated after 3 months and 6 months After 3 months despite the extensive prior therapy her scans notedthat ldquothere has been a clear response in the multiple bilateral pulmonary nodulesrdquo The response wasmaintained after 6 months of Bria-IMTtrade treatment She matches Bria-IMTtrade at 2 HLA alleles
The liver tumors were stable to slightly increased at 3 months and then progressed after 6 months
This supports our hypothesis of heightened anti-tumor activity in patients with a matched HLA types Clear path to develop BriaDXtrade to select the patients using HLA testing
1 RLL 29 Not Detectable Not Detectable2 LUL apical pleural based 34 tiny nodule lt 1mm scar tiny nodule lt 1mm scar3 xxx 39 Not Detectable Not Detectable4 40 Not Detectable Not Detectable5 RLL 45 Not Detectable Not Detectable6 LLL 49 Not Detectable Not Detectable7 xxx 52 Not Detectable Not Detectable8 RLL 52 Not Detectable Not Detectable9 RLL 56 Not Detectable Not Detectable
10 RLL costophrenic recess 56 Not Detectable Not Detectable11 XXX 58 Not Detectable Not Detectable12 LUL 60 Not Detectable Not Detectable13 XXX 67 15 1514 RUL 72 15 1515 LLL 76 Not Detectable Not Detectable16 RUL Noncalcified Nodule 77 Not Detectable Not Detectable17 RLL costophrenic recess 79 10 1018 RUL 82 Not Detectable Not Detectable19 RLL 90 Not Detectable Not Detectable20 RLL 91 lt 01 lt 0121 xxx xxx Not Detectable Not Detectable
27
Clinical Development Update ndash Summary 2018 September 26
Completed enrollment of Adv Breast cancer patients in the Phase IIIa ldquomonotherapyrdquo study of Bria-IMTtrade
We have confirmed our mechanism of action and achieved proof of concept
Initial safety data appears superior to that of the other advanced or approved drugs for breast cancer when they were at a similar clinical stage of development
Initial efficacy data is similar or superior to those of other advanced or approved drugs for breast cancer when they were at a similar clinical stage of development
Initiated Combination Study of Bria-IMTtrade with Keytrudareg or Yervoyreg in Adv breast cancer patients expecting even better response rates than those in the ldquomonotherapyrdquo study Initial safety data is expected in 4Q2018 Initial efficacy data is expected in 1Q2019
Bria-OTStrade the first off-the-shelf personalized treatment for advanced breast cancer is expected to enter the clinic in 2019
28
Bria-IMTtrade Excellent Safety Data - To Date
To date Bria-IMTtrade has been dosed in 24 patients (4 in 2004-2005 20 in 2017-2018)
Interim Data (20 patients)-Ongoing Phase IIIa Study (2017-2018)
Bria-IMTtrade has been very well tolerated (ge60 doses given to date) The majority of adverse events (AEs) were limited to expected minor local irritation at the
injection sites No related grade gt3 or unexpected AEs No related serious AEs No serious unexpected related AEs Most patients who have dropped out did so due to worsening of their underlying disease
Based on the current study Bria-IMTtrade has an excellent safety profile
29
Bria-IMTtrade - Efficacy as Predicted
Interim Data (19 patients)-Ongoing Phase IIIa Study (2017-2018) amp Original Study (2004-2005)
PD-L1 expression on circulating cancer cells amp cancer-associated cells in 100 of patients (to date) Strong rationale for combination with checkpoint inhibitors like Keytruda
30
Bria-IMTtrade appears to be most effective in patients who match with Bria-IMT trade at 2 HLA loci (types) further supporting our ldquoHLA Matching Hypothesisrdquo and the development of Bria-OTS trade to cover 90 of the patient population
Combination with immune checkpoint inhibitors may induce a more potent anti-cancer response leading to our strategy of combination studies of Bria-IMT trade with Keytruda or Yervoy
Patients (n) HLA Match
Tumor Shrinkage
Biological Response
4 ge2 50 7515 ge1 27 334 0 0 0
Biological response includes tumor shrinkage or lower circulating cancer associated cells
The confirmatory Bria-IMTtrade monotherapy Phase IIa trial has completed enrollment Additional Support for the HLA-matching hypothesis has been obtained
Bria-IMTtrade Combination Therapy study with immune checkpoint inhibitors Keytrudareg if PD-L12 positive (ge1) Yervoyreg if PD-L12 negative (lt1) Accepting patients from the monotherapy study who develop progressive disease Also enrolling patients directly into this study to enhance experience with the combination In discussion with other pharmaceutical companies to evaluate additional combinations with other
immunotherapies
Bria-OTStrade Off-the-Shelf Personalized Targeted Immunotherapy Developing Bria-OTStrade to co-express GM-CSF and interferon-α Pre-manufacture additional HLA alleles ndash Total of 15 alleles (8 Class I and 7 Class II) Co-development of BriaDXtrade companion diagnostic for HLA typing Combination therapy clinical trial with immune checkpoint inhibitors for non-responders using
information from the Bria-IMTtrade Combination Therapy Study
33
Development Timeline ndash Breast Cancer
20192018 2020 2021
Phase IIIaBria-IMTtrade
Monotherapy
Currently Enrolling Phase IIaBria-IMTtrade + Checkpoint
Currently in discussions with potential partnersPhase II Bria-IMTtrade plus Additional Combinations (1Q19 4Q22)(eg PD-1 Inhibitor PD-L1 inhibitor anti-CTLA4 anti-GITR anti-OX40)
1Q 2Q 3Q 4Q
2023
Bria-OTStrade Off-The-Shelf Personalized ImmunotherapyMonotherapy and Potential Partnered Combo Therapy
(2H19 Ongoing)
Bria-OTStradeOff-the-Shelf Cell Line cGMP Manufacturing
and BriaDXtrade(1Q18 1Q19)
Registration Studies (1Q20 2H22)Bria-IMTtrade with Checkpoint InhibitorsBria-OTStrade +- Checkpoint Inhibitors
34
Immuno-oncology Deals
Recent deals of small biotechs with big pharma in immuno-oncology
35
Date PartnershipDevelopment stage at the time of the deal Deal size
07122018 Immatics-Genmab Preclinical Up to $28B
04042018 OSE Immunotherapeutics-Boehringer Ingelheim Preclinical Up to euro113B ($139B)
02092018 Pieris Pharmaceuticals-Seattle Genetics Preclinical Up to $123B
2142018 Nektar-BMS Ph III Up to $36B
01222018 Juno-Celgene Ph II $9B (Acquisition)
11142017 Loxo-Bayer Larotrectinib (Ph II) LOXO-195 (Ph III) Up to $155B
1032017 CytomX-Amgen Preclinical Up to $15B
03202017 CytomX--BMS Ph III Up to $36B
6282016 Xencor-Novartis Preclinical Up to $24B
Early Stage Clinical Studies (Comparison)
We compared the interim data of Ph IIIa study of Bria-IMTtrade in advanced breast cancer with thedata in the early stage clinical studies of recently approved breast cancer drugs and one fasttracked product candidate
Apples to apples comparison Early Stage Clinical Studies in oncology are typically done in patientswith no other therapeutic options Thus the patients have very advanced disease and response ratesare typically quite low
The patients in our Ph IIIa study have been heavily pre-treated (median 45 prior regimens)Some recent studies of relevance in breast cancer are noted in the following slides
36
Breast Cancer Market Opportunity
Drug Technology Approved for Market (US)Ibrance (palbociclib) CDK 46 Inhibitor HR+HER2- MBC in combination with
fluvestrant or aromatase inhibitor$933M in 1Q2018 $3126M in 2017
Kisqali (ribociclib) CDK 46 Inhibitor 2017 HR+HER2- MBC in combination with fluvestrant or aromatase inhibitor
Peak sales projected at $25B
Verzenio (abemaciclib) CDK 46 Inhibitor 2017 HR+HER2- MBC in combination with fluvestrant or aromatase inhibitor
balixafortide CXCR4 antagonist Fast track designation in 2018 for HER2- MBC who have failed 2 prior regimens
The market for breast cancer drugs is a multibillion dollar market with new drugs being approvedon an ongoing basis indicating the shortage of safe and effective treatments for this deadly disease
37
Competitors- Phase III Clinical Data Bria-IMTtrade shows superior safety and similar to superior efficacy data compared with those of the multi-billion dollar drugs when they were at a similar early stage of clinical development
Injection site reactions No related SAEs or SUSARs
Tumor vol darr ampor darr circul tumor cellsAll Comers 21(419) 26(519)One or More HLA matches 27(415) 33(515)Two or More HLA matches 50 (24) 75 (34)
Sheet1 (3)
Comp -Slides
Data
HLA (2)
HLA
Data (Ph1-2+4Pt)
Competitors (2018)-Slide
Competitors (2018)
In the Pipeline Protein Kinase C delta (PKCδ) Inhibitors
30 of all human malignancies display activating RAS mutations Another 60 showing over-activity of Ras-signaling pathways
Ras has been termed ldquoundruggablerdquo (no one has been able to make a Ras inhibitor drug)
BriaCellrsquos novel proprietary PKCδ inhibitors have shown activity against multiple RAS transformed tumors Lung cancer Melanoma Breast cancer Neuroendocrine cancer Pancreatic cancer Colorectal cancer
This target has an attractive safety profile based on in vivo studies and knock out mouse studies
PKCδ inhibitors should qualify for an accelerated clinical development plan and regulatory pathway
Could be in clinic within 24 months
Cost-Effective Additional Shot-on-Goal and additional partnership opportunities
Early-Stage Preclinical Program
39
Protein Kinase C delta (PKCδ) Inhibitors
Activated PKCδ inhibits RAS degradation which in turn stimulates tumor growth
Koo et al Oncotarget 621328 2016
30 of all human malignancies display activating RASmutations with another 60 showing over-activity of Ras-signaling pathways
BriaCellrsquos novel proprietary PKCδ inhibitors have shownactivity against multiple RAS transformed tumors
This target has an attractive safety profile based on in vivostudies and knock out mouse studies
PKCδ also has potential activity as an immunotherapeuticby blocking TGFβ signaling
PKCδ inhibitors are applicable to specific niche tumor typeswhich provide an accelerated clinical development plan
Structural aspects of first generation inhibitor rottlerin and staurosporine (pan-PKC activator) were combined to create second generation inhibitor KAM1
Third generation inhibitors such as BJE6-106 have improved potency and selectivity Fourth generation inhibitors under development to optimize drug-like characteristics PKCδ inhibitors lack endothelial cell cytotoxicity amp PKCδ deficient mice develop normally and are fertile Potentially no marked intrinsic toxicity by inhibiting PKCδ
Mukai H Saeki T Shimada K Naito Y Matsubara N Nakanishi T Obaishi H Namiki M Sasaki Y Phase 1 combination study of eribulin mesylate with trastuzumab for advanced or recurrent human epidermal growth factor receptor 2 positive breast cancer Invest New Drugs 2015 Feb33(1)119-27
AstraZeneca
Lynparza (Olaparib) + Cediranib
PARP inhibitor + inhibitor of VEGF receptor tyrosine kinases
HR+ HER2- MBC
BC amp OC
2013
28 (8 BC)
3 for BC
Olaparib (a poly (ADP-ribose) polymerase (PARP) inhibitor) amp Cediranib (Vascular endothelial growth factor receptor (VEGFR) 1 2 and 3 tyrosine kinase inhibitor)3 at dose level (DL) 0 (cediranib 20mg olaparib 100mg) 3 at DL1 (cediranib 20mg olaparib 200mg) 7 at DL2 (cediranib 30mg olaparib 200mg) 6 at DL3 (cediranib 30mg olaparib 400mg)
Liu JF Tolaney SM Birrer M Fleming GF Buss MK Dahlberg SE Lee H Whalen C Tyburski K Winer E Ivy P Matulonis UA A Phase 1 trial of the poly(ADP-ribose) polymerase inhibitor olaparib (AZD2281) in combination with the anti-angiogenic cediranib (AZD2171) in recurrent epithelial ovarian or triple-negative breast cancer Eur J Cancer 2013 Sep49(14)2972-8
Reyon Pharmaceutical
VM206RY
Heterologous prime-boost with a truncated HER2 sequence
HER2+ Stage IIIampIV BC
2015
9
2 chemo
Plasmid DNA (pHM-GM-CSF expressing truncated HER2 amp GM-CSF) amp adenoviral vector (Ad-HM containing modified HER2) (2 4 and 8 mgpatientvisit) of pHM-GM-CSF 3x IM weeks 0 2 and 4 Ad-HM 3 times 109 virus particles at week 6
11 PR
4 pts showed 7 minor AEs
Unclear
Kim SB Ahn JH Kim J Jung KH A phase 1 study of a heterologous prime-boost vaccination involving a truncated HER2 sequence in patients with HER2-expressing breast cancer Mol Ther Methods Clin Dev 2015 Sep 30215031 doi 101038mtm201531 eCollection 2015
Rodon J Peacuterez-Fidalgo A Krop IE Burris H Guerrero-Zotano A Britten CD Becerra C Schellens J Richards DA Schuler M Abu-Khalaf M Johnson FM Ranson M Edenfield J Silva AP Hackl W Quadt C Demanse D Duval V Baselga J Phase 11b dose escalation and expansion study of BEZ235 a dual PI3KmTOR inhibitor in patients with advanced solid tumors including patients with advanced breast cancer Cancer Chemother Pharmacol 2018 Jun 7 doi 101007s00280-018-3610-z [Epub ahead of print]
Celgene (Abraxane)
Gemcitabine + Abraxane (nab-paclitaxel)
Chemo + Chemo
OC BC NSCLC amp Panc cancer + Lung OC BC Kaposi sarcoma
MBC
2016
9
Adjuvant chemo (100)chemo post-adjuvant (33)
Gem (nucleoside metabolic inhibitor 1250 mgm2) on days 1 and 8 nab-Pac (microtubule inhibitor) starting dose of 180 mgm2 (cohort 1) 220 mgm2 (cohort 2) and 260 mgm2 (cohort 3) on day 1 of the 21-day cycle using a 3 + 3 design
0
MTD not reached29 Gr3 Neutropenia59 Gr1 Peripheralneuropathy
Yoshitomi S Taira N Doihara H Mizoo T Nogami T Iwamoto T Motoki T Shien T Ogasawara Y Matsuoka J Tsuji H Mitsuhashi T A phase 1 dose-finding and pharmacokinetic study of gemcitabine with nab-paclitaxel in patients with metastatic breast cancer Cancer Chemother Pharmacol 2016 Aug78(2)289-94
Eli Lilly
Erbituxreg (cetuximab) + Taxane
EGFR inhibitor antineoplastic agent + Chemo
Headamp Neck Colorectal Cancer
TNBC
2007-2010
18
1 chemo
Cetuximab (epidermal growth factor receptor (EGFR) antagonist ) an initial loading dose of cetuximab 400 mgm2 followed by a weekly dose of 250 mgm2Paclitaxel (microtubule inhibitor) 80 mgm2 or Docetaxel at an initial dose of 30 mgm2 was administered weekly
56 CR 22 PR
83 Dermatologic toxicity11 Grade3+
Nechushtan H Vainer G Stainberg H Salmon AY Hamburger T Peretz T A phase 12 of a combination of cetuximab and taxane for triple negative breast cancer patients Breast 2014 Aug23(4)435-8
Polyphor
Balixafortide (POL6326) + eribulin
CXCR4 antagonist + tubulin-based antimitotic
Heavily pretreated Relapsed MBC
2014-2016
56
3rd line 3 chemo
3+3 dose escalation The highest dose was established as eribulin 14 mgmsup2 on days 2 and 9 and balixafortide 55 mgkg on days 1minus3 and 8minus10 of the 21-day cycle
30 PR
41 Gr34 Neutropenia11 Gr34 Leucopenia11 Gr34 Febrileneutropenia2 Related mortalities
Apr 2018 Fast Track for HER2-MBC who have failed 2prior regimens
Pernas S Martin M Kaufman PA Gil-Martin M Gomez Pardo P Lopez-Tarruella S Manso L Ciruelos E Perez-Fidalgo JA Hernando C Ademuyiwa FO Weilbaecher K Mayer I Pluard TJ Martinez Garcia M Vahdat L Perez-Garcia J Wach A Barker D Fung S Romagnoli B Cortes J Balixafortide plus eribulin in HER2-negative metastatic breast cancer a phase 1 single-arm dose-escalation trial Lancet Oncol 2018 Jun19(6)812-824
11 PRndashbut only + letrozole (No Resp on monotherapy)
61 Gr34 Neutropenia39 Gr34 Leucopenia
$933M in 1Q2018 $31B in 2017
Tamura K Mukai H Naito Y Yonemori K Kodaira M Tanabe Y Yamamoto N Osera S Sasaki M Mori Y Hashigaki S Nagasawa T Umeyama Y Yoshino T Phase I study of palbociclib a cyclin-dependent kinase 46 inhibitor in Japanese patients Cancer Sci 2016 Jun107(6)755-63 doi 101111cas12932 Epub 2016 May 11
Pfizer
Ibrancereg (palbociclib)
CDK 46 Inhibitor
HR+ HER2- MBC
Heavily pretreated Relapsed Metastatic Cancer
2004-2008
41 (5 BC)
chemo naiumlve (17) 1-2 (51)3 (29) 3+ (2)
Palbociclib 25-150 mg dose ranging
0
20 Gr34 Neutropenia23 Gr34 Leucopenia
$933M in 1Q2018 $31B in 2017
Flaherty KT Lorusso PM Demichele A Abramson VG Courtney R Randolph SS Shaik MN Wilner KD ODwyer PJ Schwartz GK Phase I dose-escalation trial of the oral cyclin-dependent kinase 46 inhibitor PD 0332991 administered using a 21-day schedule in patients with advanced cancer Clin Cancer Res 2012 Jan 1518(2)568-76 doi 1011581078-0432CCR-11-0509 Epub 2011 Nov 16
Novartis
Kisqalireg (ribociclib)
CDK 46 Inhibitors
Premenopausal HR+ HER2- MBC
Heavily pretreated Relapsed Metastatic Cancer
2016
132 (20 BC)
0-1 (25) 2-3 (42) 4+ (32)
Ribociclib 50 mg ranging up to 1200 mg dose escalation
23 PRndashincluded 1 in BC (5 of BC pts)
27 Gr34 Neutropenia17 Gr34 Leucopenia
Peak sales projected at $25B
Infante JR Cassier PA Gerecitano JF Witteveen PO Chugh R Ribrag V Chakraborty A Matano A Dobson JR Crystal AS Parasuraman S Shapiro GI A Phase I Study of the Cyclin-Dependent Kinase 46 Inhibitor Ribociclib (LEE011) in Patients with Advanced Solid Tumors and Lymphomas Clin Cancer Res 2016 Dec 122(23)5696-5705 Epub 2016 Aug 19
Eli Lilly
Verzenioreg (abemaciclib)
CDK 46 Inhibitors
HR+HER2minusMBC
Heavily pretreated Relapsed Metastatic Cancer
2016
12 (1 BC)
1 (312) 2 (212) 3+ (7)
Abemaciclib 100 mg ranging up to 200 mg dose escalation
17 PR (included 1 in BC)
17 Gr34 Neutropenia33 Gr34 Leucopenia
Peak sales projected at $2B
Fujiwara Y Tamura K Kondo S Tanabe Y Iwasa S Shimomura A Kitano S Ogasawara K Turner PK Mori J Asou H Chan EM Yamamoto N Phase 1 study of abemaciclib an inhibitor of CDK 4 and 6 as a single agent for Japanese patients with advanced cancer Cancer Chemother Pharmacol 2016 Aug78(2)281-8 doi 101007s00280-016-3085-8 Epub 2016 Jun 16
Mukai H Saeki T Shimada K Naito Y Matsubara N Nakanishi T Obaishi H Namiki M Sasaki Y Phase 1 combination study of eribulin mesylate with trastuzumab for advanced or recurrent human epidermal growth factor receptor 2 positive breast cancer Invest New Drugs 2015 Feb33(1)119-27
AstraZeneca
Lynparza (Olaparib)+ Cediranib
PARP inhibitor+ inhibitor of VEGF RTK
HR+ HER2- MBC
BC amp OC
13
28 (8 BC)
3 for BC
Olaparib (a poly (ADP-ribose) polymerase (PARP) inhibitor) amp Cediranib (Vascular endothelial growth factor receptor (VEGFR) 1 2 and 3 tyrosine kinase inhibitor)3 at dose level (DL) 0 (cediranib 20mg olaparib 100mg) 3 at DL1 (cediranib 20mg olaparib 200mg) 7 at DL2 (cediranib 30mg olaparib 200mg) 6 at DL3 (cediranib 30mg olaparib 400mg)
Liu JF Tolaney SM Birrer M Fleming GF Buss MK Dahlberg SE Lee H Whalen C Tyburski K Winer E Ivy P Matulonis UA A Phase 1 trial of the poly(ADP-ribose) polymerase inhibitor olaparib (AZD2281) in combination with the anti-angiogenic cediranib (AZD2171) in recurrent epithelial ovarian or triple-negative breast cancer Eur J Cancer 2013 Sep49(14)2972-8
ReyonPharma
VM206RY
Heterologous prime-boost with a truncated HER2 sequence
HER2+ Stg IIIampIV BC
15
9
2 chemo
Plasmid DNA (pHM-GM-CSF expressing truncated HER2 amp GM-CSF) amp adenoviral vector (Ad-HM containing modified HER2) (2 4 and 8 mgpatientvisit) of pHM-GM-CSF 3x IM weeks 0 2 and 4 Ad-HM 3 times 109 virus particles at week 6
11 PR
4 pts 7 minor AEs
Unclear
Kim SB Ahn JH Kim J Jung KH A phase 1 study of a heterologous prime-boost vaccination involving a truncated HER2 sequence in patients with HER2-expressing breast cancer Mol Ther Methods Clin Dev 2015 Sep 30215031 doi 101038mtm201531 eCollection 2015
Rodon J Peacuterez-Fidalgo A Krop IE Burris H Guerrero-Zotano A Britten CD Becerra C Schellens J Richards DA Schuler M Abu-Khalaf M Johnson FM Ranson M Edenfield J Silva AP Hackl W Quadt C Demanse D Duval V Baselga J Phase 11b dose escalation and expansion study of BEZ235 a dual PI3KmTOR inhibitor in patients with advanced solid tumors including patients with advanced breast cancer Cancer Chemother Pharmacol 2018 Jun 7 doi 101007s00280-018-3610-z [Epub ahead of print]
Celgene(Abraxane)
Gemcitabine + Abraxane (nab-paclitaxel)
Chemo+ Chemo
OC BC NSCLC PC + LC OC BC KS
MBC
16
9
Adjuv chemo (100)chemo post-adjuv (33)
Gem (nucleoside metabolic inhibitor 1250 mgm2) on days 1 and 8 nab-Pac (microtubule inhibitor) starting dose of 180 mgm2 (cohort 1) 220 mgm2 (cohort 2) and 260 mgm2 (cohort 3) on day 1 of the 21-day cycle using a 3 + 3 design
0
MTD not reached29 Gr3 Neutropenia59 Gr1 Peripheralneuropathy
Yoshitomi S Taira N Doihara H Mizoo T Nogami T Iwamoto T Motoki T Shien T Ogasawara Y Matsuoka J Tsuji H Mitsuhashi T A phase 1 dose-finding and pharmacokinetic study of gemcitabine with nab-paclitaxel in patients with metastatic breast cancer Cancer Chemother Pharmacol 2016 Aug78(2)289-94
Eli Lilly
Erbituxreg (cetuximab) + Taxane
EGFR inhibitor antineoplastic agent + Chemo
Head amp NeckColorectal
TNBC
07-10
18
1 chemo
Cetuximab (epidermal growth factor receptor (EGFR) antagonist ) an initial loading dose of cetuximab 400 mgm2 followed by a weekly dose of 250 mgm2Paclitaxel (microtubule inhibitor) 80 mgm2 or Docetaxel at an initial dose of 30 mgm2 was administered weekly
56 CR 22 PR
83 Dermatologic toxicity11 Grade3+
Nechushtan H Vainer G Stainberg H Salmon AY Hamburger T Peretz T A phase 12 of a combination of cetuximab and taxane for triple negative breast cancer patients Breast 2014 Aug23(4)435-8
Polyphor
Balixafortide (POL6326) + eribulin
CXCR4 antagonist + tubulin-based antimitotic
Heavily pretreatedRelapsed MBC
14-16
56
3rd line 3 chemo
3+3 dose escalation The highest dose was established as eribulin 14 mgmsup2 on days 2 and 9 and balixafortide 55 mgkg on days 1minus3 and 8minus10 of the 21-day cycle
30 PR
41 Gr34 Neutropenia11 Gr34 Leucopenia11 Gr34 Febrileneutropenia2 Related mortalities
42018 Fast Track (HER2-MBC failed 2 prior regimens)
Pernas S Martin M Kaufman PA Gil-Martin M Gomez Pardo P Lopez-Tarruella S Manso L Ciruelos E Perez-Fidalgo JA Hernando C Ademuyiwa FO Weilbaecher K Mayer I Pluard TJ Martinez Garcia M Vahdat L Perez-Garcia J Wach A Barker D Fung S Romagnoli B Cortes J Balixafortide plus eribulin in HER2-negative metastatic breast cancer a phase 1 single-arm dose-escalation trial Lancet Oncol 2018 Jun19(6)812-824
1 PRndashbut only + letrozoleNo Resp on monotherapy
61 Gr34 Neutropenia39 Gr34 Leucopenia
$933M (1Q18)$31B (2017)
Tamura K Mukai H Naito Y Yonemori K Kodaira M Tanabe Y Yamamoto N Osera S Sasaki M Mori Y Hashigaki S Nagasawa T Umeyama Y Yoshino T Phase I study of palbociclib a cyclin-dependent kinase 46 inhibitor in Japanese patients Cancer Sci 2016 Jun107(6)755-63 doi 101111cas12932 Epub 2016 May 11
Pfizer
Ibrancereg (palbociclib)
CDK 46 Inhibitor
HR+ HER2- MBC
Heavily pretreatedRelapsed Met Cancer
04-08
41 (5 BC)
chemo naiumlve (17)1-2(51) 3(29) 3+(2)
Palbociclib 25-150 mg dose ranging
0
20 Gr34 Neutropenia23 Gr34 Leucopenia
$933M (1Q18)$31B (2017)
Flaherty KT Lorusso PM Demichele A Abramson VG Courtney R Randolph SS Shaik MN Wilner KD ODwyer PJ Schwartz GK Phase I dose-escalation trial of the oral cyclin-dependent kinase 46 inhibitor PD 0332991 administered using a 21-day schedule in patients with advanced cancer Clin Cancer Res 2012 Jan 1518(2)568-76 doi 1011581078-0432CCR-11-0509 Epub 2011 Nov 16
Novartis
Kisqalireg (ribociclib)
CDK 46 Inhibitor
Premenopausal HR+ HER2- MBC
Heavily pretreatedRelapsed Met Cancer
16
132 (20 BC)
0-1 (25) 2-3 (42)4+ (32)
Ribociclib 50 mg ranging up to 1200 mg dose escalation
23 PR-included 1 BC (5 of BC pts)
27 Gr34 Neutropenia17 Gr34 Leucopenia
Peak sales est at $25B
Infante JR Cassier PA Gerecitano JF Witteveen PO Chugh R Ribrag V Chakraborty A Matano A Dobson JR Crystal AS Parasuraman S Shapiro GI A Phase I Study of the Cyclin-Dependent Kinase 46 Inhibitor Ribociclib (LEE011) in Patients with Advanced Solid Tumors and Lymphomas Clin Cancer Res 2016 Dec 122(23)5696-5705 Epub 2016 Aug 19
Eli Lilly
Verzenioreg (abemaciclib)
CDK 46 Inhibitor
HR+HER2minusMBC
Heavily pretreatedRelapsed Met Cancer
16
12 (1 BC)
1 (312) 2 (212) 3+(7)
Abemaciclib 100 mg ranging up to 200 mg dose escalation
17 PR (included 1 BC)
17 Gr34 Neutropenia33 Gr34 Leucopenia
Peak sales est at $2B
Fujiwara Y Tamura K Kondo S Tanabe Y Iwasa S Shimomura A Kitano S Ogasawara K Turner PK Mori J Asou H Chan EM Yamamoto N Phase 1 study of abemaciclib an inhibitor of CDK 4 and 6 as a single agent for Japanese patients with advanced cancer Cancer Chemother Pharmacol 2016 Aug78(2)281-8 doi 101007s00280-016-3085-8 Epub 2016 Jun 16
Mukai H Saeki T Shimada K Naito Y Matsubara N Nakanishi T Obaishi H Namiki M Sasaki Y Phase 1 combination study of eribulin mesylate with trastuzumab for advanced or recurrent human epidermal growth factor receptor 2 positive breast cancer Invest New Drugs 2015 Feb33(1)119-27
AstraZeneca
Lynparza (Olaparib) + Cediranib
PARP inhibitor + inhibitor of VEGF receptor tyrosine kinases
HR+ HER2- MBC
BC amp OC
2013
28 (8 BC)
3 for BC
Olaparib (a poly (ADP-ribose) polymerase (PARP) inhibitor) amp Cediranib (Vascular endothelial growth factor receptor (VEGFR) 1 2 and 3 tyrosine kinase inhibitor)3 at dose level (DL) 0 (cediranib 20mg olaparib 100mg) 3 at DL1 (cediranib 20mg olaparib 200mg) 7 at DL2 (cediranib 30mg olaparib 200mg) 6 at DL3 (cediranib 30mg olaparib 400mg)
Liu JF Tolaney SM Birrer M Fleming GF Buss MK Dahlberg SE Lee H Whalen C Tyburski K Winer E Ivy P Matulonis UA A Phase 1 trial of the poly(ADP-ribose) polymerase inhibitor olaparib (AZD2281) in combination with the anti-angiogenic cediranib (AZD2171) in recurrent epithelial ovarian or triple-negative breast cancer Eur J Cancer 2013 Sep49(14)2972-8
Reyon Pharmaceutical
VM206RY
Heterologous prime-boost with a truncated HER2 sequence
HER2+ Stage IIIampIV BC
2015
9
2 chemo
Plasmid DNA (pHM-GM-CSF expressing truncated HER2 amp GM-CSF) amp adenoviral vector (Ad-HM containing modified HER2) (2 4 and 8 mgpatientvisit) of pHM-GM-CSF 3x IM weeks 0 2 and 4 Ad-HM 3 times 109 virus particles at week 6
11 PR
4 pts showed 7 minor AEs
Unclear
Kim SB Ahn JH Kim J Jung KH A phase 1 study of a heterologous prime-boost vaccination involving a truncated HER2 sequence in patients with HER2-expressing breast cancer Mol Ther Methods Clin Dev 2015 Sep 30215031 doi 101038mtm201531 eCollection 2015
Rodon J Peacuterez-Fidalgo A Krop IE Burris H Guerrero-Zotano A Britten CD Becerra C Schellens J Richards DA Schuler M Abu-Khalaf M Johnson FM Ranson M Edenfield J Silva AP Hackl W Quadt C Demanse D Duval V Baselga J Phase 11b dose escalation and expansion study of BEZ235 a dual PI3KmTOR inhibitor in patients with advanced solid tumors including patients with advanced breast cancer Cancer Chemother Pharmacol 2018 Jun 7 doi 101007s00280-018-3610-z [Epub ahead of print]
Celgene (Abraxane)
Gemcitabine + Abraxane (nab-paclitaxel)
Chemo + Chemo
OC BC NSCLC amp Panc cancer + Lung OC BC Kaposi sarcoma
MBC
2016
9
Adjuvant chemo (100)chemo post-adjuvant (33)
Gem (nucleoside metabolic inhibitor 1250 mgm2) on days 1 and 8 nab-Pac (microtubule inhibitor) starting dose of 180 mgm2 (cohort 1) 220 mgm2 (cohort 2) and 260 mgm2 (cohort 3) on day 1 of the 21-day cycle using a 3 + 3 design
0
MTD not reached29 Gr3 Neutropenia59 Gr1 Peripheralneuropathy
Yoshitomi S Taira N Doihara H Mizoo T Nogami T Iwamoto T Motoki T Shien T Ogasawara Y Matsuoka J Tsuji H Mitsuhashi T A phase 1 dose-finding and pharmacokinetic study of gemcitabine with nab-paclitaxel in patients with metastatic breast cancer Cancer Chemother Pharmacol 2016 Aug78(2)289-94
Eli Lilly
Erbituxreg (cetuximab) + Taxane
EGFR inhibitor antineoplastic agent + Chemo
Headamp Neck Colorectal Cancer
TNBC
2007-2010
18
1 chemo
Cetuximab (epidermal growth factor receptor (EGFR) antagonist ) an initial loading dose of cetuximab 400 mgm2 followed by a weekly dose of 250 mgm2Paclitaxel (microtubule inhibitor) 80 mgm2 or Docetaxel at an initial dose of 30 mgm2 was administered weekly
56 CR 22 PR
83 Dermatologic toxicity11 Grade3+
Nechushtan H Vainer G Stainberg H Salmon AY Hamburger T Peretz T A phase 12 of a combination of cetuximab and taxane for triple negative breast cancer patients Breast 2014 Aug23(4)435-8
Polyphor
Balixafortide (POL6326) + eribulin
CXCR4 antagonist + tubulin-based antimitotic
Heavily pretreated Relapsed MBC
2014-2016
56
3rd line 3 chemo
3+3 dose escalation The highest dose was established as eribulin 14 mgmsup2 on days 2 and 9 and balixafortide 55 mgkg on days 1minus3 and 8minus10 of the 21-day cycle
30 PR
41 Gr34 Neutropenia11 Gr34 Leucopenia11 Gr34 Febrileneutropenia2 Related mortalities
Apr 2018 Fast Track for HER2-MBC who have failed 2prior regimens
Pernas S Martin M Kaufman PA Gil-Martin M Gomez Pardo P Lopez-Tarruella S Manso L Ciruelos E Perez-Fidalgo JA Hernando C Ademuyiwa FO Weilbaecher K Mayer I Pluard TJ Martinez Garcia M Vahdat L Perez-Garcia J Wach A Barker D Fung S Romagnoli B Cortes J Balixafortide plus eribulin in HER2-negative metastatic breast cancer a phase 1 single-arm dose-escalation trial Lancet Oncol 2018 Jun19(6)812-824
11 PRndashbut only + letrozole (No Resp on monotherapy)
61 Gr34 Neutropenia39 Gr34 Leucopenia
$933M in 1Q2018 $31B in 2017
Tamura K Mukai H Naito Y Yonemori K Kodaira M Tanabe Y Yamamoto N Osera S Sasaki M Mori Y Hashigaki S Nagasawa T Umeyama Y Yoshino T Phase I study of palbociclib a cyclin-dependent kinase 46 inhibitor in Japanese patients Cancer Sci 2016 Jun107(6)755-63 doi 101111cas12932 Epub 2016 May 11
Pfizer
Ibrancereg (palbociclib)
CDK 46 Inhibitor
HR+ HER2- MBC
Heavily pretreated Relapsed Metastatic Cancer
2004-2008
41 (5 BC)
chemo naiumlve (17) 1-2 (51)3 (29) 3+ (2)
Palbociclib 25-150 mg dose ranging
0
20 Gr34 Neutropenia23 Gr34 Leucopenia
$933M in 1Q2018 $31B in 2017
Flaherty KT Lorusso PM Demichele A Abramson VG Courtney R Randolph SS Shaik MN Wilner KD ODwyer PJ Schwartz GK Phase I dose-escalation trial of the oral cyclin-dependent kinase 46 inhibitor PD 0332991 administered using a 21-day schedule in patients with advanced cancer Clin Cancer Res 2012 Jan 1518(2)568-76 doi 1011581078-0432CCR-11-0509 Epub 2011 Nov 16
Novartis
Kisqalireg (ribociclib)
CDK 46 Inhibitors
Premenopausal HR+ HER2- MBC
Heavily pretreated Relapsed Metastatic Cancer
2016
132 (20 BC)
0-1 (25) 2-3 (42) 4+ (32)
Ribociclib 50 mg ranging up to 1200 mg dose escalation
23 PRndashincluded 1 in BC (5 of BC pts)
27 Gr34 Neutropenia17 Gr34 Leucopenia
Peak sales projected at $25B
Infante JR Cassier PA Gerecitano JF Witteveen PO Chugh R Ribrag V Chakraborty A Matano A Dobson JR Crystal AS Parasuraman S Shapiro GI A Phase I Study of the Cyclin-Dependent Kinase 46 Inhibitor Ribociclib (LEE011) in Patients with Advanced Solid Tumors and Lymphomas Clin Cancer Res 2016 Dec 122(23)5696-5705 Epub 2016 Aug 19
Eli Lilly
Verzenioreg (abemaciclib)
CDK 46 Inhibitors
HR+HER2minusMBC
Heavily pretreated Relapsed Metastatic Cancer
2016
12 (1 BC)
1 (312) 2 (212) 3+ (7)
Abemaciclib 100 mg ranging up to 200 mg dose escalation
17 PR (included 1 in BC)
17 Gr34 Neutropenia33 Gr34 Leucopenia
Peak sales projected at $2B
Fujiwara Y Tamura K Kondo S Tanabe Y Iwasa S Shimomura A Kitano S Ogasawara K Turner PK Mori J Asou H Chan EM Yamamoto N Phase 1 study of abemaciclib an inhibitor of CDK 4 and 6 as a single agent for Japanese patients with advanced cancer Cancer Chemother Pharmacol 2016 Aug78(2)281-8 doi 101007s00280-016-3085-8 Epub 2016 Jun 16
Mukai H Saeki T Shimada K Naito Y Matsubara N Nakanishi T Obaishi H Namiki M Sasaki Y Phase 1 combination study of eribulin mesylate with trastuzumab for advanced or recurrent human epidermal growth factor receptor 2 positive breast cancer Invest New Drugs 2015 Feb33(1)119-27
AstraZeneca
Lynparza (Olaparib)+ Cediranib
PARP inhibitor+ inhibitor of VEGF RTK
HR+ HER2- MBC
BC amp OC
13
28 (8 BC)
3 for BC
Olaparib (a poly (ADP-ribose) polymerase (PARP) inhibitor) amp Cediranib (Vascular endothelial growth factor receptor (VEGFR) 1 2 and 3 tyrosine kinase inhibitor)3 at dose level (DL) 0 (cediranib 20mg olaparib 100mg) 3 at DL1 (cediranib 20mg olaparib 200mg) 7 at DL2 (cediranib 30mg olaparib 200mg) 6 at DL3 (cediranib 30mg olaparib 400mg)
Liu JF Tolaney SM Birrer M Fleming GF Buss MK Dahlberg SE Lee H Whalen C Tyburski K Winer E Ivy P Matulonis UA A Phase 1 trial of the poly(ADP-ribose) polymerase inhibitor olaparib (AZD2281) in combination with the anti-angiogenic cediranib (AZD2171) in recurrent epithelial ovarian or triple-negative breast cancer Eur J Cancer 2013 Sep49(14)2972-8
ReyonPharma
VM206RY
Heterologous prime-boost with a truncated HER2 sequence
HER2+ Stg IIIampIV BC
15
9
2 chemo
Plasmid DNA (pHM-GM-CSF expressing truncated HER2 amp GM-CSF) amp adenoviral vector (Ad-HM containing modified HER2) (2 4 and 8 mgpatientvisit) of pHM-GM-CSF 3x IM weeks 0 2 and 4 Ad-HM 3 times 109 virus particles at week 6
11 PR
4 pts 7 minor AEs
Unclear
Kim SB Ahn JH Kim J Jung KH A phase 1 study of a heterologous prime-boost vaccination involving a truncated HER2 sequence in patients with HER2-expressing breast cancer Mol Ther Methods Clin Dev 2015 Sep 30215031 doi 101038mtm201531 eCollection 2015
Rodon J Peacuterez-Fidalgo A Krop IE Burris H Guerrero-Zotano A Britten CD Becerra C Schellens J Richards DA Schuler M Abu-Khalaf M Johnson FM Ranson M Edenfield J Silva AP Hackl W Quadt C Demanse D Duval V Baselga J Phase 11b dose escalation and expansion study of BEZ235 a dual PI3KmTOR inhibitor in patients with advanced solid tumors including patients with advanced breast cancer Cancer Chemother Pharmacol 2018 Jun 7 doi 101007s00280-018-3610-z [Epub ahead of print]
Celgene(Abraxane)
Gemcitabine + Abraxane (nab-paclitaxel)
Chemo+ Chemo
OC BC NSCLC PC + LC OC BC KS
MBC
16
9
Adjuv chemo (100)chemo post-adjuv (33)
Gem (nucleoside metabolic inhibitor 1250 mgm2) on days 1 and 8 nab-Pac (microtubule inhibitor) starting dose of 180 mgm2 (cohort 1) 220 mgm2 (cohort 2) and 260 mgm2 (cohort 3) on day 1 of the 21-day cycle using a 3 + 3 design
0
MTD not reached29 Gr3 Neutropenia59 Gr1 Peripheralneuropathy
Yoshitomi S Taira N Doihara H Mizoo T Nogami T Iwamoto T Motoki T Shien T Ogasawara Y Matsuoka J Tsuji H Mitsuhashi T A phase 1 dose-finding and pharmacokinetic study of gemcitabine with nab-paclitaxel in patients with metastatic breast cancer Cancer Chemother Pharmacol 2016 Aug78(2)289-94
Eli Lilly
Erbituxreg (cetuximab) + Taxane
EGFR inhibitor antineoplastic agent + Chemo
Head amp NeckColorectal
TNBC
07-10
18
1 chemo
Cetuximab (epidermal growth factor receptor (EGFR) antagonist ) an initial loading dose of cetuximab 400 mgm2 followed by a weekly dose of 250 mgm2Paclitaxel (microtubule inhibitor) 80 mgm2 or Docetaxel at an initial dose of 30 mgm2 was administered weekly
56 CR 22 PR
83 Dermatologic toxicity11 Grade3+
Nechushtan H Vainer G Stainberg H Salmon AY Hamburger T Peretz T A phase 12 of a combination of cetuximab and taxane for triple negative breast cancer patients Breast 2014 Aug23(4)435-8
Polyphor
Balixafortide (POL6326) + eribulin
CXCR4 antagonist + tubulin-based antimitotic
Heavily pretreatedRelapsed MBC
14-16
56
3rd line 3 chemo
3+3 dose escalation The highest dose was established as eribulin 14 mgmsup2 on days 2 and 9 and balixafortide 55 mgkg on days 1minus3 and 8minus10 of the 21-day cycle
30 PR
41 Gr34 Neutropenia11 Gr34 Leucopenia11 Gr34 Febrileneutropenia2 Related mortalities
42018 Fast Track (HER2-MBC failed 2 prior regimens)
Pernas S Martin M Kaufman PA Gil-Martin M Gomez Pardo P Lopez-Tarruella S Manso L Ciruelos E Perez-Fidalgo JA Hernando C Ademuyiwa FO Weilbaecher K Mayer I Pluard TJ Martinez Garcia M Vahdat L Perez-Garcia J Wach A Barker D Fung S Romagnoli B Cortes J Balixafortide plus eribulin in HER2-negative metastatic breast cancer a phase 1 single-arm dose-escalation trial Lancet Oncol 2018 Jun19(6)812-824
1 PRndashbut only + letrozoleNo Resp on monotherapy
61 Gr34 Neutropenia39 Gr34 Leucopenia
$933M (1Q18)$31B (2017)
Tamura K Mukai H Naito Y Yonemori K Kodaira M Tanabe Y Yamamoto N Osera S Sasaki M Mori Y Hashigaki S Nagasawa T Umeyama Y Yoshino T Phase I study of palbociclib a cyclin-dependent kinase 46 inhibitor in Japanese patients Cancer Sci 2016 Jun107(6)755-63 doi 101111cas12932 Epub 2016 May 11
Pfizer
Ibrancereg (palbociclib)
CDK 46 Inhibitor
HR+ HER2- MBC
Heavily pretreatedRelapsed Met Cancer
04-08
41 (5 BC)
chemo naiumlve (17)1-2(51) 3(29) 3+(2)
Palbociclib 25-150 mg dose ranging
0
20 Gr34 Neutropenia23 Gr34 Leucopenia
$933M (1Q18)$31B (2017)
Flaherty KT Lorusso PM Demichele A Abramson VG Courtney R Randolph SS Shaik MN Wilner KD ODwyer PJ Schwartz GK Phase I dose-escalation trial of the oral cyclin-dependent kinase 46 inhibitor PD 0332991 administered using a 21-day schedule in patients with advanced cancer Clin Cancer Res 2012 Jan 1518(2)568-76 doi 1011581078-0432CCR-11-0509 Epub 2011 Nov 16
Novartis
Kisqalireg (ribociclib)
CDK 46 Inhibitor
Premenopausal HR+ HER2- MBC
Heavily pretreatedRelapsed Met Cancer
16
132 (20 BC)
0-1 (25) 2-3 (42)4+ (32)
Ribociclib 50 mg ranging up to 1200 mg dose escalation
23 PR-included 1 BC (5 of BC pts)
27 Gr34 Neutropenia17 Gr34 Leucopenia
Peak sales est at $25B
Infante JR Cassier PA Gerecitano JF Witteveen PO Chugh R Ribrag V Chakraborty A Matano A Dobson JR Crystal AS Parasuraman S Shapiro GI A Phase I Study of the Cyclin-Dependent Kinase 46 Inhibitor Ribociclib (LEE011) in Patients with Advanced Solid Tumors and Lymphomas Clin Cancer Res 2016 Dec 122(23)5696-5705 Epub 2016 Aug 19
Eli Lilly
Verzenioreg (abemaciclib)
CDK 46 Inhibitor
HR+HER2minusMBC
Heavily pretreatedRelapsed Met Cancer
16
12 (1 BC)
1 (312) 2 (212) 3+(7)
Abemaciclib 100 mg ranging up to 200 mg dose escalation
17 PR (included 1 BC)
17 Gr34 Neutropenia33 Gr34 Leucopenia
Peak sales est at $2B
Fujiwara Y Tamura K Kondo S Tanabe Y Iwasa S Shimomura A Kitano S Ogasawara K Turner PK Mori J Asou H Chan EM Yamamoto N Phase 1 study of abemaciclib an inhibitor of CDK 4 and 6 as a single agent for Japanese patients with advanced cancer Cancer Chemother Pharmacol 2016 Aug78(2)281-8 doi 101007s00280-016-3085-8 Epub 2016 Jun 16
41 Gr34 Neutropenia11 Gr34 Leucopenia11 Gr34 Febrileneutropenia2 Related mortalities
30 PRs in combination with Halaven
Bria-IMTTM
20
Injection site reactions No related SAEs or SUSARs
Tumor vol darr ampor darr circul tumor cells)All Comers 21(419) 26(519)One or More HLA matches 27(415) 33(515)Two or More HLA matches 50 (24) 75 (34))
Drug
Technology
Approved for
Market (US)
Ibrance (palbociclib)
CDK 46 Inhibitor
HR+HER2- MBC in combination with fluvestrant or aromatase inhibitor
$933M in 1Q2018 $3126M in 2017
Kisqali (ribociclib)
CDK 46 Inhibitor
2017 HR+HER2- MBC in combination with fluvestrant or aromatase inhibitor
Peak sales projected at $25B
Verzenio (abemaciclib)
CDK 46 Inhibitor
2017 HR+HER2- MBC in combination with fluvestrant or aromatase inhibitor
Peak sales projected at $2B
Lynparza (olaparib)
Poly (ADP-ribose) polymerase (PARP) inhibitor
2017 ovarian amp breast cancer
$997M in 2017
Halaven (eribulin mesylate)
Tubulin-based antimitotic
2H2017 3rd line MBC amp liposarcoma
$181M in 2017
balixafortide
CXCR4 antagonist
Fast track designation in 2018 for HER2- MBC who have failed 2 prior regimens
Bria-IMTtradeCurrent Phase IIIa Data Supports HLA Matching Hypothesis Six patients treated in 2017 Bria-IMTtrade was safe and well tolerated
Patient 01-002 73-year-old woman with breast cancer diagnosed in 1995 Developed liver metastases in2010 and lung metastases in 2017 Previously treated with 7 rounds of chemotherapy with 8 differentchemotherapy agents Received 5 cycles of Bria-IMTtrade over 3 months then monthly cycles (6 months total)Evaluated after 3 months and 6 months After 3 months despite the extensive prior therapy her scans notedthat ldquothere has been a clear response in the multiple bilateral pulmonary nodulesrdquo The response wasmaintained after 6 months of Bria-IMTtrade treatment She matches Bria-IMTtrade at 2 HLA alleles
The liver tumors were stable to slightly increased at 3 months and then progressed after 6 months
This supports our hypothesis of heightened anti-tumor activity in patients with a matched HLA types Clear path to develop BriaDXtrade to select the patients using HLA testing
1 RLL 29 Not Detectable Not Detectable2 LUL apical pleural based 34 tiny nodule lt 1mm scar tiny nodule lt 1mm scar3 xxx 39 Not Detectable Not Detectable4 40 Not Detectable Not Detectable5 RLL 45 Not Detectable Not Detectable6 LLL 49 Not Detectable Not Detectable7 xxx 52 Not Detectable Not Detectable8 RLL 52 Not Detectable Not Detectable9 RLL 56 Not Detectable Not Detectable
10 RLL costophrenic recess 56 Not Detectable Not Detectable11 XXX 58 Not Detectable Not Detectable12 LUL 60 Not Detectable Not Detectable13 XXX 67 15 1514 RUL 72 15 1515 LLL 76 Not Detectable Not Detectable16 RUL Noncalcified Nodule 77 Not Detectable Not Detectable17 RLL costophrenic recess 79 10 1018 RUL 82 Not Detectable Not Detectable19 RLL 90 Not Detectable Not Detectable20 RLL 91 lt 01 lt 0121 xxx xxx Not Detectable Not Detectable
27
Clinical Development Update ndash Summary 2018 September 26
Completed enrollment of Adv Breast cancer patients in the Phase IIIa ldquomonotherapyrdquo study of Bria-IMTtrade
We have confirmed our mechanism of action and achieved proof of concept
Initial safety data appears superior to that of the other advanced or approved drugs for breast cancer when they were at a similar clinical stage of development
Initial efficacy data is similar or superior to those of other advanced or approved drugs for breast cancer when they were at a similar clinical stage of development
Initiated Combination Study of Bria-IMTtrade with Keytrudareg or Yervoyreg in Adv breast cancer patients expecting even better response rates than those in the ldquomonotherapyrdquo study Initial safety data is expected in 4Q2018 Initial efficacy data is expected in 1Q2019
Bria-OTStrade the first off-the-shelf personalized treatment for advanced breast cancer is expected to enter the clinic in 2019
28
Bria-IMTtrade Excellent Safety Data - To Date
To date Bria-IMTtrade has been dosed in 24 patients (4 in 2004-2005 20 in 2017-2018)
Interim Data (20 patients)-Ongoing Phase IIIa Study (2017-2018)
Bria-IMTtrade has been very well tolerated (ge60 doses given to date) The majority of adverse events (AEs) were limited to expected minor local irritation at the
injection sites No related grade gt3 or unexpected AEs No related serious AEs No serious unexpected related AEs Most patients who have dropped out did so due to worsening of their underlying disease
Based on the current study Bria-IMTtrade has an excellent safety profile
29
Bria-IMTtrade - Efficacy as Predicted
Interim Data (19 patients)-Ongoing Phase IIIa Study (2017-2018) amp Original Study (2004-2005)
PD-L1 expression on circulating cancer cells amp cancer-associated cells in 100 of patients (to date) Strong rationale for combination with checkpoint inhibitors like Keytruda
30
Bria-IMTtrade appears to be most effective in patients who match with Bria-IMT trade at 2 HLA loci (types) further supporting our ldquoHLA Matching Hypothesisrdquo and the development of Bria-OTS trade to cover 90 of the patient population
Combination with immune checkpoint inhibitors may induce a more potent anti-cancer response leading to our strategy of combination studies of Bria-IMT trade with Keytruda or Yervoy
Patients (n) HLA Match
Tumor Shrinkage
Biological Response
4 ge2 50 7515 ge1 27 334 0 0 0
Biological response includes tumor shrinkage or lower circulating cancer associated cells
The confirmatory Bria-IMTtrade monotherapy Phase IIa trial has completed enrollment Additional Support for the HLA-matching hypothesis has been obtained
Bria-IMTtrade Combination Therapy study with immune checkpoint inhibitors Keytrudareg if PD-L12 positive (ge1) Yervoyreg if PD-L12 negative (lt1) Accepting patients from the monotherapy study who develop progressive disease Also enrolling patients directly into this study to enhance experience with the combination In discussion with other pharmaceutical companies to evaluate additional combinations with other
immunotherapies
Bria-OTStrade Off-the-Shelf Personalized Targeted Immunotherapy Developing Bria-OTStrade to co-express GM-CSF and interferon-α Pre-manufacture additional HLA alleles ndash Total of 15 alleles (8 Class I and 7 Class II) Co-development of BriaDXtrade companion diagnostic for HLA typing Combination therapy clinical trial with immune checkpoint inhibitors for non-responders using
information from the Bria-IMTtrade Combination Therapy Study
33
Development Timeline ndash Breast Cancer
20192018 2020 2021
Phase IIIaBria-IMTtrade
Monotherapy
Currently Enrolling Phase IIaBria-IMTtrade + Checkpoint
Currently in discussions with potential partnersPhase II Bria-IMTtrade plus Additional Combinations (1Q19 4Q22)(eg PD-1 Inhibitor PD-L1 inhibitor anti-CTLA4 anti-GITR anti-OX40)
1Q 2Q 3Q 4Q
2023
Bria-OTStrade Off-The-Shelf Personalized ImmunotherapyMonotherapy and Potential Partnered Combo Therapy
(2H19 Ongoing)
Bria-OTStradeOff-the-Shelf Cell Line cGMP Manufacturing
and BriaDXtrade(1Q18 1Q19)
Registration Studies (1Q20 2H22)Bria-IMTtrade with Checkpoint InhibitorsBria-OTStrade +- Checkpoint Inhibitors
34
Immuno-oncology Deals
Recent deals of small biotechs with big pharma in immuno-oncology
35
Date PartnershipDevelopment stage at the time of the deal Deal size
07122018 Immatics-Genmab Preclinical Up to $28B
04042018 OSE Immunotherapeutics-Boehringer Ingelheim Preclinical Up to euro113B ($139B)
02092018 Pieris Pharmaceuticals-Seattle Genetics Preclinical Up to $123B
2142018 Nektar-BMS Ph III Up to $36B
01222018 Juno-Celgene Ph II $9B (Acquisition)
11142017 Loxo-Bayer Larotrectinib (Ph II) LOXO-195 (Ph III) Up to $155B
1032017 CytomX-Amgen Preclinical Up to $15B
03202017 CytomX--BMS Ph III Up to $36B
6282016 Xencor-Novartis Preclinical Up to $24B
Early Stage Clinical Studies (Comparison)
We compared the interim data of Ph IIIa study of Bria-IMTtrade in advanced breast cancer with thedata in the early stage clinical studies of recently approved breast cancer drugs and one fasttracked product candidate
Apples to apples comparison Early Stage Clinical Studies in oncology are typically done in patientswith no other therapeutic options Thus the patients have very advanced disease and response ratesare typically quite low
The patients in our Ph IIIa study have been heavily pre-treated (median 45 prior regimens)Some recent studies of relevance in breast cancer are noted in the following slides
36
Breast Cancer Market Opportunity
Drug Technology Approved for Market (US)Ibrance (palbociclib) CDK 46 Inhibitor HR+HER2- MBC in combination with
fluvestrant or aromatase inhibitor$933M in 1Q2018 $3126M in 2017
Kisqali (ribociclib) CDK 46 Inhibitor 2017 HR+HER2- MBC in combination with fluvestrant or aromatase inhibitor
Peak sales projected at $25B
Verzenio (abemaciclib) CDK 46 Inhibitor 2017 HR+HER2- MBC in combination with fluvestrant or aromatase inhibitor
balixafortide CXCR4 antagonist Fast track designation in 2018 for HER2- MBC who have failed 2 prior regimens
The market for breast cancer drugs is a multibillion dollar market with new drugs being approvedon an ongoing basis indicating the shortage of safe and effective treatments for this deadly disease
37
Competitors- Phase III Clinical Data Bria-IMTtrade shows superior safety and similar to superior efficacy data compared with those of the multi-billion dollar drugs when they were at a similar early stage of clinical development
Injection site reactions No related SAEs or SUSARs
Tumor vol darr ampor darr circul tumor cellsAll Comers 21(419) 26(519)One or More HLA matches 27(415) 33(515)Two or More HLA matches 50 (24) 75 (34)
Sheet1 (3)
Comp -Slides
Data
HLA (2)
HLA
Data (Ph1-2+4Pt)
Competitors (2018)-Slide
Competitors (2018)
In the Pipeline Protein Kinase C delta (PKCδ) Inhibitors
30 of all human malignancies display activating RAS mutations Another 60 showing over-activity of Ras-signaling pathways
Ras has been termed ldquoundruggablerdquo (no one has been able to make a Ras inhibitor drug)
BriaCellrsquos novel proprietary PKCδ inhibitors have shown activity against multiple RAS transformed tumors Lung cancer Melanoma Breast cancer Neuroendocrine cancer Pancreatic cancer Colorectal cancer
This target has an attractive safety profile based on in vivo studies and knock out mouse studies
PKCδ inhibitors should qualify for an accelerated clinical development plan and regulatory pathway
Could be in clinic within 24 months
Cost-Effective Additional Shot-on-Goal and additional partnership opportunities
Early-Stage Preclinical Program
39
Protein Kinase C delta (PKCδ) Inhibitors
Activated PKCδ inhibits RAS degradation which in turn stimulates tumor growth
Koo et al Oncotarget 621328 2016
30 of all human malignancies display activating RASmutations with another 60 showing over-activity of Ras-signaling pathways
BriaCellrsquos novel proprietary PKCδ inhibitors have shownactivity against multiple RAS transformed tumors
This target has an attractive safety profile based on in vivostudies and knock out mouse studies
PKCδ also has potential activity as an immunotherapeuticby blocking TGFβ signaling
PKCδ inhibitors are applicable to specific niche tumor typeswhich provide an accelerated clinical development plan
Structural aspects of first generation inhibitor rottlerin and staurosporine (pan-PKC activator) were combined to create second generation inhibitor KAM1
Third generation inhibitors such as BJE6-106 have improved potency and selectivity Fourth generation inhibitors under development to optimize drug-like characteristics PKCδ inhibitors lack endothelial cell cytotoxicity amp PKCδ deficient mice develop normally and are fertile Potentially no marked intrinsic toxicity by inhibiting PKCδ
Mukai H Saeki T Shimada K Naito Y Matsubara N Nakanishi T Obaishi H Namiki M Sasaki Y Phase 1 combination study of eribulin mesylate with trastuzumab for advanced or recurrent human epidermal growth factor receptor 2 positive breast cancer Invest New Drugs 2015 Feb33(1)119-27
AstraZeneca
Lynparza (Olaparib) + Cediranib
PARP inhibitor + inhibitor of VEGF receptor tyrosine kinases
HR+ HER2- MBC
BC amp OC
2013
28 (8 BC)
3 for BC
Olaparib (a poly (ADP-ribose) polymerase (PARP) inhibitor) amp Cediranib (Vascular endothelial growth factor receptor (VEGFR) 1 2 and 3 tyrosine kinase inhibitor)3 at dose level (DL) 0 (cediranib 20mg olaparib 100mg) 3 at DL1 (cediranib 20mg olaparib 200mg) 7 at DL2 (cediranib 30mg olaparib 200mg) 6 at DL3 (cediranib 30mg olaparib 400mg)
Liu JF Tolaney SM Birrer M Fleming GF Buss MK Dahlberg SE Lee H Whalen C Tyburski K Winer E Ivy P Matulonis UA A Phase 1 trial of the poly(ADP-ribose) polymerase inhibitor olaparib (AZD2281) in combination with the anti-angiogenic cediranib (AZD2171) in recurrent epithelial ovarian or triple-negative breast cancer Eur J Cancer 2013 Sep49(14)2972-8
Reyon Pharmaceutical
VM206RY
Heterologous prime-boost with a truncated HER2 sequence
HER2+ Stage IIIampIV BC
2015
9
2 chemo
Plasmid DNA (pHM-GM-CSF expressing truncated HER2 amp GM-CSF) amp adenoviral vector (Ad-HM containing modified HER2) (2 4 and 8 mgpatientvisit) of pHM-GM-CSF 3x IM weeks 0 2 and 4 Ad-HM 3 times 109 virus particles at week 6
11 PR
4 pts showed 7 minor AEs
Unclear
Kim SB Ahn JH Kim J Jung KH A phase 1 study of a heterologous prime-boost vaccination involving a truncated HER2 sequence in patients with HER2-expressing breast cancer Mol Ther Methods Clin Dev 2015 Sep 30215031 doi 101038mtm201531 eCollection 2015
Rodon J Peacuterez-Fidalgo A Krop IE Burris H Guerrero-Zotano A Britten CD Becerra C Schellens J Richards DA Schuler M Abu-Khalaf M Johnson FM Ranson M Edenfield J Silva AP Hackl W Quadt C Demanse D Duval V Baselga J Phase 11b dose escalation and expansion study of BEZ235 a dual PI3KmTOR inhibitor in patients with advanced solid tumors including patients with advanced breast cancer Cancer Chemother Pharmacol 2018 Jun 7 doi 101007s00280-018-3610-z [Epub ahead of print]
Celgene (Abraxane)
Gemcitabine + Abraxane (nab-paclitaxel)
Chemo + Chemo
OC BC NSCLC amp Panc cancer + Lung OC BC Kaposi sarcoma
MBC
2016
9
Adjuvant chemo (100)chemo post-adjuvant (33)
Gem (nucleoside metabolic inhibitor 1250 mgm2) on days 1 and 8 nab-Pac (microtubule inhibitor) starting dose of 180 mgm2 (cohort 1) 220 mgm2 (cohort 2) and 260 mgm2 (cohort 3) on day 1 of the 21-day cycle using a 3 + 3 design
0
MTD not reached29 Gr3 Neutropenia59 Gr1 Peripheralneuropathy
Yoshitomi S Taira N Doihara H Mizoo T Nogami T Iwamoto T Motoki T Shien T Ogasawara Y Matsuoka J Tsuji H Mitsuhashi T A phase 1 dose-finding and pharmacokinetic study of gemcitabine with nab-paclitaxel in patients with metastatic breast cancer Cancer Chemother Pharmacol 2016 Aug78(2)289-94
Eli Lilly
Erbituxreg (cetuximab) + Taxane
EGFR inhibitor antineoplastic agent + Chemo
Headamp Neck Colorectal Cancer
TNBC
2007-2010
18
1 chemo
Cetuximab (epidermal growth factor receptor (EGFR) antagonist ) an initial loading dose of cetuximab 400 mgm2 followed by a weekly dose of 250 mgm2Paclitaxel (microtubule inhibitor) 80 mgm2 or Docetaxel at an initial dose of 30 mgm2 was administered weekly
56 CR 22 PR
83 Dermatologic toxicity11 Grade3+
Nechushtan H Vainer G Stainberg H Salmon AY Hamburger T Peretz T A phase 12 of a combination of cetuximab and taxane for triple negative breast cancer patients Breast 2014 Aug23(4)435-8
Polyphor
Balixafortide (POL6326) + eribulin
CXCR4 antagonist + tubulin-based antimitotic
Heavily pretreated Relapsed MBC
2014-2016
56
3rd line 3 chemo
3+3 dose escalation The highest dose was established as eribulin 14 mgmsup2 on days 2 and 9 and balixafortide 55 mgkg on days 1minus3 and 8minus10 of the 21-day cycle
30 PR
41 Gr34 Neutropenia11 Gr34 Leucopenia11 Gr34 Febrileneutropenia2 Related mortalities
Apr 2018 Fast Track for HER2-MBC who have failed 2prior regimens
Pernas S Martin M Kaufman PA Gil-Martin M Gomez Pardo P Lopez-Tarruella S Manso L Ciruelos E Perez-Fidalgo JA Hernando C Ademuyiwa FO Weilbaecher K Mayer I Pluard TJ Martinez Garcia M Vahdat L Perez-Garcia J Wach A Barker D Fung S Romagnoli B Cortes J Balixafortide plus eribulin in HER2-negative metastatic breast cancer a phase 1 single-arm dose-escalation trial Lancet Oncol 2018 Jun19(6)812-824
11 PRndashbut only + letrozole (No Resp on monotherapy)
61 Gr34 Neutropenia39 Gr34 Leucopenia
$933M in 1Q2018 $31B in 2017
Tamura K Mukai H Naito Y Yonemori K Kodaira M Tanabe Y Yamamoto N Osera S Sasaki M Mori Y Hashigaki S Nagasawa T Umeyama Y Yoshino T Phase I study of palbociclib a cyclin-dependent kinase 46 inhibitor in Japanese patients Cancer Sci 2016 Jun107(6)755-63 doi 101111cas12932 Epub 2016 May 11
Pfizer
Ibrancereg (palbociclib)
CDK 46 Inhibitor
HR+ HER2- MBC
Heavily pretreated Relapsed Metastatic Cancer
2004-2008
41 (5 BC)
chemo naiumlve (17) 1-2 (51)3 (29) 3+ (2)
Palbociclib 25-150 mg dose ranging
0
20 Gr34 Neutropenia23 Gr34 Leucopenia
$933M in 1Q2018 $31B in 2017
Flaherty KT Lorusso PM Demichele A Abramson VG Courtney R Randolph SS Shaik MN Wilner KD ODwyer PJ Schwartz GK Phase I dose-escalation trial of the oral cyclin-dependent kinase 46 inhibitor PD 0332991 administered using a 21-day schedule in patients with advanced cancer Clin Cancer Res 2012 Jan 1518(2)568-76 doi 1011581078-0432CCR-11-0509 Epub 2011 Nov 16
Novartis
Kisqalireg (ribociclib)
CDK 46 Inhibitors
Premenopausal HR+ HER2- MBC
Heavily pretreated Relapsed Metastatic Cancer
2016
132 (20 BC)
0-1 (25) 2-3 (42) 4+ (32)
Ribociclib 50 mg ranging up to 1200 mg dose escalation
23 PRndashincluded 1 in BC (5 of BC pts)
27 Gr34 Neutropenia17 Gr34 Leucopenia
Peak sales projected at $25B
Infante JR Cassier PA Gerecitano JF Witteveen PO Chugh R Ribrag V Chakraborty A Matano A Dobson JR Crystal AS Parasuraman S Shapiro GI A Phase I Study of the Cyclin-Dependent Kinase 46 Inhibitor Ribociclib (LEE011) in Patients with Advanced Solid Tumors and Lymphomas Clin Cancer Res 2016 Dec 122(23)5696-5705 Epub 2016 Aug 19
Eli Lilly
Verzenioreg (abemaciclib)
CDK 46 Inhibitors
HR+HER2minusMBC
Heavily pretreated Relapsed Metastatic Cancer
2016
12 (1 BC)
1 (312) 2 (212) 3+ (7)
Abemaciclib 100 mg ranging up to 200 mg dose escalation
17 PR (included 1 in BC)
17 Gr34 Neutropenia33 Gr34 Leucopenia
Peak sales projected at $2B
Fujiwara Y Tamura K Kondo S Tanabe Y Iwasa S Shimomura A Kitano S Ogasawara K Turner PK Mori J Asou H Chan EM Yamamoto N Phase 1 study of abemaciclib an inhibitor of CDK 4 and 6 as a single agent for Japanese patients with advanced cancer Cancer Chemother Pharmacol 2016 Aug78(2)281-8 doi 101007s00280-016-3085-8 Epub 2016 Jun 16
Mukai H Saeki T Shimada K Naito Y Matsubara N Nakanishi T Obaishi H Namiki M Sasaki Y Phase 1 combination study of eribulin mesylate with trastuzumab for advanced or recurrent human epidermal growth factor receptor 2 positive breast cancer Invest New Drugs 2015 Feb33(1)119-27
AstraZeneca
Lynparza (Olaparib)+ Cediranib
PARP inhibitor+ inhibitor of VEGF RTK
HR+ HER2- MBC
BC amp OC
13
28 (8 BC)
3 for BC
Olaparib (a poly (ADP-ribose) polymerase (PARP) inhibitor) amp Cediranib (Vascular endothelial growth factor receptor (VEGFR) 1 2 and 3 tyrosine kinase inhibitor)3 at dose level (DL) 0 (cediranib 20mg olaparib 100mg) 3 at DL1 (cediranib 20mg olaparib 200mg) 7 at DL2 (cediranib 30mg olaparib 200mg) 6 at DL3 (cediranib 30mg olaparib 400mg)
Liu JF Tolaney SM Birrer M Fleming GF Buss MK Dahlberg SE Lee H Whalen C Tyburski K Winer E Ivy P Matulonis UA A Phase 1 trial of the poly(ADP-ribose) polymerase inhibitor olaparib (AZD2281) in combination with the anti-angiogenic cediranib (AZD2171) in recurrent epithelial ovarian or triple-negative breast cancer Eur J Cancer 2013 Sep49(14)2972-8
ReyonPharma
VM206RY
Heterologous prime-boost with a truncated HER2 sequence
HER2+ Stg IIIampIV BC
15
9
2 chemo
Plasmid DNA (pHM-GM-CSF expressing truncated HER2 amp GM-CSF) amp adenoviral vector (Ad-HM containing modified HER2) (2 4 and 8 mgpatientvisit) of pHM-GM-CSF 3x IM weeks 0 2 and 4 Ad-HM 3 times 109 virus particles at week 6
11 PR
4 pts 7 minor AEs
Unclear
Kim SB Ahn JH Kim J Jung KH A phase 1 study of a heterologous prime-boost vaccination involving a truncated HER2 sequence in patients with HER2-expressing breast cancer Mol Ther Methods Clin Dev 2015 Sep 30215031 doi 101038mtm201531 eCollection 2015
Rodon J Peacuterez-Fidalgo A Krop IE Burris H Guerrero-Zotano A Britten CD Becerra C Schellens J Richards DA Schuler M Abu-Khalaf M Johnson FM Ranson M Edenfield J Silva AP Hackl W Quadt C Demanse D Duval V Baselga J Phase 11b dose escalation and expansion study of BEZ235 a dual PI3KmTOR inhibitor in patients with advanced solid tumors including patients with advanced breast cancer Cancer Chemother Pharmacol 2018 Jun 7 doi 101007s00280-018-3610-z [Epub ahead of print]
Celgene(Abraxane)
Gemcitabine + Abraxane (nab-paclitaxel)
Chemo+ Chemo
OC BC NSCLC PC + LC OC BC KS
MBC
16
9
Adjuv chemo (100)chemo post-adjuv (33)
Gem (nucleoside metabolic inhibitor 1250 mgm2) on days 1 and 8 nab-Pac (microtubule inhibitor) starting dose of 180 mgm2 (cohort 1) 220 mgm2 (cohort 2) and 260 mgm2 (cohort 3) on day 1 of the 21-day cycle using a 3 + 3 design
0
MTD not reached29 Gr3 Neutropenia59 Gr1 Peripheralneuropathy
Yoshitomi S Taira N Doihara H Mizoo T Nogami T Iwamoto T Motoki T Shien T Ogasawara Y Matsuoka J Tsuji H Mitsuhashi T A phase 1 dose-finding and pharmacokinetic study of gemcitabine with nab-paclitaxel in patients with metastatic breast cancer Cancer Chemother Pharmacol 2016 Aug78(2)289-94
Eli Lilly
Erbituxreg (cetuximab) + Taxane
EGFR inhibitor antineoplastic agent + Chemo
Head amp NeckColorectal
TNBC
07-10
18
1 chemo
Cetuximab (epidermal growth factor receptor (EGFR) antagonist ) an initial loading dose of cetuximab 400 mgm2 followed by a weekly dose of 250 mgm2Paclitaxel (microtubule inhibitor) 80 mgm2 or Docetaxel at an initial dose of 30 mgm2 was administered weekly
56 CR 22 PR
83 Dermatologic toxicity11 Grade3+
Nechushtan H Vainer G Stainberg H Salmon AY Hamburger T Peretz T A phase 12 of a combination of cetuximab and taxane for triple negative breast cancer patients Breast 2014 Aug23(4)435-8
Polyphor
Balixafortide (POL6326) + eribulin
CXCR4 antagonist + tubulin-based antimitotic
Heavily pretreatedRelapsed MBC
14-16
56
3rd line 3 chemo
3+3 dose escalation The highest dose was established as eribulin 14 mgmsup2 on days 2 and 9 and balixafortide 55 mgkg on days 1minus3 and 8minus10 of the 21-day cycle
30 PR
41 Gr34 Neutropenia11 Gr34 Leucopenia11 Gr34 Febrileneutropenia2 Related mortalities
42018 Fast Track (HER2-MBC failed 2 prior regimens)
Pernas S Martin M Kaufman PA Gil-Martin M Gomez Pardo P Lopez-Tarruella S Manso L Ciruelos E Perez-Fidalgo JA Hernando C Ademuyiwa FO Weilbaecher K Mayer I Pluard TJ Martinez Garcia M Vahdat L Perez-Garcia J Wach A Barker D Fung S Romagnoli B Cortes J Balixafortide plus eribulin in HER2-negative metastatic breast cancer a phase 1 single-arm dose-escalation trial Lancet Oncol 2018 Jun19(6)812-824
1 PRndashbut only + letrozoleNo Resp on monotherapy
61 Gr34 Neutropenia39 Gr34 Leucopenia
$933M (1Q18)$31B (2017)
Tamura K Mukai H Naito Y Yonemori K Kodaira M Tanabe Y Yamamoto N Osera S Sasaki M Mori Y Hashigaki S Nagasawa T Umeyama Y Yoshino T Phase I study of palbociclib a cyclin-dependent kinase 46 inhibitor in Japanese patients Cancer Sci 2016 Jun107(6)755-63 doi 101111cas12932 Epub 2016 May 11
Pfizer
Ibrancereg (palbociclib)
CDK 46 Inhibitor
HR+ HER2- MBC
Heavily pretreatedRelapsed Met Cancer
04-08
41 (5 BC)
chemo naiumlve (17)1-2(51) 3(29) 3+(2)
Palbociclib 25-150 mg dose ranging
0
20 Gr34 Neutropenia23 Gr34 Leucopenia
$933M (1Q18)$31B (2017)
Flaherty KT Lorusso PM Demichele A Abramson VG Courtney R Randolph SS Shaik MN Wilner KD ODwyer PJ Schwartz GK Phase I dose-escalation trial of the oral cyclin-dependent kinase 46 inhibitor PD 0332991 administered using a 21-day schedule in patients with advanced cancer Clin Cancer Res 2012 Jan 1518(2)568-76 doi 1011581078-0432CCR-11-0509 Epub 2011 Nov 16
Novartis
Kisqalireg (ribociclib)
CDK 46 Inhibitor
Premenopausal HR+ HER2- MBC
Heavily pretreatedRelapsed Met Cancer
16
132 (20 BC)
0-1 (25) 2-3 (42)4+ (32)
Ribociclib 50 mg ranging up to 1200 mg dose escalation
23 PR-included 1 BC (5 of BC pts)
27 Gr34 Neutropenia17 Gr34 Leucopenia
Peak sales est at $25B
Infante JR Cassier PA Gerecitano JF Witteveen PO Chugh R Ribrag V Chakraborty A Matano A Dobson JR Crystal AS Parasuraman S Shapiro GI A Phase I Study of the Cyclin-Dependent Kinase 46 Inhibitor Ribociclib (LEE011) in Patients with Advanced Solid Tumors and Lymphomas Clin Cancer Res 2016 Dec 122(23)5696-5705 Epub 2016 Aug 19
Eli Lilly
Verzenioreg (abemaciclib)
CDK 46 Inhibitor
HR+HER2minusMBC
Heavily pretreatedRelapsed Met Cancer
16
12 (1 BC)
1 (312) 2 (212) 3+(7)
Abemaciclib 100 mg ranging up to 200 mg dose escalation
17 PR (included 1 BC)
17 Gr34 Neutropenia33 Gr34 Leucopenia
Peak sales est at $2B
Fujiwara Y Tamura K Kondo S Tanabe Y Iwasa S Shimomura A Kitano S Ogasawara K Turner PK Mori J Asou H Chan EM Yamamoto N Phase 1 study of abemaciclib an inhibitor of CDK 4 and 6 as a single agent for Japanese patients with advanced cancer Cancer Chemother Pharmacol 2016 Aug78(2)281-8 doi 101007s00280-016-3085-8 Epub 2016 Jun 16
Mukai H Saeki T Shimada K Naito Y Matsubara N Nakanishi T Obaishi H Namiki M Sasaki Y Phase 1 combination study of eribulin mesylate with trastuzumab for advanced or recurrent human epidermal growth factor receptor 2 positive breast cancer Invest New Drugs 2015 Feb33(1)119-27
AstraZeneca
Lynparza (Olaparib) + Cediranib
PARP inhibitor + inhibitor of VEGF receptor tyrosine kinases
HR+ HER2- MBC
BC amp OC
2013
28 (8 BC)
3 for BC
Olaparib (a poly (ADP-ribose) polymerase (PARP) inhibitor) amp Cediranib (Vascular endothelial growth factor receptor (VEGFR) 1 2 and 3 tyrosine kinase inhibitor)3 at dose level (DL) 0 (cediranib 20mg olaparib 100mg) 3 at DL1 (cediranib 20mg olaparib 200mg) 7 at DL2 (cediranib 30mg olaparib 200mg) 6 at DL3 (cediranib 30mg olaparib 400mg)
Liu JF Tolaney SM Birrer M Fleming GF Buss MK Dahlberg SE Lee H Whalen C Tyburski K Winer E Ivy P Matulonis UA A Phase 1 trial of the poly(ADP-ribose) polymerase inhibitor olaparib (AZD2281) in combination with the anti-angiogenic cediranib (AZD2171) in recurrent epithelial ovarian or triple-negative breast cancer Eur J Cancer 2013 Sep49(14)2972-8
Reyon Pharmaceutical
VM206RY
Heterologous prime-boost with a truncated HER2 sequence
HER2+ Stage IIIampIV BC
2015
9
2 chemo
Plasmid DNA (pHM-GM-CSF expressing truncated HER2 amp GM-CSF) amp adenoviral vector (Ad-HM containing modified HER2) (2 4 and 8 mgpatientvisit) of pHM-GM-CSF 3x IM weeks 0 2 and 4 Ad-HM 3 times 109 virus particles at week 6
11 PR
4 pts showed 7 minor AEs
Unclear
Kim SB Ahn JH Kim J Jung KH A phase 1 study of a heterologous prime-boost vaccination involving a truncated HER2 sequence in patients with HER2-expressing breast cancer Mol Ther Methods Clin Dev 2015 Sep 30215031 doi 101038mtm201531 eCollection 2015
Rodon J Peacuterez-Fidalgo A Krop IE Burris H Guerrero-Zotano A Britten CD Becerra C Schellens J Richards DA Schuler M Abu-Khalaf M Johnson FM Ranson M Edenfield J Silva AP Hackl W Quadt C Demanse D Duval V Baselga J Phase 11b dose escalation and expansion study of BEZ235 a dual PI3KmTOR inhibitor in patients with advanced solid tumors including patients with advanced breast cancer Cancer Chemother Pharmacol 2018 Jun 7 doi 101007s00280-018-3610-z [Epub ahead of print]
Celgene (Abraxane)
Gemcitabine + Abraxane (nab-paclitaxel)
Chemo + Chemo
OC BC NSCLC amp Panc cancer + Lung OC BC Kaposi sarcoma
MBC
2016
9
Adjuvant chemo (100)chemo post-adjuvant (33)
Gem (nucleoside metabolic inhibitor 1250 mgm2) on days 1 and 8 nab-Pac (microtubule inhibitor) starting dose of 180 mgm2 (cohort 1) 220 mgm2 (cohort 2) and 260 mgm2 (cohort 3) on day 1 of the 21-day cycle using a 3 + 3 design
0
MTD not reached29 Gr3 Neutropenia59 Gr1 Peripheralneuropathy
Yoshitomi S Taira N Doihara H Mizoo T Nogami T Iwamoto T Motoki T Shien T Ogasawara Y Matsuoka J Tsuji H Mitsuhashi T A phase 1 dose-finding and pharmacokinetic study of gemcitabine with nab-paclitaxel in patients with metastatic breast cancer Cancer Chemother Pharmacol 2016 Aug78(2)289-94
Eli Lilly
Erbituxreg (cetuximab) + Taxane
EGFR inhibitor antineoplastic agent + Chemo
Headamp Neck Colorectal Cancer
TNBC
2007-2010
18
1 chemo
Cetuximab (epidermal growth factor receptor (EGFR) antagonist ) an initial loading dose of cetuximab 400 mgm2 followed by a weekly dose of 250 mgm2Paclitaxel (microtubule inhibitor) 80 mgm2 or Docetaxel at an initial dose of 30 mgm2 was administered weekly
56 CR 22 PR
83 Dermatologic toxicity11 Grade3+
Nechushtan H Vainer G Stainberg H Salmon AY Hamburger T Peretz T A phase 12 of a combination of cetuximab and taxane for triple negative breast cancer patients Breast 2014 Aug23(4)435-8
Polyphor
Balixafortide (POL6326) + eribulin
CXCR4 antagonist + tubulin-based antimitotic
Heavily pretreated Relapsed MBC
2014-2016
56
3rd line 3 chemo
3+3 dose escalation The highest dose was established as eribulin 14 mgmsup2 on days 2 and 9 and balixafortide 55 mgkg on days 1minus3 and 8minus10 of the 21-day cycle
30 PR
41 Gr34 Neutropenia11 Gr34 Leucopenia11 Gr34 Febrileneutropenia2 Related mortalities
Apr 2018 Fast Track for HER2-MBC who have failed 2prior regimens
Pernas S Martin M Kaufman PA Gil-Martin M Gomez Pardo P Lopez-Tarruella S Manso L Ciruelos E Perez-Fidalgo JA Hernando C Ademuyiwa FO Weilbaecher K Mayer I Pluard TJ Martinez Garcia M Vahdat L Perez-Garcia J Wach A Barker D Fung S Romagnoli B Cortes J Balixafortide plus eribulin in HER2-negative metastatic breast cancer a phase 1 single-arm dose-escalation trial Lancet Oncol 2018 Jun19(6)812-824
11 PRndashbut only + letrozole (No Resp on monotherapy)
61 Gr34 Neutropenia39 Gr34 Leucopenia
$933M in 1Q2018 $31B in 2017
Tamura K Mukai H Naito Y Yonemori K Kodaira M Tanabe Y Yamamoto N Osera S Sasaki M Mori Y Hashigaki S Nagasawa T Umeyama Y Yoshino T Phase I study of palbociclib a cyclin-dependent kinase 46 inhibitor in Japanese patients Cancer Sci 2016 Jun107(6)755-63 doi 101111cas12932 Epub 2016 May 11
Pfizer
Ibrancereg (palbociclib)
CDK 46 Inhibitor
HR+ HER2- MBC
Heavily pretreated Relapsed Metastatic Cancer
2004-2008
41 (5 BC)
chemo naiumlve (17) 1-2 (51)3 (29) 3+ (2)
Palbociclib 25-150 mg dose ranging
0
20 Gr34 Neutropenia23 Gr34 Leucopenia
$933M in 1Q2018 $31B in 2017
Flaherty KT Lorusso PM Demichele A Abramson VG Courtney R Randolph SS Shaik MN Wilner KD ODwyer PJ Schwartz GK Phase I dose-escalation trial of the oral cyclin-dependent kinase 46 inhibitor PD 0332991 administered using a 21-day schedule in patients with advanced cancer Clin Cancer Res 2012 Jan 1518(2)568-76 doi 1011581078-0432CCR-11-0509 Epub 2011 Nov 16
Novartis
Kisqalireg (ribociclib)
CDK 46 Inhibitors
Premenopausal HR+ HER2- MBC
Heavily pretreated Relapsed Metastatic Cancer
2016
132 (20 BC)
0-1 (25) 2-3 (42) 4+ (32)
Ribociclib 50 mg ranging up to 1200 mg dose escalation
23 PRndashincluded 1 in BC (5 of BC pts)
27 Gr34 Neutropenia17 Gr34 Leucopenia
Peak sales projected at $25B
Infante JR Cassier PA Gerecitano JF Witteveen PO Chugh R Ribrag V Chakraborty A Matano A Dobson JR Crystal AS Parasuraman S Shapiro GI A Phase I Study of the Cyclin-Dependent Kinase 46 Inhibitor Ribociclib (LEE011) in Patients with Advanced Solid Tumors and Lymphomas Clin Cancer Res 2016 Dec 122(23)5696-5705 Epub 2016 Aug 19
Eli Lilly
Verzenioreg (abemaciclib)
CDK 46 Inhibitors
HR+HER2minusMBC
Heavily pretreated Relapsed Metastatic Cancer
2016
12 (1 BC)
1 (312) 2 (212) 3+ (7)
Abemaciclib 100 mg ranging up to 200 mg dose escalation
17 PR (included 1 in BC)
17 Gr34 Neutropenia33 Gr34 Leucopenia
Peak sales projected at $2B
Fujiwara Y Tamura K Kondo S Tanabe Y Iwasa S Shimomura A Kitano S Ogasawara K Turner PK Mori J Asou H Chan EM Yamamoto N Phase 1 study of abemaciclib an inhibitor of CDK 4 and 6 as a single agent for Japanese patients with advanced cancer Cancer Chemother Pharmacol 2016 Aug78(2)281-8 doi 101007s00280-016-3085-8 Epub 2016 Jun 16
Mukai H Saeki T Shimada K Naito Y Matsubara N Nakanishi T Obaishi H Namiki M Sasaki Y Phase 1 combination study of eribulin mesylate with trastuzumab for advanced or recurrent human epidermal growth factor receptor 2 positive breast cancer Invest New Drugs 2015 Feb33(1)119-27
AstraZeneca
Lynparza (Olaparib)+ Cediranib
PARP inhibitor+ inhibitor of VEGF RTK
HR+ HER2- MBC
BC amp OC
13
28 (8 BC)
3 for BC
Olaparib (a poly (ADP-ribose) polymerase (PARP) inhibitor) amp Cediranib (Vascular endothelial growth factor receptor (VEGFR) 1 2 and 3 tyrosine kinase inhibitor)3 at dose level (DL) 0 (cediranib 20mg olaparib 100mg) 3 at DL1 (cediranib 20mg olaparib 200mg) 7 at DL2 (cediranib 30mg olaparib 200mg) 6 at DL3 (cediranib 30mg olaparib 400mg)
Liu JF Tolaney SM Birrer M Fleming GF Buss MK Dahlberg SE Lee H Whalen C Tyburski K Winer E Ivy P Matulonis UA A Phase 1 trial of the poly(ADP-ribose) polymerase inhibitor olaparib (AZD2281) in combination with the anti-angiogenic cediranib (AZD2171) in recurrent epithelial ovarian or triple-negative breast cancer Eur J Cancer 2013 Sep49(14)2972-8
ReyonPharma
VM206RY
Heterologous prime-boost with a truncated HER2 sequence
HER2+ Stg IIIampIV BC
15
9
2 chemo
Plasmid DNA (pHM-GM-CSF expressing truncated HER2 amp GM-CSF) amp adenoviral vector (Ad-HM containing modified HER2) (2 4 and 8 mgpatientvisit) of pHM-GM-CSF 3x IM weeks 0 2 and 4 Ad-HM 3 times 109 virus particles at week 6
11 PR
4 pts 7 minor AEs
Unclear
Kim SB Ahn JH Kim J Jung KH A phase 1 study of a heterologous prime-boost vaccination involving a truncated HER2 sequence in patients with HER2-expressing breast cancer Mol Ther Methods Clin Dev 2015 Sep 30215031 doi 101038mtm201531 eCollection 2015
Rodon J Peacuterez-Fidalgo A Krop IE Burris H Guerrero-Zotano A Britten CD Becerra C Schellens J Richards DA Schuler M Abu-Khalaf M Johnson FM Ranson M Edenfield J Silva AP Hackl W Quadt C Demanse D Duval V Baselga J Phase 11b dose escalation and expansion study of BEZ235 a dual PI3KmTOR inhibitor in patients with advanced solid tumors including patients with advanced breast cancer Cancer Chemother Pharmacol 2018 Jun 7 doi 101007s00280-018-3610-z [Epub ahead of print]
Celgene(Abraxane)
Gemcitabine + Abraxane (nab-paclitaxel)
Chemo+ Chemo
OC BC NSCLC PC + LC OC BC KS
MBC
16
9
Adjuv chemo (100)chemo post-adjuv (33)
Gem (nucleoside metabolic inhibitor 1250 mgm2) on days 1 and 8 nab-Pac (microtubule inhibitor) starting dose of 180 mgm2 (cohort 1) 220 mgm2 (cohort 2) and 260 mgm2 (cohort 3) on day 1 of the 21-day cycle using a 3 + 3 design
0
MTD not reached29 Gr3 Neutropenia59 Gr1 Peripheralneuropathy
Yoshitomi S Taira N Doihara H Mizoo T Nogami T Iwamoto T Motoki T Shien T Ogasawara Y Matsuoka J Tsuji H Mitsuhashi T A phase 1 dose-finding and pharmacokinetic study of gemcitabine with nab-paclitaxel in patients with metastatic breast cancer Cancer Chemother Pharmacol 2016 Aug78(2)289-94
Eli Lilly
Erbituxreg (cetuximab) + Taxane
EGFR inhibitor antineoplastic agent + Chemo
Head amp NeckColorectal
TNBC
07-10
18
1 chemo
Cetuximab (epidermal growth factor receptor (EGFR) antagonist ) an initial loading dose of cetuximab 400 mgm2 followed by a weekly dose of 250 mgm2Paclitaxel (microtubule inhibitor) 80 mgm2 or Docetaxel at an initial dose of 30 mgm2 was administered weekly
56 CR 22 PR
83 Dermatologic toxicity11 Grade3+
Nechushtan H Vainer G Stainberg H Salmon AY Hamburger T Peretz T A phase 12 of a combination of cetuximab and taxane for triple negative breast cancer patients Breast 2014 Aug23(4)435-8
Polyphor
Balixafortide (POL6326) + eribulin
CXCR4 antagonist + tubulin-based antimitotic
Heavily pretreatedRelapsed MBC
14-16
56
3rd line 3 chemo
3+3 dose escalation The highest dose was established as eribulin 14 mgmsup2 on days 2 and 9 and balixafortide 55 mgkg on days 1minus3 and 8minus10 of the 21-day cycle
30 PR
41 Gr34 Neutropenia11 Gr34 Leucopenia11 Gr34 Febrileneutropenia2 Related mortalities
42018 Fast Track (HER2-MBC failed 2 prior regimens)
Pernas S Martin M Kaufman PA Gil-Martin M Gomez Pardo P Lopez-Tarruella S Manso L Ciruelos E Perez-Fidalgo JA Hernando C Ademuyiwa FO Weilbaecher K Mayer I Pluard TJ Martinez Garcia M Vahdat L Perez-Garcia J Wach A Barker D Fung S Romagnoli B Cortes J Balixafortide plus eribulin in HER2-negative metastatic breast cancer a phase 1 single-arm dose-escalation trial Lancet Oncol 2018 Jun19(6)812-824
1 PRndashbut only + letrozoleNo Resp on monotherapy
61 Gr34 Neutropenia39 Gr34 Leucopenia
$933M (1Q18)$31B (2017)
Tamura K Mukai H Naito Y Yonemori K Kodaira M Tanabe Y Yamamoto N Osera S Sasaki M Mori Y Hashigaki S Nagasawa T Umeyama Y Yoshino T Phase I study of palbociclib a cyclin-dependent kinase 46 inhibitor in Japanese patients Cancer Sci 2016 Jun107(6)755-63 doi 101111cas12932 Epub 2016 May 11
Pfizer
Ibrancereg (palbociclib)
CDK 46 Inhibitor
HR+ HER2- MBC
Heavily pretreatedRelapsed Met Cancer
04-08
41 (5 BC)
chemo naiumlve (17)1-2(51) 3(29) 3+(2)
Palbociclib 25-150 mg dose ranging
0
20 Gr34 Neutropenia23 Gr34 Leucopenia
$933M (1Q18)$31B (2017)
Flaherty KT Lorusso PM Demichele A Abramson VG Courtney R Randolph SS Shaik MN Wilner KD ODwyer PJ Schwartz GK Phase I dose-escalation trial of the oral cyclin-dependent kinase 46 inhibitor PD 0332991 administered using a 21-day schedule in patients with advanced cancer Clin Cancer Res 2012 Jan 1518(2)568-76 doi 1011581078-0432CCR-11-0509 Epub 2011 Nov 16
Novartis
Kisqalireg (ribociclib)
CDK 46 Inhibitor
Premenopausal HR+ HER2- MBC
Heavily pretreatedRelapsed Met Cancer
16
132 (20 BC)
0-1 (25) 2-3 (42)4+ (32)
Ribociclib 50 mg ranging up to 1200 mg dose escalation
23 PR-included 1 BC (5 of BC pts)
27 Gr34 Neutropenia17 Gr34 Leucopenia
Peak sales est at $25B
Infante JR Cassier PA Gerecitano JF Witteveen PO Chugh R Ribrag V Chakraborty A Matano A Dobson JR Crystal AS Parasuraman S Shapiro GI A Phase I Study of the Cyclin-Dependent Kinase 46 Inhibitor Ribociclib (LEE011) in Patients with Advanced Solid Tumors and Lymphomas Clin Cancer Res 2016 Dec 122(23)5696-5705 Epub 2016 Aug 19
Eli Lilly
Verzenioreg (abemaciclib)
CDK 46 Inhibitor
HR+HER2minusMBC
Heavily pretreatedRelapsed Met Cancer
16
12 (1 BC)
1 (312) 2 (212) 3+(7)
Abemaciclib 100 mg ranging up to 200 mg dose escalation
17 PR (included 1 BC)
17 Gr34 Neutropenia33 Gr34 Leucopenia
Peak sales est at $2B
Fujiwara Y Tamura K Kondo S Tanabe Y Iwasa S Shimomura A Kitano S Ogasawara K Turner PK Mori J Asou H Chan EM Yamamoto N Phase 1 study of abemaciclib an inhibitor of CDK 4 and 6 as a single agent for Japanese patients with advanced cancer Cancer Chemother Pharmacol 2016 Aug78(2)281-8 doi 101007s00280-016-3085-8 Epub 2016 Jun 16
1 RLL 29 Not Detectable Not Detectable2 LUL apical pleural based 34 tiny nodule lt 1mm scar tiny nodule lt 1mm scar3 xxx 39 Not Detectable Not Detectable4 40 Not Detectable Not Detectable5 RLL 45 Not Detectable Not Detectable6 LLL 49 Not Detectable Not Detectable7 xxx 52 Not Detectable Not Detectable8 RLL 52 Not Detectable Not Detectable9 RLL 56 Not Detectable Not Detectable
10 RLL costophrenic recess 56 Not Detectable Not Detectable11 XXX 58 Not Detectable Not Detectable12 LUL 60 Not Detectable Not Detectable13 XXX 67 15 1514 RUL 72 15 1515 LLL 76 Not Detectable Not Detectable16 RUL Noncalcified Nodule 77 Not Detectable Not Detectable17 RLL costophrenic recess 79 10 1018 RUL 82 Not Detectable Not Detectable19 RLL 90 Not Detectable Not Detectable20 RLL 91 lt 01 lt 0121 xxx xxx Not Detectable Not Detectable
27
Clinical Development Update ndash Summary 2018 September 26
Completed enrollment of Adv Breast cancer patients in the Phase IIIa ldquomonotherapyrdquo study of Bria-IMTtrade
We have confirmed our mechanism of action and achieved proof of concept
Initial safety data appears superior to that of the other advanced or approved drugs for breast cancer when they were at a similar clinical stage of development
Initial efficacy data is similar or superior to those of other advanced or approved drugs for breast cancer when they were at a similar clinical stage of development
Initiated Combination Study of Bria-IMTtrade with Keytrudareg or Yervoyreg in Adv breast cancer patients expecting even better response rates than those in the ldquomonotherapyrdquo study Initial safety data is expected in 4Q2018 Initial efficacy data is expected in 1Q2019
Bria-OTStrade the first off-the-shelf personalized treatment for advanced breast cancer is expected to enter the clinic in 2019
28
Bria-IMTtrade Excellent Safety Data - To Date
To date Bria-IMTtrade has been dosed in 24 patients (4 in 2004-2005 20 in 2017-2018)
Interim Data (20 patients)-Ongoing Phase IIIa Study (2017-2018)
Bria-IMTtrade has been very well tolerated (ge60 doses given to date) The majority of adverse events (AEs) were limited to expected minor local irritation at the
injection sites No related grade gt3 or unexpected AEs No related serious AEs No serious unexpected related AEs Most patients who have dropped out did so due to worsening of their underlying disease
Based on the current study Bria-IMTtrade has an excellent safety profile
29
Bria-IMTtrade - Efficacy as Predicted
Interim Data (19 patients)-Ongoing Phase IIIa Study (2017-2018) amp Original Study (2004-2005)
PD-L1 expression on circulating cancer cells amp cancer-associated cells in 100 of patients (to date) Strong rationale for combination with checkpoint inhibitors like Keytruda
30
Bria-IMTtrade appears to be most effective in patients who match with Bria-IMT trade at 2 HLA loci (types) further supporting our ldquoHLA Matching Hypothesisrdquo and the development of Bria-OTS trade to cover 90 of the patient population
Combination with immune checkpoint inhibitors may induce a more potent anti-cancer response leading to our strategy of combination studies of Bria-IMT trade with Keytruda or Yervoy
Patients (n) HLA Match
Tumor Shrinkage
Biological Response
4 ge2 50 7515 ge1 27 334 0 0 0
Biological response includes tumor shrinkage or lower circulating cancer associated cells
The confirmatory Bria-IMTtrade monotherapy Phase IIa trial has completed enrollment Additional Support for the HLA-matching hypothesis has been obtained
Bria-IMTtrade Combination Therapy study with immune checkpoint inhibitors Keytrudareg if PD-L12 positive (ge1) Yervoyreg if PD-L12 negative (lt1) Accepting patients from the monotherapy study who develop progressive disease Also enrolling patients directly into this study to enhance experience with the combination In discussion with other pharmaceutical companies to evaluate additional combinations with other
immunotherapies
Bria-OTStrade Off-the-Shelf Personalized Targeted Immunotherapy Developing Bria-OTStrade to co-express GM-CSF and interferon-α Pre-manufacture additional HLA alleles ndash Total of 15 alleles (8 Class I and 7 Class II) Co-development of BriaDXtrade companion diagnostic for HLA typing Combination therapy clinical trial with immune checkpoint inhibitors for non-responders using
information from the Bria-IMTtrade Combination Therapy Study
33
Development Timeline ndash Breast Cancer
20192018 2020 2021
Phase IIIaBria-IMTtrade
Monotherapy
Currently Enrolling Phase IIaBria-IMTtrade + Checkpoint
Currently in discussions with potential partnersPhase II Bria-IMTtrade plus Additional Combinations (1Q19 4Q22)(eg PD-1 Inhibitor PD-L1 inhibitor anti-CTLA4 anti-GITR anti-OX40)
1Q 2Q 3Q 4Q
2023
Bria-OTStrade Off-The-Shelf Personalized ImmunotherapyMonotherapy and Potential Partnered Combo Therapy
(2H19 Ongoing)
Bria-OTStradeOff-the-Shelf Cell Line cGMP Manufacturing
and BriaDXtrade(1Q18 1Q19)
Registration Studies (1Q20 2H22)Bria-IMTtrade with Checkpoint InhibitorsBria-OTStrade +- Checkpoint Inhibitors
34
Immuno-oncology Deals
Recent deals of small biotechs with big pharma in immuno-oncology
35
Date PartnershipDevelopment stage at the time of the deal Deal size
07122018 Immatics-Genmab Preclinical Up to $28B
04042018 OSE Immunotherapeutics-Boehringer Ingelheim Preclinical Up to euro113B ($139B)
02092018 Pieris Pharmaceuticals-Seattle Genetics Preclinical Up to $123B
2142018 Nektar-BMS Ph III Up to $36B
01222018 Juno-Celgene Ph II $9B (Acquisition)
11142017 Loxo-Bayer Larotrectinib (Ph II) LOXO-195 (Ph III) Up to $155B
1032017 CytomX-Amgen Preclinical Up to $15B
03202017 CytomX--BMS Ph III Up to $36B
6282016 Xencor-Novartis Preclinical Up to $24B
Early Stage Clinical Studies (Comparison)
We compared the interim data of Ph IIIa study of Bria-IMTtrade in advanced breast cancer with thedata in the early stage clinical studies of recently approved breast cancer drugs and one fasttracked product candidate
Apples to apples comparison Early Stage Clinical Studies in oncology are typically done in patientswith no other therapeutic options Thus the patients have very advanced disease and response ratesare typically quite low
The patients in our Ph IIIa study have been heavily pre-treated (median 45 prior regimens)Some recent studies of relevance in breast cancer are noted in the following slides
36
Breast Cancer Market Opportunity
Drug Technology Approved for Market (US)Ibrance (palbociclib) CDK 46 Inhibitor HR+HER2- MBC in combination with
fluvestrant or aromatase inhibitor$933M in 1Q2018 $3126M in 2017
Kisqali (ribociclib) CDK 46 Inhibitor 2017 HR+HER2- MBC in combination with fluvestrant or aromatase inhibitor
Peak sales projected at $25B
Verzenio (abemaciclib) CDK 46 Inhibitor 2017 HR+HER2- MBC in combination with fluvestrant or aromatase inhibitor
balixafortide CXCR4 antagonist Fast track designation in 2018 for HER2- MBC who have failed 2 prior regimens
The market for breast cancer drugs is a multibillion dollar market with new drugs being approvedon an ongoing basis indicating the shortage of safe and effective treatments for this deadly disease
37
Competitors- Phase III Clinical Data Bria-IMTtrade shows superior safety and similar to superior efficacy data compared with those of the multi-billion dollar drugs when they were at a similar early stage of clinical development
Injection site reactions No related SAEs or SUSARs
Tumor vol darr ampor darr circul tumor cellsAll Comers 21(419) 26(519)One or More HLA matches 27(415) 33(515)Two or More HLA matches 50 (24) 75 (34)
Sheet1 (3)
Comp -Slides
Data
HLA (2)
HLA
Data (Ph1-2+4Pt)
Competitors (2018)-Slide
Competitors (2018)
In the Pipeline Protein Kinase C delta (PKCδ) Inhibitors
30 of all human malignancies display activating RAS mutations Another 60 showing over-activity of Ras-signaling pathways
Ras has been termed ldquoundruggablerdquo (no one has been able to make a Ras inhibitor drug)
BriaCellrsquos novel proprietary PKCδ inhibitors have shown activity against multiple RAS transformed tumors Lung cancer Melanoma Breast cancer Neuroendocrine cancer Pancreatic cancer Colorectal cancer
This target has an attractive safety profile based on in vivo studies and knock out mouse studies
PKCδ inhibitors should qualify for an accelerated clinical development plan and regulatory pathway
Could be in clinic within 24 months
Cost-Effective Additional Shot-on-Goal and additional partnership opportunities
Early-Stage Preclinical Program
39
Protein Kinase C delta (PKCδ) Inhibitors
Activated PKCδ inhibits RAS degradation which in turn stimulates tumor growth
Koo et al Oncotarget 621328 2016
30 of all human malignancies display activating RASmutations with another 60 showing over-activity of Ras-signaling pathways
BriaCellrsquos novel proprietary PKCδ inhibitors have shownactivity against multiple RAS transformed tumors
This target has an attractive safety profile based on in vivostudies and knock out mouse studies
PKCδ also has potential activity as an immunotherapeuticby blocking TGFβ signaling
PKCδ inhibitors are applicable to specific niche tumor typeswhich provide an accelerated clinical development plan
Structural aspects of first generation inhibitor rottlerin and staurosporine (pan-PKC activator) were combined to create second generation inhibitor KAM1
Third generation inhibitors such as BJE6-106 have improved potency and selectivity Fourth generation inhibitors under development to optimize drug-like characteristics PKCδ inhibitors lack endothelial cell cytotoxicity amp PKCδ deficient mice develop normally and are fertile Potentially no marked intrinsic toxicity by inhibiting PKCδ
Mukai H Saeki T Shimada K Naito Y Matsubara N Nakanishi T Obaishi H Namiki M Sasaki Y Phase 1 combination study of eribulin mesylate with trastuzumab for advanced or recurrent human epidermal growth factor receptor 2 positive breast cancer Invest New Drugs 2015 Feb33(1)119-27
AstraZeneca
Lynparza (Olaparib) + Cediranib
PARP inhibitor + inhibitor of VEGF receptor tyrosine kinases
HR+ HER2- MBC
BC amp OC
2013
28 (8 BC)
3 for BC
Olaparib (a poly (ADP-ribose) polymerase (PARP) inhibitor) amp Cediranib (Vascular endothelial growth factor receptor (VEGFR) 1 2 and 3 tyrosine kinase inhibitor)3 at dose level (DL) 0 (cediranib 20mg olaparib 100mg) 3 at DL1 (cediranib 20mg olaparib 200mg) 7 at DL2 (cediranib 30mg olaparib 200mg) 6 at DL3 (cediranib 30mg olaparib 400mg)
Liu JF Tolaney SM Birrer M Fleming GF Buss MK Dahlberg SE Lee H Whalen C Tyburski K Winer E Ivy P Matulonis UA A Phase 1 trial of the poly(ADP-ribose) polymerase inhibitor olaparib (AZD2281) in combination with the anti-angiogenic cediranib (AZD2171) in recurrent epithelial ovarian or triple-negative breast cancer Eur J Cancer 2013 Sep49(14)2972-8
Reyon Pharmaceutical
VM206RY
Heterologous prime-boost with a truncated HER2 sequence
HER2+ Stage IIIampIV BC
2015
9
2 chemo
Plasmid DNA (pHM-GM-CSF expressing truncated HER2 amp GM-CSF) amp adenoviral vector (Ad-HM containing modified HER2) (2 4 and 8 mgpatientvisit) of pHM-GM-CSF 3x IM weeks 0 2 and 4 Ad-HM 3 times 109 virus particles at week 6
11 PR
4 pts showed 7 minor AEs
Unclear
Kim SB Ahn JH Kim J Jung KH A phase 1 study of a heterologous prime-boost vaccination involving a truncated HER2 sequence in patients with HER2-expressing breast cancer Mol Ther Methods Clin Dev 2015 Sep 30215031 doi 101038mtm201531 eCollection 2015
Rodon J Peacuterez-Fidalgo A Krop IE Burris H Guerrero-Zotano A Britten CD Becerra C Schellens J Richards DA Schuler M Abu-Khalaf M Johnson FM Ranson M Edenfield J Silva AP Hackl W Quadt C Demanse D Duval V Baselga J Phase 11b dose escalation and expansion study of BEZ235 a dual PI3KmTOR inhibitor in patients with advanced solid tumors including patients with advanced breast cancer Cancer Chemother Pharmacol 2018 Jun 7 doi 101007s00280-018-3610-z [Epub ahead of print]
Celgene (Abraxane)
Gemcitabine + Abraxane (nab-paclitaxel)
Chemo + Chemo
OC BC NSCLC amp Panc cancer + Lung OC BC Kaposi sarcoma
MBC
2016
9
Adjuvant chemo (100)chemo post-adjuvant (33)
Gem (nucleoside metabolic inhibitor 1250 mgm2) on days 1 and 8 nab-Pac (microtubule inhibitor) starting dose of 180 mgm2 (cohort 1) 220 mgm2 (cohort 2) and 260 mgm2 (cohort 3) on day 1 of the 21-day cycle using a 3 + 3 design
0
MTD not reached29 Gr3 Neutropenia59 Gr1 Peripheralneuropathy
Yoshitomi S Taira N Doihara H Mizoo T Nogami T Iwamoto T Motoki T Shien T Ogasawara Y Matsuoka J Tsuji H Mitsuhashi T A phase 1 dose-finding and pharmacokinetic study of gemcitabine with nab-paclitaxel in patients with metastatic breast cancer Cancer Chemother Pharmacol 2016 Aug78(2)289-94
Eli Lilly
Erbituxreg (cetuximab) + Taxane
EGFR inhibitor antineoplastic agent + Chemo
Headamp Neck Colorectal Cancer
TNBC
2007-2010
18
1 chemo
Cetuximab (epidermal growth factor receptor (EGFR) antagonist ) an initial loading dose of cetuximab 400 mgm2 followed by a weekly dose of 250 mgm2Paclitaxel (microtubule inhibitor) 80 mgm2 or Docetaxel at an initial dose of 30 mgm2 was administered weekly
56 CR 22 PR
83 Dermatologic toxicity11 Grade3+
Nechushtan H Vainer G Stainberg H Salmon AY Hamburger T Peretz T A phase 12 of a combination of cetuximab and taxane for triple negative breast cancer patients Breast 2014 Aug23(4)435-8
Polyphor
Balixafortide (POL6326) + eribulin
CXCR4 antagonist + tubulin-based antimitotic
Heavily pretreated Relapsed MBC
2014-2016
56
3rd line 3 chemo
3+3 dose escalation The highest dose was established as eribulin 14 mgmsup2 on days 2 and 9 and balixafortide 55 mgkg on days 1minus3 and 8minus10 of the 21-day cycle
30 PR
41 Gr34 Neutropenia11 Gr34 Leucopenia11 Gr34 Febrileneutropenia2 Related mortalities
Apr 2018 Fast Track for HER2-MBC who have failed 2prior regimens
Pernas S Martin M Kaufman PA Gil-Martin M Gomez Pardo P Lopez-Tarruella S Manso L Ciruelos E Perez-Fidalgo JA Hernando C Ademuyiwa FO Weilbaecher K Mayer I Pluard TJ Martinez Garcia M Vahdat L Perez-Garcia J Wach A Barker D Fung S Romagnoli B Cortes J Balixafortide plus eribulin in HER2-negative metastatic breast cancer a phase 1 single-arm dose-escalation trial Lancet Oncol 2018 Jun19(6)812-824
11 PRndashbut only + letrozole (No Resp on monotherapy)
61 Gr34 Neutropenia39 Gr34 Leucopenia
$933M in 1Q2018 $31B in 2017
Tamura K Mukai H Naito Y Yonemori K Kodaira M Tanabe Y Yamamoto N Osera S Sasaki M Mori Y Hashigaki S Nagasawa T Umeyama Y Yoshino T Phase I study of palbociclib a cyclin-dependent kinase 46 inhibitor in Japanese patients Cancer Sci 2016 Jun107(6)755-63 doi 101111cas12932 Epub 2016 May 11
Pfizer
Ibrancereg (palbociclib)
CDK 46 Inhibitor
HR+ HER2- MBC
Heavily pretreated Relapsed Metastatic Cancer
2004-2008
41 (5 BC)
chemo naiumlve (17) 1-2 (51)3 (29) 3+ (2)
Palbociclib 25-150 mg dose ranging
0
20 Gr34 Neutropenia23 Gr34 Leucopenia
$933M in 1Q2018 $31B in 2017
Flaherty KT Lorusso PM Demichele A Abramson VG Courtney R Randolph SS Shaik MN Wilner KD ODwyer PJ Schwartz GK Phase I dose-escalation trial of the oral cyclin-dependent kinase 46 inhibitor PD 0332991 administered using a 21-day schedule in patients with advanced cancer Clin Cancer Res 2012 Jan 1518(2)568-76 doi 1011581078-0432CCR-11-0509 Epub 2011 Nov 16
Novartis
Kisqalireg (ribociclib)
CDK 46 Inhibitors
Premenopausal HR+ HER2- MBC
Heavily pretreated Relapsed Metastatic Cancer
2016
132 (20 BC)
0-1 (25) 2-3 (42) 4+ (32)
Ribociclib 50 mg ranging up to 1200 mg dose escalation
23 PRndashincluded 1 in BC (5 of BC pts)
27 Gr34 Neutropenia17 Gr34 Leucopenia
Peak sales projected at $25B
Infante JR Cassier PA Gerecitano JF Witteveen PO Chugh R Ribrag V Chakraborty A Matano A Dobson JR Crystal AS Parasuraman S Shapiro GI A Phase I Study of the Cyclin-Dependent Kinase 46 Inhibitor Ribociclib (LEE011) in Patients with Advanced Solid Tumors and Lymphomas Clin Cancer Res 2016 Dec 122(23)5696-5705 Epub 2016 Aug 19
Eli Lilly
Verzenioreg (abemaciclib)
CDK 46 Inhibitors
HR+HER2minusMBC
Heavily pretreated Relapsed Metastatic Cancer
2016
12 (1 BC)
1 (312) 2 (212) 3+ (7)
Abemaciclib 100 mg ranging up to 200 mg dose escalation
17 PR (included 1 in BC)
17 Gr34 Neutropenia33 Gr34 Leucopenia
Peak sales projected at $2B
Fujiwara Y Tamura K Kondo S Tanabe Y Iwasa S Shimomura A Kitano S Ogasawara K Turner PK Mori J Asou H Chan EM Yamamoto N Phase 1 study of abemaciclib an inhibitor of CDK 4 and 6 as a single agent for Japanese patients with advanced cancer Cancer Chemother Pharmacol 2016 Aug78(2)281-8 doi 101007s00280-016-3085-8 Epub 2016 Jun 16
Mukai H Saeki T Shimada K Naito Y Matsubara N Nakanishi T Obaishi H Namiki M Sasaki Y Phase 1 combination study of eribulin mesylate with trastuzumab for advanced or recurrent human epidermal growth factor receptor 2 positive breast cancer Invest New Drugs 2015 Feb33(1)119-27
AstraZeneca
Lynparza (Olaparib)+ Cediranib
PARP inhibitor+ inhibitor of VEGF RTK
HR+ HER2- MBC
BC amp OC
13
28 (8 BC)
3 for BC
Olaparib (a poly (ADP-ribose) polymerase (PARP) inhibitor) amp Cediranib (Vascular endothelial growth factor receptor (VEGFR) 1 2 and 3 tyrosine kinase inhibitor)3 at dose level (DL) 0 (cediranib 20mg olaparib 100mg) 3 at DL1 (cediranib 20mg olaparib 200mg) 7 at DL2 (cediranib 30mg olaparib 200mg) 6 at DL3 (cediranib 30mg olaparib 400mg)
Liu JF Tolaney SM Birrer M Fleming GF Buss MK Dahlberg SE Lee H Whalen C Tyburski K Winer E Ivy P Matulonis UA A Phase 1 trial of the poly(ADP-ribose) polymerase inhibitor olaparib (AZD2281) in combination with the anti-angiogenic cediranib (AZD2171) in recurrent epithelial ovarian or triple-negative breast cancer Eur J Cancer 2013 Sep49(14)2972-8
ReyonPharma
VM206RY
Heterologous prime-boost with a truncated HER2 sequence
HER2+ Stg IIIampIV BC
15
9
2 chemo
Plasmid DNA (pHM-GM-CSF expressing truncated HER2 amp GM-CSF) amp adenoviral vector (Ad-HM containing modified HER2) (2 4 and 8 mgpatientvisit) of pHM-GM-CSF 3x IM weeks 0 2 and 4 Ad-HM 3 times 109 virus particles at week 6
11 PR
4 pts 7 minor AEs
Unclear
Kim SB Ahn JH Kim J Jung KH A phase 1 study of a heterologous prime-boost vaccination involving a truncated HER2 sequence in patients with HER2-expressing breast cancer Mol Ther Methods Clin Dev 2015 Sep 30215031 doi 101038mtm201531 eCollection 2015
Rodon J Peacuterez-Fidalgo A Krop IE Burris H Guerrero-Zotano A Britten CD Becerra C Schellens J Richards DA Schuler M Abu-Khalaf M Johnson FM Ranson M Edenfield J Silva AP Hackl W Quadt C Demanse D Duval V Baselga J Phase 11b dose escalation and expansion study of BEZ235 a dual PI3KmTOR inhibitor in patients with advanced solid tumors including patients with advanced breast cancer Cancer Chemother Pharmacol 2018 Jun 7 doi 101007s00280-018-3610-z [Epub ahead of print]
Celgene(Abraxane)
Gemcitabine + Abraxane (nab-paclitaxel)
Chemo+ Chemo
OC BC NSCLC PC + LC OC BC KS
MBC
16
9
Adjuv chemo (100)chemo post-adjuv (33)
Gem (nucleoside metabolic inhibitor 1250 mgm2) on days 1 and 8 nab-Pac (microtubule inhibitor) starting dose of 180 mgm2 (cohort 1) 220 mgm2 (cohort 2) and 260 mgm2 (cohort 3) on day 1 of the 21-day cycle using a 3 + 3 design
0
MTD not reached29 Gr3 Neutropenia59 Gr1 Peripheralneuropathy
Yoshitomi S Taira N Doihara H Mizoo T Nogami T Iwamoto T Motoki T Shien T Ogasawara Y Matsuoka J Tsuji H Mitsuhashi T A phase 1 dose-finding and pharmacokinetic study of gemcitabine with nab-paclitaxel in patients with metastatic breast cancer Cancer Chemother Pharmacol 2016 Aug78(2)289-94
Eli Lilly
Erbituxreg (cetuximab) + Taxane
EGFR inhibitor antineoplastic agent + Chemo
Head amp NeckColorectal
TNBC
07-10
18
1 chemo
Cetuximab (epidermal growth factor receptor (EGFR) antagonist ) an initial loading dose of cetuximab 400 mgm2 followed by a weekly dose of 250 mgm2Paclitaxel (microtubule inhibitor) 80 mgm2 or Docetaxel at an initial dose of 30 mgm2 was administered weekly
56 CR 22 PR
83 Dermatologic toxicity11 Grade3+
Nechushtan H Vainer G Stainberg H Salmon AY Hamburger T Peretz T A phase 12 of a combination of cetuximab and taxane for triple negative breast cancer patients Breast 2014 Aug23(4)435-8
Polyphor
Balixafortide (POL6326) + eribulin
CXCR4 antagonist + tubulin-based antimitotic
Heavily pretreatedRelapsed MBC
14-16
56
3rd line 3 chemo
3+3 dose escalation The highest dose was established as eribulin 14 mgmsup2 on days 2 and 9 and balixafortide 55 mgkg on days 1minus3 and 8minus10 of the 21-day cycle
30 PR
41 Gr34 Neutropenia11 Gr34 Leucopenia11 Gr34 Febrileneutropenia2 Related mortalities
42018 Fast Track (HER2-MBC failed 2 prior regimens)
Pernas S Martin M Kaufman PA Gil-Martin M Gomez Pardo P Lopez-Tarruella S Manso L Ciruelos E Perez-Fidalgo JA Hernando C Ademuyiwa FO Weilbaecher K Mayer I Pluard TJ Martinez Garcia M Vahdat L Perez-Garcia J Wach A Barker D Fung S Romagnoli B Cortes J Balixafortide plus eribulin in HER2-negative metastatic breast cancer a phase 1 single-arm dose-escalation trial Lancet Oncol 2018 Jun19(6)812-824
1 PRndashbut only + letrozoleNo Resp on monotherapy
61 Gr34 Neutropenia39 Gr34 Leucopenia
$933M (1Q18)$31B (2017)
Tamura K Mukai H Naito Y Yonemori K Kodaira M Tanabe Y Yamamoto N Osera S Sasaki M Mori Y Hashigaki S Nagasawa T Umeyama Y Yoshino T Phase I study of palbociclib a cyclin-dependent kinase 46 inhibitor in Japanese patients Cancer Sci 2016 Jun107(6)755-63 doi 101111cas12932 Epub 2016 May 11
Pfizer
Ibrancereg (palbociclib)
CDK 46 Inhibitor
HR+ HER2- MBC
Heavily pretreatedRelapsed Met Cancer
04-08
41 (5 BC)
chemo naiumlve (17)1-2(51) 3(29) 3+(2)
Palbociclib 25-150 mg dose ranging
0
20 Gr34 Neutropenia23 Gr34 Leucopenia
$933M (1Q18)$31B (2017)
Flaherty KT Lorusso PM Demichele A Abramson VG Courtney R Randolph SS Shaik MN Wilner KD ODwyer PJ Schwartz GK Phase I dose-escalation trial of the oral cyclin-dependent kinase 46 inhibitor PD 0332991 administered using a 21-day schedule in patients with advanced cancer Clin Cancer Res 2012 Jan 1518(2)568-76 doi 1011581078-0432CCR-11-0509 Epub 2011 Nov 16
Novartis
Kisqalireg (ribociclib)
CDK 46 Inhibitor
Premenopausal HR+ HER2- MBC
Heavily pretreatedRelapsed Met Cancer
16
132 (20 BC)
0-1 (25) 2-3 (42)4+ (32)
Ribociclib 50 mg ranging up to 1200 mg dose escalation
23 PR-included 1 BC (5 of BC pts)
27 Gr34 Neutropenia17 Gr34 Leucopenia
Peak sales est at $25B
Infante JR Cassier PA Gerecitano JF Witteveen PO Chugh R Ribrag V Chakraborty A Matano A Dobson JR Crystal AS Parasuraman S Shapiro GI A Phase I Study of the Cyclin-Dependent Kinase 46 Inhibitor Ribociclib (LEE011) in Patients with Advanced Solid Tumors and Lymphomas Clin Cancer Res 2016 Dec 122(23)5696-5705 Epub 2016 Aug 19
Eli Lilly
Verzenioreg (abemaciclib)
CDK 46 Inhibitor
HR+HER2minusMBC
Heavily pretreatedRelapsed Met Cancer
16
12 (1 BC)
1 (312) 2 (212) 3+(7)
Abemaciclib 100 mg ranging up to 200 mg dose escalation
17 PR (included 1 BC)
17 Gr34 Neutropenia33 Gr34 Leucopenia
Peak sales est at $2B
Fujiwara Y Tamura K Kondo S Tanabe Y Iwasa S Shimomura A Kitano S Ogasawara K Turner PK Mori J Asou H Chan EM Yamamoto N Phase 1 study of abemaciclib an inhibitor of CDK 4 and 6 as a single agent for Japanese patients with advanced cancer Cancer Chemother Pharmacol 2016 Aug78(2)281-8 doi 101007s00280-016-3085-8 Epub 2016 Jun 16
Mukai H Saeki T Shimada K Naito Y Matsubara N Nakanishi T Obaishi H Namiki M Sasaki Y Phase 1 combination study of eribulin mesylate with trastuzumab for advanced or recurrent human epidermal growth factor receptor 2 positive breast cancer Invest New Drugs 2015 Feb33(1)119-27
AstraZeneca
Lynparza (Olaparib) + Cediranib
PARP inhibitor + inhibitor of VEGF receptor tyrosine kinases
HR+ HER2- MBC
BC amp OC
2013
28 (8 BC)
3 for BC
Olaparib (a poly (ADP-ribose) polymerase (PARP) inhibitor) amp Cediranib (Vascular endothelial growth factor receptor (VEGFR) 1 2 and 3 tyrosine kinase inhibitor)3 at dose level (DL) 0 (cediranib 20mg olaparib 100mg) 3 at DL1 (cediranib 20mg olaparib 200mg) 7 at DL2 (cediranib 30mg olaparib 200mg) 6 at DL3 (cediranib 30mg olaparib 400mg)
Liu JF Tolaney SM Birrer M Fleming GF Buss MK Dahlberg SE Lee H Whalen C Tyburski K Winer E Ivy P Matulonis UA A Phase 1 trial of the poly(ADP-ribose) polymerase inhibitor olaparib (AZD2281) in combination with the anti-angiogenic cediranib (AZD2171) in recurrent epithelial ovarian or triple-negative breast cancer Eur J Cancer 2013 Sep49(14)2972-8
Reyon Pharmaceutical
VM206RY
Heterologous prime-boost with a truncated HER2 sequence
HER2+ Stage IIIampIV BC
2015
9
2 chemo
Plasmid DNA (pHM-GM-CSF expressing truncated HER2 amp GM-CSF) amp adenoviral vector (Ad-HM containing modified HER2) (2 4 and 8 mgpatientvisit) of pHM-GM-CSF 3x IM weeks 0 2 and 4 Ad-HM 3 times 109 virus particles at week 6
11 PR
4 pts showed 7 minor AEs
Unclear
Kim SB Ahn JH Kim J Jung KH A phase 1 study of a heterologous prime-boost vaccination involving a truncated HER2 sequence in patients with HER2-expressing breast cancer Mol Ther Methods Clin Dev 2015 Sep 30215031 doi 101038mtm201531 eCollection 2015
Rodon J Peacuterez-Fidalgo A Krop IE Burris H Guerrero-Zotano A Britten CD Becerra C Schellens J Richards DA Schuler M Abu-Khalaf M Johnson FM Ranson M Edenfield J Silva AP Hackl W Quadt C Demanse D Duval V Baselga J Phase 11b dose escalation and expansion study of BEZ235 a dual PI3KmTOR inhibitor in patients with advanced solid tumors including patients with advanced breast cancer Cancer Chemother Pharmacol 2018 Jun 7 doi 101007s00280-018-3610-z [Epub ahead of print]
Celgene (Abraxane)
Gemcitabine + Abraxane (nab-paclitaxel)
Chemo + Chemo
OC BC NSCLC amp Panc cancer + Lung OC BC Kaposi sarcoma
MBC
2016
9
Adjuvant chemo (100)chemo post-adjuvant (33)
Gem (nucleoside metabolic inhibitor 1250 mgm2) on days 1 and 8 nab-Pac (microtubule inhibitor) starting dose of 180 mgm2 (cohort 1) 220 mgm2 (cohort 2) and 260 mgm2 (cohort 3) on day 1 of the 21-day cycle using a 3 + 3 design
0
MTD not reached29 Gr3 Neutropenia59 Gr1 Peripheralneuropathy
Yoshitomi S Taira N Doihara H Mizoo T Nogami T Iwamoto T Motoki T Shien T Ogasawara Y Matsuoka J Tsuji H Mitsuhashi T A phase 1 dose-finding and pharmacokinetic study of gemcitabine with nab-paclitaxel in patients with metastatic breast cancer Cancer Chemother Pharmacol 2016 Aug78(2)289-94
Eli Lilly
Erbituxreg (cetuximab) + Taxane
EGFR inhibitor antineoplastic agent + Chemo
Headamp Neck Colorectal Cancer
TNBC
2007-2010
18
1 chemo
Cetuximab (epidermal growth factor receptor (EGFR) antagonist ) an initial loading dose of cetuximab 400 mgm2 followed by a weekly dose of 250 mgm2Paclitaxel (microtubule inhibitor) 80 mgm2 or Docetaxel at an initial dose of 30 mgm2 was administered weekly
56 CR 22 PR
83 Dermatologic toxicity11 Grade3+
Nechushtan H Vainer G Stainberg H Salmon AY Hamburger T Peretz T A phase 12 of a combination of cetuximab and taxane for triple negative breast cancer patients Breast 2014 Aug23(4)435-8
Polyphor
Balixafortide (POL6326) + eribulin
CXCR4 antagonist + tubulin-based antimitotic
Heavily pretreated Relapsed MBC
2014-2016
56
3rd line 3 chemo
3+3 dose escalation The highest dose was established as eribulin 14 mgmsup2 on days 2 and 9 and balixafortide 55 mgkg on days 1minus3 and 8minus10 of the 21-day cycle
30 PR
41 Gr34 Neutropenia11 Gr34 Leucopenia11 Gr34 Febrileneutropenia2 Related mortalities
Apr 2018 Fast Track for HER2-MBC who have failed 2prior regimens
Pernas S Martin M Kaufman PA Gil-Martin M Gomez Pardo P Lopez-Tarruella S Manso L Ciruelos E Perez-Fidalgo JA Hernando C Ademuyiwa FO Weilbaecher K Mayer I Pluard TJ Martinez Garcia M Vahdat L Perez-Garcia J Wach A Barker D Fung S Romagnoli B Cortes J Balixafortide plus eribulin in HER2-negative metastatic breast cancer a phase 1 single-arm dose-escalation trial Lancet Oncol 2018 Jun19(6)812-824
11 PRndashbut only + letrozole (No Resp on monotherapy)
61 Gr34 Neutropenia39 Gr34 Leucopenia
$933M in 1Q2018 $31B in 2017
Tamura K Mukai H Naito Y Yonemori K Kodaira M Tanabe Y Yamamoto N Osera S Sasaki M Mori Y Hashigaki S Nagasawa T Umeyama Y Yoshino T Phase I study of palbociclib a cyclin-dependent kinase 46 inhibitor in Japanese patients Cancer Sci 2016 Jun107(6)755-63 doi 101111cas12932 Epub 2016 May 11
Pfizer
Ibrancereg (palbociclib)
CDK 46 Inhibitor
HR+ HER2- MBC
Heavily pretreated Relapsed Metastatic Cancer
2004-2008
41 (5 BC)
chemo naiumlve (17) 1-2 (51)3 (29) 3+ (2)
Palbociclib 25-150 mg dose ranging
0
20 Gr34 Neutropenia23 Gr34 Leucopenia
$933M in 1Q2018 $31B in 2017
Flaherty KT Lorusso PM Demichele A Abramson VG Courtney R Randolph SS Shaik MN Wilner KD ODwyer PJ Schwartz GK Phase I dose-escalation trial of the oral cyclin-dependent kinase 46 inhibitor PD 0332991 administered using a 21-day schedule in patients with advanced cancer Clin Cancer Res 2012 Jan 1518(2)568-76 doi 1011581078-0432CCR-11-0509 Epub 2011 Nov 16
Novartis
Kisqalireg (ribociclib)
CDK 46 Inhibitors
Premenopausal HR+ HER2- MBC
Heavily pretreated Relapsed Metastatic Cancer
2016
132 (20 BC)
0-1 (25) 2-3 (42) 4+ (32)
Ribociclib 50 mg ranging up to 1200 mg dose escalation
23 PRndashincluded 1 in BC (5 of BC pts)
27 Gr34 Neutropenia17 Gr34 Leucopenia
Peak sales projected at $25B
Infante JR Cassier PA Gerecitano JF Witteveen PO Chugh R Ribrag V Chakraborty A Matano A Dobson JR Crystal AS Parasuraman S Shapiro GI A Phase I Study of the Cyclin-Dependent Kinase 46 Inhibitor Ribociclib (LEE011) in Patients with Advanced Solid Tumors and Lymphomas Clin Cancer Res 2016 Dec 122(23)5696-5705 Epub 2016 Aug 19
Eli Lilly
Verzenioreg (abemaciclib)
CDK 46 Inhibitors
HR+HER2minusMBC
Heavily pretreated Relapsed Metastatic Cancer
2016
12 (1 BC)
1 (312) 2 (212) 3+ (7)
Abemaciclib 100 mg ranging up to 200 mg dose escalation
17 PR (included 1 in BC)
17 Gr34 Neutropenia33 Gr34 Leucopenia
Peak sales projected at $2B
Fujiwara Y Tamura K Kondo S Tanabe Y Iwasa S Shimomura A Kitano S Ogasawara K Turner PK Mori J Asou H Chan EM Yamamoto N Phase 1 study of abemaciclib an inhibitor of CDK 4 and 6 as a single agent for Japanese patients with advanced cancer Cancer Chemother Pharmacol 2016 Aug78(2)281-8 doi 101007s00280-016-3085-8 Epub 2016 Jun 16
Mukai H Saeki T Shimada K Naito Y Matsubara N Nakanishi T Obaishi H Namiki M Sasaki Y Phase 1 combination study of eribulin mesylate with trastuzumab for advanced or recurrent human epidermal growth factor receptor 2 positive breast cancer Invest New Drugs 2015 Feb33(1)119-27
AstraZeneca
Lynparza (Olaparib)+ Cediranib
PARP inhibitor+ inhibitor of VEGF RTK
HR+ HER2- MBC
BC amp OC
13
28 (8 BC)
3 for BC
Olaparib (a poly (ADP-ribose) polymerase (PARP) inhibitor) amp Cediranib (Vascular endothelial growth factor receptor (VEGFR) 1 2 and 3 tyrosine kinase inhibitor)3 at dose level (DL) 0 (cediranib 20mg olaparib 100mg) 3 at DL1 (cediranib 20mg olaparib 200mg) 7 at DL2 (cediranib 30mg olaparib 200mg) 6 at DL3 (cediranib 30mg olaparib 400mg)
Liu JF Tolaney SM Birrer M Fleming GF Buss MK Dahlberg SE Lee H Whalen C Tyburski K Winer E Ivy P Matulonis UA A Phase 1 trial of the poly(ADP-ribose) polymerase inhibitor olaparib (AZD2281) in combination with the anti-angiogenic cediranib (AZD2171) in recurrent epithelial ovarian or triple-negative breast cancer Eur J Cancer 2013 Sep49(14)2972-8
ReyonPharma
VM206RY
Heterologous prime-boost with a truncated HER2 sequence
HER2+ Stg IIIampIV BC
15
9
2 chemo
Plasmid DNA (pHM-GM-CSF expressing truncated HER2 amp GM-CSF) amp adenoviral vector (Ad-HM containing modified HER2) (2 4 and 8 mgpatientvisit) of pHM-GM-CSF 3x IM weeks 0 2 and 4 Ad-HM 3 times 109 virus particles at week 6
11 PR
4 pts 7 minor AEs
Unclear
Kim SB Ahn JH Kim J Jung KH A phase 1 study of a heterologous prime-boost vaccination involving a truncated HER2 sequence in patients with HER2-expressing breast cancer Mol Ther Methods Clin Dev 2015 Sep 30215031 doi 101038mtm201531 eCollection 2015
Rodon J Peacuterez-Fidalgo A Krop IE Burris H Guerrero-Zotano A Britten CD Becerra C Schellens J Richards DA Schuler M Abu-Khalaf M Johnson FM Ranson M Edenfield J Silva AP Hackl W Quadt C Demanse D Duval V Baselga J Phase 11b dose escalation and expansion study of BEZ235 a dual PI3KmTOR inhibitor in patients with advanced solid tumors including patients with advanced breast cancer Cancer Chemother Pharmacol 2018 Jun 7 doi 101007s00280-018-3610-z [Epub ahead of print]
Celgene(Abraxane)
Gemcitabine + Abraxane (nab-paclitaxel)
Chemo+ Chemo
OC BC NSCLC PC + LC OC BC KS
MBC
16
9
Adjuv chemo (100)chemo post-adjuv (33)
Gem (nucleoside metabolic inhibitor 1250 mgm2) on days 1 and 8 nab-Pac (microtubule inhibitor) starting dose of 180 mgm2 (cohort 1) 220 mgm2 (cohort 2) and 260 mgm2 (cohort 3) on day 1 of the 21-day cycle using a 3 + 3 design
0
MTD not reached29 Gr3 Neutropenia59 Gr1 Peripheralneuropathy
Yoshitomi S Taira N Doihara H Mizoo T Nogami T Iwamoto T Motoki T Shien T Ogasawara Y Matsuoka J Tsuji H Mitsuhashi T A phase 1 dose-finding and pharmacokinetic study of gemcitabine with nab-paclitaxel in patients with metastatic breast cancer Cancer Chemother Pharmacol 2016 Aug78(2)289-94
Eli Lilly
Erbituxreg (cetuximab) + Taxane
EGFR inhibitor antineoplastic agent + Chemo
Head amp NeckColorectal
TNBC
07-10
18
1 chemo
Cetuximab (epidermal growth factor receptor (EGFR) antagonist ) an initial loading dose of cetuximab 400 mgm2 followed by a weekly dose of 250 mgm2Paclitaxel (microtubule inhibitor) 80 mgm2 or Docetaxel at an initial dose of 30 mgm2 was administered weekly
56 CR 22 PR
83 Dermatologic toxicity11 Grade3+
Nechushtan H Vainer G Stainberg H Salmon AY Hamburger T Peretz T A phase 12 of a combination of cetuximab and taxane for triple negative breast cancer patients Breast 2014 Aug23(4)435-8
Polyphor
Balixafortide (POL6326) + eribulin
CXCR4 antagonist + tubulin-based antimitotic
Heavily pretreatedRelapsed MBC
14-16
56
3rd line 3 chemo
3+3 dose escalation The highest dose was established as eribulin 14 mgmsup2 on days 2 and 9 and balixafortide 55 mgkg on days 1minus3 and 8minus10 of the 21-day cycle
30 PR
41 Gr34 Neutropenia11 Gr34 Leucopenia11 Gr34 Febrileneutropenia2 Related mortalities
42018 Fast Track (HER2-MBC failed 2 prior regimens)
Pernas S Martin M Kaufman PA Gil-Martin M Gomez Pardo P Lopez-Tarruella S Manso L Ciruelos E Perez-Fidalgo JA Hernando C Ademuyiwa FO Weilbaecher K Mayer I Pluard TJ Martinez Garcia M Vahdat L Perez-Garcia J Wach A Barker D Fung S Romagnoli B Cortes J Balixafortide plus eribulin in HER2-negative metastatic breast cancer a phase 1 single-arm dose-escalation trial Lancet Oncol 2018 Jun19(6)812-824
1 PRndashbut only + letrozoleNo Resp on monotherapy
61 Gr34 Neutropenia39 Gr34 Leucopenia
$933M (1Q18)$31B (2017)
Tamura K Mukai H Naito Y Yonemori K Kodaira M Tanabe Y Yamamoto N Osera S Sasaki M Mori Y Hashigaki S Nagasawa T Umeyama Y Yoshino T Phase I study of palbociclib a cyclin-dependent kinase 46 inhibitor in Japanese patients Cancer Sci 2016 Jun107(6)755-63 doi 101111cas12932 Epub 2016 May 11
Pfizer
Ibrancereg (palbociclib)
CDK 46 Inhibitor
HR+ HER2- MBC
Heavily pretreatedRelapsed Met Cancer
04-08
41 (5 BC)
chemo naiumlve (17)1-2(51) 3(29) 3+(2)
Palbociclib 25-150 mg dose ranging
0
20 Gr34 Neutropenia23 Gr34 Leucopenia
$933M (1Q18)$31B (2017)
Flaherty KT Lorusso PM Demichele A Abramson VG Courtney R Randolph SS Shaik MN Wilner KD ODwyer PJ Schwartz GK Phase I dose-escalation trial of the oral cyclin-dependent kinase 46 inhibitor PD 0332991 administered using a 21-day schedule in patients with advanced cancer Clin Cancer Res 2012 Jan 1518(2)568-76 doi 1011581078-0432CCR-11-0509 Epub 2011 Nov 16
Novartis
Kisqalireg (ribociclib)
CDK 46 Inhibitor
Premenopausal HR+ HER2- MBC
Heavily pretreatedRelapsed Met Cancer
16
132 (20 BC)
0-1 (25) 2-3 (42)4+ (32)
Ribociclib 50 mg ranging up to 1200 mg dose escalation
23 PR-included 1 BC (5 of BC pts)
27 Gr34 Neutropenia17 Gr34 Leucopenia
Peak sales est at $25B
Infante JR Cassier PA Gerecitano JF Witteveen PO Chugh R Ribrag V Chakraborty A Matano A Dobson JR Crystal AS Parasuraman S Shapiro GI A Phase I Study of the Cyclin-Dependent Kinase 46 Inhibitor Ribociclib (LEE011) in Patients with Advanced Solid Tumors and Lymphomas Clin Cancer Res 2016 Dec 122(23)5696-5705 Epub 2016 Aug 19
Eli Lilly
Verzenioreg (abemaciclib)
CDK 46 Inhibitor
HR+HER2minusMBC
Heavily pretreatedRelapsed Met Cancer
16
12 (1 BC)
1 (312) 2 (212) 3+(7)
Abemaciclib 100 mg ranging up to 200 mg dose escalation
17 PR (included 1 BC)
17 Gr34 Neutropenia33 Gr34 Leucopenia
Peak sales est at $2B
Fujiwara Y Tamura K Kondo S Tanabe Y Iwasa S Shimomura A Kitano S Ogasawara K Turner PK Mori J Asou H Chan EM Yamamoto N Phase 1 study of abemaciclib an inhibitor of CDK 4 and 6 as a single agent for Japanese patients with advanced cancer Cancer Chemother Pharmacol 2016 Aug78(2)281-8 doi 101007s00280-016-3085-8 Epub 2016 Jun 16
1 RLL 29 Not Detectable Not Detectable2 LUL apical pleural based 34 tiny nodule lt 1mm scar tiny nodule lt 1mm scar3 xxx 39 Not Detectable Not Detectable4 40 Not Detectable Not Detectable5 RLL 45 Not Detectable Not Detectable6 LLL 49 Not Detectable Not Detectable7 xxx 52 Not Detectable Not Detectable8 RLL 52 Not Detectable Not Detectable9 RLL 56 Not Detectable Not Detectable
10 RLL costophrenic recess 56 Not Detectable Not Detectable11 XXX 58 Not Detectable Not Detectable12 LUL 60 Not Detectable Not Detectable13 XXX 67 15 1514 RUL 72 15 1515 LLL 76 Not Detectable Not Detectable16 RUL Noncalcified Nodule 77 Not Detectable Not Detectable17 RLL costophrenic recess 79 10 1018 RUL 82 Not Detectable Not Detectable19 RLL 90 Not Detectable Not Detectable20 RLL 91 lt 01 lt 0121 xxx xxx Not Detectable Not Detectable
27
Clinical Development Update ndash Summary 2018 September 26
Completed enrollment of Adv Breast cancer patients in the Phase IIIa ldquomonotherapyrdquo study of Bria-IMTtrade
We have confirmed our mechanism of action and achieved proof of concept
Initial safety data appears superior to that of the other advanced or approved drugs for breast cancer when they were at a similar clinical stage of development
Initial efficacy data is similar or superior to those of other advanced or approved drugs for breast cancer when they were at a similar clinical stage of development
Initiated Combination Study of Bria-IMTtrade with Keytrudareg or Yervoyreg in Adv breast cancer patients expecting even better response rates than those in the ldquomonotherapyrdquo study Initial safety data is expected in 4Q2018 Initial efficacy data is expected in 1Q2019
Bria-OTStrade the first off-the-shelf personalized treatment for advanced breast cancer is expected to enter the clinic in 2019
28
Bria-IMTtrade Excellent Safety Data - To Date
To date Bria-IMTtrade has been dosed in 24 patients (4 in 2004-2005 20 in 2017-2018)
Interim Data (20 patients)-Ongoing Phase IIIa Study (2017-2018)
Bria-IMTtrade has been very well tolerated (ge60 doses given to date) The majority of adverse events (AEs) were limited to expected minor local irritation at the
injection sites No related grade gt3 or unexpected AEs No related serious AEs No serious unexpected related AEs Most patients who have dropped out did so due to worsening of their underlying disease
Based on the current study Bria-IMTtrade has an excellent safety profile
29
Bria-IMTtrade - Efficacy as Predicted
Interim Data (19 patients)-Ongoing Phase IIIa Study (2017-2018) amp Original Study (2004-2005)
PD-L1 expression on circulating cancer cells amp cancer-associated cells in 100 of patients (to date) Strong rationale for combination with checkpoint inhibitors like Keytruda
30
Bria-IMTtrade appears to be most effective in patients who match with Bria-IMT trade at 2 HLA loci (types) further supporting our ldquoHLA Matching Hypothesisrdquo and the development of Bria-OTS trade to cover 90 of the patient population
Combination with immune checkpoint inhibitors may induce a more potent anti-cancer response leading to our strategy of combination studies of Bria-IMT trade with Keytruda or Yervoy
Patients (n) HLA Match
Tumor Shrinkage
Biological Response
4 ge2 50 7515 ge1 27 334 0 0 0
Biological response includes tumor shrinkage or lower circulating cancer associated cells
The confirmatory Bria-IMTtrade monotherapy Phase IIa trial has completed enrollment Additional Support for the HLA-matching hypothesis has been obtained
Bria-IMTtrade Combination Therapy study with immune checkpoint inhibitors Keytrudareg if PD-L12 positive (ge1) Yervoyreg if PD-L12 negative (lt1) Accepting patients from the monotherapy study who develop progressive disease Also enrolling patients directly into this study to enhance experience with the combination In discussion with other pharmaceutical companies to evaluate additional combinations with other
immunotherapies
Bria-OTStrade Off-the-Shelf Personalized Targeted Immunotherapy Developing Bria-OTStrade to co-express GM-CSF and interferon-α Pre-manufacture additional HLA alleles ndash Total of 15 alleles (8 Class I and 7 Class II) Co-development of BriaDXtrade companion diagnostic for HLA typing Combination therapy clinical trial with immune checkpoint inhibitors for non-responders using
information from the Bria-IMTtrade Combination Therapy Study
33
Development Timeline ndash Breast Cancer
20192018 2020 2021
Phase IIIaBria-IMTtrade
Monotherapy
Currently Enrolling Phase IIaBria-IMTtrade + Checkpoint
Currently in discussions with potential partnersPhase II Bria-IMTtrade plus Additional Combinations (1Q19 4Q22)(eg PD-1 Inhibitor PD-L1 inhibitor anti-CTLA4 anti-GITR anti-OX40)
1Q 2Q 3Q 4Q
2023
Bria-OTStrade Off-The-Shelf Personalized ImmunotherapyMonotherapy and Potential Partnered Combo Therapy
(2H19 Ongoing)
Bria-OTStradeOff-the-Shelf Cell Line cGMP Manufacturing
and BriaDXtrade(1Q18 1Q19)
Registration Studies (1Q20 2H22)Bria-IMTtrade with Checkpoint InhibitorsBria-OTStrade +- Checkpoint Inhibitors
34
Immuno-oncology Deals
Recent deals of small biotechs with big pharma in immuno-oncology
35
Date PartnershipDevelopment stage at the time of the deal Deal size
07122018 Immatics-Genmab Preclinical Up to $28B
04042018 OSE Immunotherapeutics-Boehringer Ingelheim Preclinical Up to euro113B ($139B)
02092018 Pieris Pharmaceuticals-Seattle Genetics Preclinical Up to $123B
2142018 Nektar-BMS Ph III Up to $36B
01222018 Juno-Celgene Ph II $9B (Acquisition)
11142017 Loxo-Bayer Larotrectinib (Ph II) LOXO-195 (Ph III) Up to $155B
1032017 CytomX-Amgen Preclinical Up to $15B
03202017 CytomX--BMS Ph III Up to $36B
6282016 Xencor-Novartis Preclinical Up to $24B
Early Stage Clinical Studies (Comparison)
We compared the interim data of Ph IIIa study of Bria-IMTtrade in advanced breast cancer with thedata in the early stage clinical studies of recently approved breast cancer drugs and one fasttracked product candidate
Apples to apples comparison Early Stage Clinical Studies in oncology are typically done in patientswith no other therapeutic options Thus the patients have very advanced disease and response ratesare typically quite low
The patients in our Ph IIIa study have been heavily pre-treated (median 45 prior regimens)Some recent studies of relevance in breast cancer are noted in the following slides
36
Breast Cancer Market Opportunity
Drug Technology Approved for Market (US)Ibrance (palbociclib) CDK 46 Inhibitor HR+HER2- MBC in combination with
fluvestrant or aromatase inhibitor$933M in 1Q2018 $3126M in 2017
Kisqali (ribociclib) CDK 46 Inhibitor 2017 HR+HER2- MBC in combination with fluvestrant or aromatase inhibitor
Peak sales projected at $25B
Verzenio (abemaciclib) CDK 46 Inhibitor 2017 HR+HER2- MBC in combination with fluvestrant or aromatase inhibitor
balixafortide CXCR4 antagonist Fast track designation in 2018 for HER2- MBC who have failed 2 prior regimens
The market for breast cancer drugs is a multibillion dollar market with new drugs being approvedon an ongoing basis indicating the shortage of safe and effective treatments for this deadly disease
37
Competitors- Phase III Clinical Data Bria-IMTtrade shows superior safety and similar to superior efficacy data compared with those of the multi-billion dollar drugs when they were at a similar early stage of clinical development
Injection site reactions No related SAEs or SUSARs
Tumor vol darr ampor darr circul tumor cellsAll Comers 21(419) 26(519)One or More HLA matches 27(415) 33(515)Two or More HLA matches 50 (24) 75 (34)
Sheet1 (3)
Comp -Slides
Data
HLA (2)
HLA
Data (Ph1-2+4Pt)
Competitors (2018)-Slide
Competitors (2018)
In the Pipeline Protein Kinase C delta (PKCδ) Inhibitors
30 of all human malignancies display activating RAS mutations Another 60 showing over-activity of Ras-signaling pathways
Ras has been termed ldquoundruggablerdquo (no one has been able to make a Ras inhibitor drug)
BriaCellrsquos novel proprietary PKCδ inhibitors have shown activity against multiple RAS transformed tumors Lung cancer Melanoma Breast cancer Neuroendocrine cancer Pancreatic cancer Colorectal cancer
This target has an attractive safety profile based on in vivo studies and knock out mouse studies
PKCδ inhibitors should qualify for an accelerated clinical development plan and regulatory pathway
Could be in clinic within 24 months
Cost-Effective Additional Shot-on-Goal and additional partnership opportunities
Early-Stage Preclinical Program
39
Protein Kinase C delta (PKCδ) Inhibitors
Activated PKCδ inhibits RAS degradation which in turn stimulates tumor growth
Koo et al Oncotarget 621328 2016
30 of all human malignancies display activating RASmutations with another 60 showing over-activity of Ras-signaling pathways
BriaCellrsquos novel proprietary PKCδ inhibitors have shownactivity against multiple RAS transformed tumors
This target has an attractive safety profile based on in vivostudies and knock out mouse studies
PKCδ also has potential activity as an immunotherapeuticby blocking TGFβ signaling
PKCδ inhibitors are applicable to specific niche tumor typeswhich provide an accelerated clinical development plan
Structural aspects of first generation inhibitor rottlerin and staurosporine (pan-PKC activator) were combined to create second generation inhibitor KAM1
Third generation inhibitors such as BJE6-106 have improved potency and selectivity Fourth generation inhibitors under development to optimize drug-like characteristics PKCδ inhibitors lack endothelial cell cytotoxicity amp PKCδ deficient mice develop normally and are fertile Potentially no marked intrinsic toxicity by inhibiting PKCδ
Mukai H Saeki T Shimada K Naito Y Matsubara N Nakanishi T Obaishi H Namiki M Sasaki Y Phase 1 combination study of eribulin mesylate with trastuzumab for advanced or recurrent human epidermal growth factor receptor 2 positive breast cancer Invest New Drugs 2015 Feb33(1)119-27
AstraZeneca
Lynparza (Olaparib) + Cediranib
PARP inhibitor + inhibitor of VEGF receptor tyrosine kinases
HR+ HER2- MBC
BC amp OC
2013
28 (8 BC)
3 for BC
Olaparib (a poly (ADP-ribose) polymerase (PARP) inhibitor) amp Cediranib (Vascular endothelial growth factor receptor (VEGFR) 1 2 and 3 tyrosine kinase inhibitor)3 at dose level (DL) 0 (cediranib 20mg olaparib 100mg) 3 at DL1 (cediranib 20mg olaparib 200mg) 7 at DL2 (cediranib 30mg olaparib 200mg) 6 at DL3 (cediranib 30mg olaparib 400mg)
Liu JF Tolaney SM Birrer M Fleming GF Buss MK Dahlberg SE Lee H Whalen C Tyburski K Winer E Ivy P Matulonis UA A Phase 1 trial of the poly(ADP-ribose) polymerase inhibitor olaparib (AZD2281) in combination with the anti-angiogenic cediranib (AZD2171) in recurrent epithelial ovarian or triple-negative breast cancer Eur J Cancer 2013 Sep49(14)2972-8
Reyon Pharmaceutical
VM206RY
Heterologous prime-boost with a truncated HER2 sequence
HER2+ Stage IIIampIV BC
2015
9
2 chemo
Plasmid DNA (pHM-GM-CSF expressing truncated HER2 amp GM-CSF) amp adenoviral vector (Ad-HM containing modified HER2) (2 4 and 8 mgpatientvisit) of pHM-GM-CSF 3x IM weeks 0 2 and 4 Ad-HM 3 times 109 virus particles at week 6
11 PR
4 pts showed 7 minor AEs
Unclear
Kim SB Ahn JH Kim J Jung KH A phase 1 study of a heterologous prime-boost vaccination involving a truncated HER2 sequence in patients with HER2-expressing breast cancer Mol Ther Methods Clin Dev 2015 Sep 30215031 doi 101038mtm201531 eCollection 2015
Rodon J Peacuterez-Fidalgo A Krop IE Burris H Guerrero-Zotano A Britten CD Becerra C Schellens J Richards DA Schuler M Abu-Khalaf M Johnson FM Ranson M Edenfield J Silva AP Hackl W Quadt C Demanse D Duval V Baselga J Phase 11b dose escalation and expansion study of BEZ235 a dual PI3KmTOR inhibitor in patients with advanced solid tumors including patients with advanced breast cancer Cancer Chemother Pharmacol 2018 Jun 7 doi 101007s00280-018-3610-z [Epub ahead of print]
Celgene (Abraxane)
Gemcitabine + Abraxane (nab-paclitaxel)
Chemo + Chemo
OC BC NSCLC amp Panc cancer + Lung OC BC Kaposi sarcoma
MBC
2016
9
Adjuvant chemo (100)chemo post-adjuvant (33)
Gem (nucleoside metabolic inhibitor 1250 mgm2) on days 1 and 8 nab-Pac (microtubule inhibitor) starting dose of 180 mgm2 (cohort 1) 220 mgm2 (cohort 2) and 260 mgm2 (cohort 3) on day 1 of the 21-day cycle using a 3 + 3 design
0
MTD not reached29 Gr3 Neutropenia59 Gr1 Peripheralneuropathy
Yoshitomi S Taira N Doihara H Mizoo T Nogami T Iwamoto T Motoki T Shien T Ogasawara Y Matsuoka J Tsuji H Mitsuhashi T A phase 1 dose-finding and pharmacokinetic study of gemcitabine with nab-paclitaxel in patients with metastatic breast cancer Cancer Chemother Pharmacol 2016 Aug78(2)289-94
Eli Lilly
Erbituxreg (cetuximab) + Taxane
EGFR inhibitor antineoplastic agent + Chemo
Headamp Neck Colorectal Cancer
TNBC
2007-2010
18
1 chemo
Cetuximab (epidermal growth factor receptor (EGFR) antagonist ) an initial loading dose of cetuximab 400 mgm2 followed by a weekly dose of 250 mgm2Paclitaxel (microtubule inhibitor) 80 mgm2 or Docetaxel at an initial dose of 30 mgm2 was administered weekly
56 CR 22 PR
83 Dermatologic toxicity11 Grade3+
Nechushtan H Vainer G Stainberg H Salmon AY Hamburger T Peretz T A phase 12 of a combination of cetuximab and taxane for triple negative breast cancer patients Breast 2014 Aug23(4)435-8
Polyphor
Balixafortide (POL6326) + eribulin
CXCR4 antagonist + tubulin-based antimitotic
Heavily pretreated Relapsed MBC
2014-2016
56
3rd line 3 chemo
3+3 dose escalation The highest dose was established as eribulin 14 mgmsup2 on days 2 and 9 and balixafortide 55 mgkg on days 1minus3 and 8minus10 of the 21-day cycle
30 PR
41 Gr34 Neutropenia11 Gr34 Leucopenia11 Gr34 Febrileneutropenia2 Related mortalities
Apr 2018 Fast Track for HER2-MBC who have failed 2prior regimens
Pernas S Martin M Kaufman PA Gil-Martin M Gomez Pardo P Lopez-Tarruella S Manso L Ciruelos E Perez-Fidalgo JA Hernando C Ademuyiwa FO Weilbaecher K Mayer I Pluard TJ Martinez Garcia M Vahdat L Perez-Garcia J Wach A Barker D Fung S Romagnoli B Cortes J Balixafortide plus eribulin in HER2-negative metastatic breast cancer a phase 1 single-arm dose-escalation trial Lancet Oncol 2018 Jun19(6)812-824
11 PRndashbut only + letrozole (No Resp on monotherapy)
61 Gr34 Neutropenia39 Gr34 Leucopenia
$933M in 1Q2018 $31B in 2017
Tamura K Mukai H Naito Y Yonemori K Kodaira M Tanabe Y Yamamoto N Osera S Sasaki M Mori Y Hashigaki S Nagasawa T Umeyama Y Yoshino T Phase I study of palbociclib a cyclin-dependent kinase 46 inhibitor in Japanese patients Cancer Sci 2016 Jun107(6)755-63 doi 101111cas12932 Epub 2016 May 11
Pfizer
Ibrancereg (palbociclib)
CDK 46 Inhibitor
HR+ HER2- MBC
Heavily pretreated Relapsed Metastatic Cancer
2004-2008
41 (5 BC)
chemo naiumlve (17) 1-2 (51)3 (29) 3+ (2)
Palbociclib 25-150 mg dose ranging
0
20 Gr34 Neutropenia23 Gr34 Leucopenia
$933M in 1Q2018 $31B in 2017
Flaherty KT Lorusso PM Demichele A Abramson VG Courtney R Randolph SS Shaik MN Wilner KD ODwyer PJ Schwartz GK Phase I dose-escalation trial of the oral cyclin-dependent kinase 46 inhibitor PD 0332991 administered using a 21-day schedule in patients with advanced cancer Clin Cancer Res 2012 Jan 1518(2)568-76 doi 1011581078-0432CCR-11-0509 Epub 2011 Nov 16
Novartis
Kisqalireg (ribociclib)
CDK 46 Inhibitors
Premenopausal HR+ HER2- MBC
Heavily pretreated Relapsed Metastatic Cancer
2016
132 (20 BC)
0-1 (25) 2-3 (42) 4+ (32)
Ribociclib 50 mg ranging up to 1200 mg dose escalation
23 PRndashincluded 1 in BC (5 of BC pts)
27 Gr34 Neutropenia17 Gr34 Leucopenia
Peak sales projected at $25B
Infante JR Cassier PA Gerecitano JF Witteveen PO Chugh R Ribrag V Chakraborty A Matano A Dobson JR Crystal AS Parasuraman S Shapiro GI A Phase I Study of the Cyclin-Dependent Kinase 46 Inhibitor Ribociclib (LEE011) in Patients with Advanced Solid Tumors and Lymphomas Clin Cancer Res 2016 Dec 122(23)5696-5705 Epub 2016 Aug 19
Eli Lilly
Verzenioreg (abemaciclib)
CDK 46 Inhibitors
HR+HER2minusMBC
Heavily pretreated Relapsed Metastatic Cancer
2016
12 (1 BC)
1 (312) 2 (212) 3+ (7)
Abemaciclib 100 mg ranging up to 200 mg dose escalation
17 PR (included 1 in BC)
17 Gr34 Neutropenia33 Gr34 Leucopenia
Peak sales projected at $2B
Fujiwara Y Tamura K Kondo S Tanabe Y Iwasa S Shimomura A Kitano S Ogasawara K Turner PK Mori J Asou H Chan EM Yamamoto N Phase 1 study of abemaciclib an inhibitor of CDK 4 and 6 as a single agent for Japanese patients with advanced cancer Cancer Chemother Pharmacol 2016 Aug78(2)281-8 doi 101007s00280-016-3085-8 Epub 2016 Jun 16
Mukai H Saeki T Shimada K Naito Y Matsubara N Nakanishi T Obaishi H Namiki M Sasaki Y Phase 1 combination study of eribulin mesylate with trastuzumab for advanced or recurrent human epidermal growth factor receptor 2 positive breast cancer Invest New Drugs 2015 Feb33(1)119-27
AstraZeneca
Lynparza (Olaparib)+ Cediranib
PARP inhibitor+ inhibitor of VEGF RTK
HR+ HER2- MBC
BC amp OC
13
28 (8 BC)
3 for BC
Olaparib (a poly (ADP-ribose) polymerase (PARP) inhibitor) amp Cediranib (Vascular endothelial growth factor receptor (VEGFR) 1 2 and 3 tyrosine kinase inhibitor)3 at dose level (DL) 0 (cediranib 20mg olaparib 100mg) 3 at DL1 (cediranib 20mg olaparib 200mg) 7 at DL2 (cediranib 30mg olaparib 200mg) 6 at DL3 (cediranib 30mg olaparib 400mg)
Liu JF Tolaney SM Birrer M Fleming GF Buss MK Dahlberg SE Lee H Whalen C Tyburski K Winer E Ivy P Matulonis UA A Phase 1 trial of the poly(ADP-ribose) polymerase inhibitor olaparib (AZD2281) in combination with the anti-angiogenic cediranib (AZD2171) in recurrent epithelial ovarian or triple-negative breast cancer Eur J Cancer 2013 Sep49(14)2972-8
ReyonPharma
VM206RY
Heterologous prime-boost with a truncated HER2 sequence
HER2+ Stg IIIampIV BC
15
9
2 chemo
Plasmid DNA (pHM-GM-CSF expressing truncated HER2 amp GM-CSF) amp adenoviral vector (Ad-HM containing modified HER2) (2 4 and 8 mgpatientvisit) of pHM-GM-CSF 3x IM weeks 0 2 and 4 Ad-HM 3 times 109 virus particles at week 6
11 PR
4 pts 7 minor AEs
Unclear
Kim SB Ahn JH Kim J Jung KH A phase 1 study of a heterologous prime-boost vaccination involving a truncated HER2 sequence in patients with HER2-expressing breast cancer Mol Ther Methods Clin Dev 2015 Sep 30215031 doi 101038mtm201531 eCollection 2015
Rodon J Peacuterez-Fidalgo A Krop IE Burris H Guerrero-Zotano A Britten CD Becerra C Schellens J Richards DA Schuler M Abu-Khalaf M Johnson FM Ranson M Edenfield J Silva AP Hackl W Quadt C Demanse D Duval V Baselga J Phase 11b dose escalation and expansion study of BEZ235 a dual PI3KmTOR inhibitor in patients with advanced solid tumors including patients with advanced breast cancer Cancer Chemother Pharmacol 2018 Jun 7 doi 101007s00280-018-3610-z [Epub ahead of print]
Celgene(Abraxane)
Gemcitabine + Abraxane (nab-paclitaxel)
Chemo+ Chemo
OC BC NSCLC PC + LC OC BC KS
MBC
16
9
Adjuv chemo (100)chemo post-adjuv (33)
Gem (nucleoside metabolic inhibitor 1250 mgm2) on days 1 and 8 nab-Pac (microtubule inhibitor) starting dose of 180 mgm2 (cohort 1) 220 mgm2 (cohort 2) and 260 mgm2 (cohort 3) on day 1 of the 21-day cycle using a 3 + 3 design
0
MTD not reached29 Gr3 Neutropenia59 Gr1 Peripheralneuropathy
Yoshitomi S Taira N Doihara H Mizoo T Nogami T Iwamoto T Motoki T Shien T Ogasawara Y Matsuoka J Tsuji H Mitsuhashi T A phase 1 dose-finding and pharmacokinetic study of gemcitabine with nab-paclitaxel in patients with metastatic breast cancer Cancer Chemother Pharmacol 2016 Aug78(2)289-94
Eli Lilly
Erbituxreg (cetuximab) + Taxane
EGFR inhibitor antineoplastic agent + Chemo
Head amp NeckColorectal
TNBC
07-10
18
1 chemo
Cetuximab (epidermal growth factor receptor (EGFR) antagonist ) an initial loading dose of cetuximab 400 mgm2 followed by a weekly dose of 250 mgm2Paclitaxel (microtubule inhibitor) 80 mgm2 or Docetaxel at an initial dose of 30 mgm2 was administered weekly
56 CR 22 PR
83 Dermatologic toxicity11 Grade3+
Nechushtan H Vainer G Stainberg H Salmon AY Hamburger T Peretz T A phase 12 of a combination of cetuximab and taxane for triple negative breast cancer patients Breast 2014 Aug23(4)435-8
Polyphor
Balixafortide (POL6326) + eribulin
CXCR4 antagonist + tubulin-based antimitotic
Heavily pretreatedRelapsed MBC
14-16
56
3rd line 3 chemo
3+3 dose escalation The highest dose was established as eribulin 14 mgmsup2 on days 2 and 9 and balixafortide 55 mgkg on days 1minus3 and 8minus10 of the 21-day cycle
30 PR
41 Gr34 Neutropenia11 Gr34 Leucopenia11 Gr34 Febrileneutropenia2 Related mortalities
42018 Fast Track (HER2-MBC failed 2 prior regimens)
Pernas S Martin M Kaufman PA Gil-Martin M Gomez Pardo P Lopez-Tarruella S Manso L Ciruelos E Perez-Fidalgo JA Hernando C Ademuyiwa FO Weilbaecher K Mayer I Pluard TJ Martinez Garcia M Vahdat L Perez-Garcia J Wach A Barker D Fung S Romagnoli B Cortes J Balixafortide plus eribulin in HER2-negative metastatic breast cancer a phase 1 single-arm dose-escalation trial Lancet Oncol 2018 Jun19(6)812-824
1 PRndashbut only + letrozoleNo Resp on monotherapy
61 Gr34 Neutropenia39 Gr34 Leucopenia
$933M (1Q18)$31B (2017)
Tamura K Mukai H Naito Y Yonemori K Kodaira M Tanabe Y Yamamoto N Osera S Sasaki M Mori Y Hashigaki S Nagasawa T Umeyama Y Yoshino T Phase I study of palbociclib a cyclin-dependent kinase 46 inhibitor in Japanese patients Cancer Sci 2016 Jun107(6)755-63 doi 101111cas12932 Epub 2016 May 11
Pfizer
Ibrancereg (palbociclib)
CDK 46 Inhibitor
HR+ HER2- MBC
Heavily pretreatedRelapsed Met Cancer
04-08
41 (5 BC)
chemo naiumlve (17)1-2(51) 3(29) 3+(2)
Palbociclib 25-150 mg dose ranging
0
20 Gr34 Neutropenia23 Gr34 Leucopenia
$933M (1Q18)$31B (2017)
Flaherty KT Lorusso PM Demichele A Abramson VG Courtney R Randolph SS Shaik MN Wilner KD ODwyer PJ Schwartz GK Phase I dose-escalation trial of the oral cyclin-dependent kinase 46 inhibitor PD 0332991 administered using a 21-day schedule in patients with advanced cancer Clin Cancer Res 2012 Jan 1518(2)568-76 doi 1011581078-0432CCR-11-0509 Epub 2011 Nov 16
Novartis
Kisqalireg (ribociclib)
CDK 46 Inhibitor
Premenopausal HR+ HER2- MBC
Heavily pretreatedRelapsed Met Cancer
16
132 (20 BC)
0-1 (25) 2-3 (42)4+ (32)
Ribociclib 50 mg ranging up to 1200 mg dose escalation
23 PR-included 1 BC (5 of BC pts)
27 Gr34 Neutropenia17 Gr34 Leucopenia
Peak sales est at $25B
Infante JR Cassier PA Gerecitano JF Witteveen PO Chugh R Ribrag V Chakraborty A Matano A Dobson JR Crystal AS Parasuraman S Shapiro GI A Phase I Study of the Cyclin-Dependent Kinase 46 Inhibitor Ribociclib (LEE011) in Patients with Advanced Solid Tumors and Lymphomas Clin Cancer Res 2016 Dec 122(23)5696-5705 Epub 2016 Aug 19
Eli Lilly
Verzenioreg (abemaciclib)
CDK 46 Inhibitor
HR+HER2minusMBC
Heavily pretreatedRelapsed Met Cancer
16
12 (1 BC)
1 (312) 2 (212) 3+(7)
Abemaciclib 100 mg ranging up to 200 mg dose escalation
17 PR (included 1 BC)
17 Gr34 Neutropenia33 Gr34 Leucopenia
Peak sales est at $2B
Fujiwara Y Tamura K Kondo S Tanabe Y Iwasa S Shimomura A Kitano S Ogasawara K Turner PK Mori J Asou H Chan EM Yamamoto N Phase 1 study of abemaciclib an inhibitor of CDK 4 and 6 as a single agent for Japanese patients with advanced cancer Cancer Chemother Pharmacol 2016 Aug78(2)281-8 doi 101007s00280-016-3085-8 Epub 2016 Jun 16
Mukai H Saeki T Shimada K Naito Y Matsubara N Nakanishi T Obaishi H Namiki M Sasaki Y Phase 1 combination study of eribulin mesylate with trastuzumab for advanced or recurrent human epidermal growth factor receptor 2 positive breast cancer Invest New Drugs 2015 Feb33(1)119-27
AstraZeneca
Lynparza (Olaparib) + Cediranib
PARP inhibitor + inhibitor of VEGF receptor tyrosine kinases
HR+ HER2- MBC
BC amp OC
2013
28 (8 BC)
3 for BC
Olaparib (a poly (ADP-ribose) polymerase (PARP) inhibitor) amp Cediranib (Vascular endothelial growth factor receptor (VEGFR) 1 2 and 3 tyrosine kinase inhibitor)3 at dose level (DL) 0 (cediranib 20mg olaparib 100mg) 3 at DL1 (cediranib 20mg olaparib 200mg) 7 at DL2 (cediranib 30mg olaparib 200mg) 6 at DL3 (cediranib 30mg olaparib 400mg)
Liu JF Tolaney SM Birrer M Fleming GF Buss MK Dahlberg SE Lee H Whalen C Tyburski K Winer E Ivy P Matulonis UA A Phase 1 trial of the poly(ADP-ribose) polymerase inhibitor olaparib (AZD2281) in combination with the anti-angiogenic cediranib (AZD2171) in recurrent epithelial ovarian or triple-negative breast cancer Eur J Cancer 2013 Sep49(14)2972-8
Reyon Pharmaceutical
VM206RY
Heterologous prime-boost with a truncated HER2 sequence
HER2+ Stage IIIampIV BC
2015
9
2 chemo
Plasmid DNA (pHM-GM-CSF expressing truncated HER2 amp GM-CSF) amp adenoviral vector (Ad-HM containing modified HER2) (2 4 and 8 mgpatientvisit) of pHM-GM-CSF 3x IM weeks 0 2 and 4 Ad-HM 3 times 109 virus particles at week 6
11 PR
4 pts showed 7 minor AEs
Unclear
Kim SB Ahn JH Kim J Jung KH A phase 1 study of a heterologous prime-boost vaccination involving a truncated HER2 sequence in patients with HER2-expressing breast cancer Mol Ther Methods Clin Dev 2015 Sep 30215031 doi 101038mtm201531 eCollection 2015
Rodon J Peacuterez-Fidalgo A Krop IE Burris H Guerrero-Zotano A Britten CD Becerra C Schellens J Richards DA Schuler M Abu-Khalaf M Johnson FM Ranson M Edenfield J Silva AP Hackl W Quadt C Demanse D Duval V Baselga J Phase 11b dose escalation and expansion study of BEZ235 a dual PI3KmTOR inhibitor in patients with advanced solid tumors including patients with advanced breast cancer Cancer Chemother Pharmacol 2018 Jun 7 doi 101007s00280-018-3610-z [Epub ahead of print]
Celgene (Abraxane)
Gemcitabine + Abraxane (nab-paclitaxel)
Chemo + Chemo
OC BC NSCLC amp Panc cancer + Lung OC BC Kaposi sarcoma
MBC
2016
9
Adjuvant chemo (100)chemo post-adjuvant (33)
Gem (nucleoside metabolic inhibitor 1250 mgm2) on days 1 and 8 nab-Pac (microtubule inhibitor) starting dose of 180 mgm2 (cohort 1) 220 mgm2 (cohort 2) and 260 mgm2 (cohort 3) on day 1 of the 21-day cycle using a 3 + 3 design
0
MTD not reached29 Gr3 Neutropenia59 Gr1 Peripheralneuropathy
Yoshitomi S Taira N Doihara H Mizoo T Nogami T Iwamoto T Motoki T Shien T Ogasawara Y Matsuoka J Tsuji H Mitsuhashi T A phase 1 dose-finding and pharmacokinetic study of gemcitabine with nab-paclitaxel in patients with metastatic breast cancer Cancer Chemother Pharmacol 2016 Aug78(2)289-94
Eli Lilly
Erbituxreg (cetuximab) + Taxane
EGFR inhibitor antineoplastic agent + Chemo
Headamp Neck Colorectal Cancer
TNBC
2007-2010
18
1 chemo
Cetuximab (epidermal growth factor receptor (EGFR) antagonist ) an initial loading dose of cetuximab 400 mgm2 followed by a weekly dose of 250 mgm2Paclitaxel (microtubule inhibitor) 80 mgm2 or Docetaxel at an initial dose of 30 mgm2 was administered weekly
56 CR 22 PR
83 Dermatologic toxicity11 Grade3+
Nechushtan H Vainer G Stainberg H Salmon AY Hamburger T Peretz T A phase 12 of a combination of cetuximab and taxane for triple negative breast cancer patients Breast 2014 Aug23(4)435-8
Polyphor
Balixafortide (POL6326) + eribulin
CXCR4 antagonist + tubulin-based antimitotic
Heavily pretreated Relapsed MBC
2014-2016
56
3rd line 3 chemo
3+3 dose escalation The highest dose was established as eribulin 14 mgmsup2 on days 2 and 9 and balixafortide 55 mgkg on days 1minus3 and 8minus10 of the 21-day cycle
30 PR
41 Gr34 Neutropenia11 Gr34 Leucopenia11 Gr34 Febrileneutropenia2 Related mortalities
Apr 2018 Fast Track for HER2-MBC who have failed 2prior regimens
Pernas S Martin M Kaufman PA Gil-Martin M Gomez Pardo P Lopez-Tarruella S Manso L Ciruelos E Perez-Fidalgo JA Hernando C Ademuyiwa FO Weilbaecher K Mayer I Pluard TJ Martinez Garcia M Vahdat L Perez-Garcia J Wach A Barker D Fung S Romagnoli B Cortes J Balixafortide plus eribulin in HER2-negative metastatic breast cancer a phase 1 single-arm dose-escalation trial Lancet Oncol 2018 Jun19(6)812-824
11 PRndashbut only + letrozole (No Resp on monotherapy)
61 Gr34 Neutropenia39 Gr34 Leucopenia
$933M in 1Q2018 $31B in 2017
Tamura K Mukai H Naito Y Yonemori K Kodaira M Tanabe Y Yamamoto N Osera S Sasaki M Mori Y Hashigaki S Nagasawa T Umeyama Y Yoshino T Phase I study of palbociclib a cyclin-dependent kinase 46 inhibitor in Japanese patients Cancer Sci 2016 Jun107(6)755-63 doi 101111cas12932 Epub 2016 May 11
Pfizer
Ibrancereg (palbociclib)
CDK 46 Inhibitor
HR+ HER2- MBC
Heavily pretreated Relapsed Metastatic Cancer
2004-2008
41 (5 BC)
chemo naiumlve (17) 1-2 (51)3 (29) 3+ (2)
Palbociclib 25-150 mg dose ranging
0
20 Gr34 Neutropenia23 Gr34 Leucopenia
$933M in 1Q2018 $31B in 2017
Flaherty KT Lorusso PM Demichele A Abramson VG Courtney R Randolph SS Shaik MN Wilner KD ODwyer PJ Schwartz GK Phase I dose-escalation trial of the oral cyclin-dependent kinase 46 inhibitor PD 0332991 administered using a 21-day schedule in patients with advanced cancer Clin Cancer Res 2012 Jan 1518(2)568-76 doi 1011581078-0432CCR-11-0509 Epub 2011 Nov 16
Novartis
Kisqalireg (ribociclib)
CDK 46 Inhibitors
Premenopausal HR+ HER2- MBC
Heavily pretreated Relapsed Metastatic Cancer
2016
132 (20 BC)
0-1 (25) 2-3 (42) 4+ (32)
Ribociclib 50 mg ranging up to 1200 mg dose escalation
23 PRndashincluded 1 in BC (5 of BC pts)
27 Gr34 Neutropenia17 Gr34 Leucopenia
Peak sales projected at $25B
Infante JR Cassier PA Gerecitano JF Witteveen PO Chugh R Ribrag V Chakraborty A Matano A Dobson JR Crystal AS Parasuraman S Shapiro GI A Phase I Study of the Cyclin-Dependent Kinase 46 Inhibitor Ribociclib (LEE011) in Patients with Advanced Solid Tumors and Lymphomas Clin Cancer Res 2016 Dec 122(23)5696-5705 Epub 2016 Aug 19
Eli Lilly
Verzenioreg (abemaciclib)
CDK 46 Inhibitors
HR+HER2minusMBC
Heavily pretreated Relapsed Metastatic Cancer
2016
12 (1 BC)
1 (312) 2 (212) 3+ (7)
Abemaciclib 100 mg ranging up to 200 mg dose escalation
17 PR (included 1 in BC)
17 Gr34 Neutropenia33 Gr34 Leucopenia
Peak sales projected at $2B
Fujiwara Y Tamura K Kondo S Tanabe Y Iwasa S Shimomura A Kitano S Ogasawara K Turner PK Mori J Asou H Chan EM Yamamoto N Phase 1 study of abemaciclib an inhibitor of CDK 4 and 6 as a single agent for Japanese patients with advanced cancer Cancer Chemother Pharmacol 2016 Aug78(2)281-8 doi 101007s00280-016-3085-8 Epub 2016 Jun 16
Mukai H Saeki T Shimada K Naito Y Matsubara N Nakanishi T Obaishi H Namiki M Sasaki Y Phase 1 combination study of eribulin mesylate with trastuzumab for advanced or recurrent human epidermal growth factor receptor 2 positive breast cancer Invest New Drugs 2015 Feb33(1)119-27
AstraZeneca
Lynparza (Olaparib)+ Cediranib
PARP inhibitor+ inhibitor of VEGF RTK
HR+ HER2- MBC
BC amp OC
13
28 (8 BC)
3 for BC
Olaparib (a poly (ADP-ribose) polymerase (PARP) inhibitor) amp Cediranib (Vascular endothelial growth factor receptor (VEGFR) 1 2 and 3 tyrosine kinase inhibitor)3 at dose level (DL) 0 (cediranib 20mg olaparib 100mg) 3 at DL1 (cediranib 20mg olaparib 200mg) 7 at DL2 (cediranib 30mg olaparib 200mg) 6 at DL3 (cediranib 30mg olaparib 400mg)
Liu JF Tolaney SM Birrer M Fleming GF Buss MK Dahlberg SE Lee H Whalen C Tyburski K Winer E Ivy P Matulonis UA A Phase 1 trial of the poly(ADP-ribose) polymerase inhibitor olaparib (AZD2281) in combination with the anti-angiogenic cediranib (AZD2171) in recurrent epithelial ovarian or triple-negative breast cancer Eur J Cancer 2013 Sep49(14)2972-8
ReyonPharma
VM206RY
Heterologous prime-boost with a truncated HER2 sequence
HER2+ Stg IIIampIV BC
15
9
2 chemo
Plasmid DNA (pHM-GM-CSF expressing truncated HER2 amp GM-CSF) amp adenoviral vector (Ad-HM containing modified HER2) (2 4 and 8 mgpatientvisit) of pHM-GM-CSF 3x IM weeks 0 2 and 4 Ad-HM 3 times 109 virus particles at week 6
11 PR
4 pts 7 minor AEs
Unclear
Kim SB Ahn JH Kim J Jung KH A phase 1 study of a heterologous prime-boost vaccination involving a truncated HER2 sequence in patients with HER2-expressing breast cancer Mol Ther Methods Clin Dev 2015 Sep 30215031 doi 101038mtm201531 eCollection 2015
Rodon J Peacuterez-Fidalgo A Krop IE Burris H Guerrero-Zotano A Britten CD Becerra C Schellens J Richards DA Schuler M Abu-Khalaf M Johnson FM Ranson M Edenfield J Silva AP Hackl W Quadt C Demanse D Duval V Baselga J Phase 11b dose escalation and expansion study of BEZ235 a dual PI3KmTOR inhibitor in patients with advanced solid tumors including patients with advanced breast cancer Cancer Chemother Pharmacol 2018 Jun 7 doi 101007s00280-018-3610-z [Epub ahead of print]
Celgene(Abraxane)
Gemcitabine + Abraxane (nab-paclitaxel)
Chemo+ Chemo
OC BC NSCLC PC + LC OC BC KS
MBC
16
9
Adjuv chemo (100)chemo post-adjuv (33)
Gem (nucleoside metabolic inhibitor 1250 mgm2) on days 1 and 8 nab-Pac (microtubule inhibitor) starting dose of 180 mgm2 (cohort 1) 220 mgm2 (cohort 2) and 260 mgm2 (cohort 3) on day 1 of the 21-day cycle using a 3 + 3 design
0
MTD not reached29 Gr3 Neutropenia59 Gr1 Peripheralneuropathy
Yoshitomi S Taira N Doihara H Mizoo T Nogami T Iwamoto T Motoki T Shien T Ogasawara Y Matsuoka J Tsuji H Mitsuhashi T A phase 1 dose-finding and pharmacokinetic study of gemcitabine with nab-paclitaxel in patients with metastatic breast cancer Cancer Chemother Pharmacol 2016 Aug78(2)289-94
Eli Lilly
Erbituxreg (cetuximab) + Taxane
EGFR inhibitor antineoplastic agent + Chemo
Head amp NeckColorectal
TNBC
07-10
18
1 chemo
Cetuximab (epidermal growth factor receptor (EGFR) antagonist ) an initial loading dose of cetuximab 400 mgm2 followed by a weekly dose of 250 mgm2Paclitaxel (microtubule inhibitor) 80 mgm2 or Docetaxel at an initial dose of 30 mgm2 was administered weekly
56 CR 22 PR
83 Dermatologic toxicity11 Grade3+
Nechushtan H Vainer G Stainberg H Salmon AY Hamburger T Peretz T A phase 12 of a combination of cetuximab and taxane for triple negative breast cancer patients Breast 2014 Aug23(4)435-8
Polyphor
Balixafortide (POL6326) + eribulin
CXCR4 antagonist + tubulin-based antimitotic
Heavily pretreatedRelapsed MBC
14-16
56
3rd line 3 chemo
3+3 dose escalation The highest dose was established as eribulin 14 mgmsup2 on days 2 and 9 and balixafortide 55 mgkg on days 1minus3 and 8minus10 of the 21-day cycle
30 PR
41 Gr34 Neutropenia11 Gr34 Leucopenia11 Gr34 Febrileneutropenia2 Related mortalities
42018 Fast Track (HER2-MBC failed 2 prior regimens)
Pernas S Martin M Kaufman PA Gil-Martin M Gomez Pardo P Lopez-Tarruella S Manso L Ciruelos E Perez-Fidalgo JA Hernando C Ademuyiwa FO Weilbaecher K Mayer I Pluard TJ Martinez Garcia M Vahdat L Perez-Garcia J Wach A Barker D Fung S Romagnoli B Cortes J Balixafortide plus eribulin in HER2-negative metastatic breast cancer a phase 1 single-arm dose-escalation trial Lancet Oncol 2018 Jun19(6)812-824
1 PRndashbut only + letrozoleNo Resp on monotherapy
61 Gr34 Neutropenia39 Gr34 Leucopenia
$933M (1Q18)$31B (2017)
Tamura K Mukai H Naito Y Yonemori K Kodaira M Tanabe Y Yamamoto N Osera S Sasaki M Mori Y Hashigaki S Nagasawa T Umeyama Y Yoshino T Phase I study of palbociclib a cyclin-dependent kinase 46 inhibitor in Japanese patients Cancer Sci 2016 Jun107(6)755-63 doi 101111cas12932 Epub 2016 May 11
Pfizer
Ibrancereg (palbociclib)
CDK 46 Inhibitor
HR+ HER2- MBC
Heavily pretreatedRelapsed Met Cancer
04-08
41 (5 BC)
chemo naiumlve (17)1-2(51) 3(29) 3+(2)
Palbociclib 25-150 mg dose ranging
0
20 Gr34 Neutropenia23 Gr34 Leucopenia
$933M (1Q18)$31B (2017)
Flaherty KT Lorusso PM Demichele A Abramson VG Courtney R Randolph SS Shaik MN Wilner KD ODwyer PJ Schwartz GK Phase I dose-escalation trial of the oral cyclin-dependent kinase 46 inhibitor PD 0332991 administered using a 21-day schedule in patients with advanced cancer Clin Cancer Res 2012 Jan 1518(2)568-76 doi 1011581078-0432CCR-11-0509 Epub 2011 Nov 16
Novartis
Kisqalireg (ribociclib)
CDK 46 Inhibitor
Premenopausal HR+ HER2- MBC
Heavily pretreatedRelapsed Met Cancer
16
132 (20 BC)
0-1 (25) 2-3 (42)4+ (32)
Ribociclib 50 mg ranging up to 1200 mg dose escalation
23 PR-included 1 BC (5 of BC pts)
27 Gr34 Neutropenia17 Gr34 Leucopenia
Peak sales est at $25B
Infante JR Cassier PA Gerecitano JF Witteveen PO Chugh R Ribrag V Chakraborty A Matano A Dobson JR Crystal AS Parasuraman S Shapiro GI A Phase I Study of the Cyclin-Dependent Kinase 46 Inhibitor Ribociclib (LEE011) in Patients with Advanced Solid Tumors and Lymphomas Clin Cancer Res 2016 Dec 122(23)5696-5705 Epub 2016 Aug 19
Eli Lilly
Verzenioreg (abemaciclib)
CDK 46 Inhibitor
HR+HER2minusMBC
Heavily pretreatedRelapsed Met Cancer
16
12 (1 BC)
1 (312) 2 (212) 3+(7)
Abemaciclib 100 mg ranging up to 200 mg dose escalation
17 PR (included 1 BC)
17 Gr34 Neutropenia33 Gr34 Leucopenia
Peak sales est at $2B
Fujiwara Y Tamura K Kondo S Tanabe Y Iwasa S Shimomura A Kitano S Ogasawara K Turner PK Mori J Asou H Chan EM Yamamoto N Phase 1 study of abemaciclib an inhibitor of CDK 4 and 6 as a single agent for Japanese patients with advanced cancer Cancer Chemother Pharmacol 2016 Aug78(2)281-8 doi 101007s00280-016-3085-8 Epub 2016 Jun 16
41 Gr34 Neutropenia11 Gr34 Leucopenia11 Gr34 Febrileneutropenia2 Related mortalities
30 PRs in combination with Halaven
Bria-IMTTM
20
Injection site reactions No related SAEs or SUSARs
Tumor vol darr ampor darr circul tumor cells)All Comers 21(419) 26(519)One or More HLA matches 27(415) 33(515)Two or More HLA matches 50 (24) 75 (34))
Drug
Technology
Approved for
Market (US)
Ibrance (palbociclib)
CDK 46 Inhibitor
HR+HER2- MBC in combination with fluvestrant or aromatase inhibitor
$933M in 1Q2018 $3126M in 2017
Kisqali (ribociclib)
CDK 46 Inhibitor
2017 HR+HER2- MBC in combination with fluvestrant or aromatase inhibitor
Peak sales projected at $25B
Verzenio (abemaciclib)
CDK 46 Inhibitor
2017 HR+HER2- MBC in combination with fluvestrant or aromatase inhibitor
Peak sales projected at $2B
Lynparza (olaparib)
Poly (ADP-ribose) polymerase (PARP) inhibitor
2017 ovarian amp breast cancer
$997M in 2017
Halaven (eribulin mesylate)
Tubulin-based antimitotic
2H2017 3rd line MBC amp liposarcoma
$181M in 2017
balixafortide
CXCR4 antagonist
Fast track designation in 2018 for HER2- MBC who have failed 2 prior regimens
Clinical Development Update ndash Summary 2018 September 26
Completed enrollment of Adv Breast cancer patients in the Phase IIIa ldquomonotherapyrdquo study of Bria-IMTtrade
We have confirmed our mechanism of action and achieved proof of concept
Initial safety data appears superior to that of the other advanced or approved drugs for breast cancer when they were at a similar clinical stage of development
Initial efficacy data is similar or superior to those of other advanced or approved drugs for breast cancer when they were at a similar clinical stage of development
Initiated Combination Study of Bria-IMTtrade with Keytrudareg or Yervoyreg in Adv breast cancer patients expecting even better response rates than those in the ldquomonotherapyrdquo study Initial safety data is expected in 4Q2018 Initial efficacy data is expected in 1Q2019
Bria-OTStrade the first off-the-shelf personalized treatment for advanced breast cancer is expected to enter the clinic in 2019
28
Bria-IMTtrade Excellent Safety Data - To Date
To date Bria-IMTtrade has been dosed in 24 patients (4 in 2004-2005 20 in 2017-2018)
Interim Data (20 patients)-Ongoing Phase IIIa Study (2017-2018)
Bria-IMTtrade has been very well tolerated (ge60 doses given to date) The majority of adverse events (AEs) were limited to expected minor local irritation at the
injection sites No related grade gt3 or unexpected AEs No related serious AEs No serious unexpected related AEs Most patients who have dropped out did so due to worsening of their underlying disease
Based on the current study Bria-IMTtrade has an excellent safety profile
29
Bria-IMTtrade - Efficacy as Predicted
Interim Data (19 patients)-Ongoing Phase IIIa Study (2017-2018) amp Original Study (2004-2005)
PD-L1 expression on circulating cancer cells amp cancer-associated cells in 100 of patients (to date) Strong rationale for combination with checkpoint inhibitors like Keytruda
30
Bria-IMTtrade appears to be most effective in patients who match with Bria-IMT trade at 2 HLA loci (types) further supporting our ldquoHLA Matching Hypothesisrdquo and the development of Bria-OTS trade to cover 90 of the patient population
Combination with immune checkpoint inhibitors may induce a more potent anti-cancer response leading to our strategy of combination studies of Bria-IMT trade with Keytruda or Yervoy
Patients (n) HLA Match
Tumor Shrinkage
Biological Response
4 ge2 50 7515 ge1 27 334 0 0 0
Biological response includes tumor shrinkage or lower circulating cancer associated cells
The confirmatory Bria-IMTtrade monotherapy Phase IIa trial has completed enrollment Additional Support for the HLA-matching hypothesis has been obtained
Bria-IMTtrade Combination Therapy study with immune checkpoint inhibitors Keytrudareg if PD-L12 positive (ge1) Yervoyreg if PD-L12 negative (lt1) Accepting patients from the monotherapy study who develop progressive disease Also enrolling patients directly into this study to enhance experience with the combination In discussion with other pharmaceutical companies to evaluate additional combinations with other
immunotherapies
Bria-OTStrade Off-the-Shelf Personalized Targeted Immunotherapy Developing Bria-OTStrade to co-express GM-CSF and interferon-α Pre-manufacture additional HLA alleles ndash Total of 15 alleles (8 Class I and 7 Class II) Co-development of BriaDXtrade companion diagnostic for HLA typing Combination therapy clinical trial with immune checkpoint inhibitors for non-responders using
information from the Bria-IMTtrade Combination Therapy Study
33
Development Timeline ndash Breast Cancer
20192018 2020 2021
Phase IIIaBria-IMTtrade
Monotherapy
Currently Enrolling Phase IIaBria-IMTtrade + Checkpoint
Currently in discussions with potential partnersPhase II Bria-IMTtrade plus Additional Combinations (1Q19 4Q22)(eg PD-1 Inhibitor PD-L1 inhibitor anti-CTLA4 anti-GITR anti-OX40)
1Q 2Q 3Q 4Q
2023
Bria-OTStrade Off-The-Shelf Personalized ImmunotherapyMonotherapy and Potential Partnered Combo Therapy
(2H19 Ongoing)
Bria-OTStradeOff-the-Shelf Cell Line cGMP Manufacturing
and BriaDXtrade(1Q18 1Q19)
Registration Studies (1Q20 2H22)Bria-IMTtrade with Checkpoint InhibitorsBria-OTStrade +- Checkpoint Inhibitors
34
Immuno-oncology Deals
Recent deals of small biotechs with big pharma in immuno-oncology
35
Date PartnershipDevelopment stage at the time of the deal Deal size
07122018 Immatics-Genmab Preclinical Up to $28B
04042018 OSE Immunotherapeutics-Boehringer Ingelheim Preclinical Up to euro113B ($139B)
02092018 Pieris Pharmaceuticals-Seattle Genetics Preclinical Up to $123B
2142018 Nektar-BMS Ph III Up to $36B
01222018 Juno-Celgene Ph II $9B (Acquisition)
11142017 Loxo-Bayer Larotrectinib (Ph II) LOXO-195 (Ph III) Up to $155B
1032017 CytomX-Amgen Preclinical Up to $15B
03202017 CytomX--BMS Ph III Up to $36B
6282016 Xencor-Novartis Preclinical Up to $24B
Early Stage Clinical Studies (Comparison)
We compared the interim data of Ph IIIa study of Bria-IMTtrade in advanced breast cancer with thedata in the early stage clinical studies of recently approved breast cancer drugs and one fasttracked product candidate
Apples to apples comparison Early Stage Clinical Studies in oncology are typically done in patientswith no other therapeutic options Thus the patients have very advanced disease and response ratesare typically quite low
The patients in our Ph IIIa study have been heavily pre-treated (median 45 prior regimens)Some recent studies of relevance in breast cancer are noted in the following slides
36
Breast Cancer Market Opportunity
Drug Technology Approved for Market (US)Ibrance (palbociclib) CDK 46 Inhibitor HR+HER2- MBC in combination with
fluvestrant or aromatase inhibitor$933M in 1Q2018 $3126M in 2017
Kisqali (ribociclib) CDK 46 Inhibitor 2017 HR+HER2- MBC in combination with fluvestrant or aromatase inhibitor
Peak sales projected at $25B
Verzenio (abemaciclib) CDK 46 Inhibitor 2017 HR+HER2- MBC in combination with fluvestrant or aromatase inhibitor
balixafortide CXCR4 antagonist Fast track designation in 2018 for HER2- MBC who have failed 2 prior regimens
The market for breast cancer drugs is a multibillion dollar market with new drugs being approvedon an ongoing basis indicating the shortage of safe and effective treatments for this deadly disease
37
Competitors- Phase III Clinical Data Bria-IMTtrade shows superior safety and similar to superior efficacy data compared with those of the multi-billion dollar drugs when they were at a similar early stage of clinical development
Injection site reactions No related SAEs or SUSARs
Tumor vol darr ampor darr circul tumor cellsAll Comers 21(419) 26(519)One or More HLA matches 27(415) 33(515)Two or More HLA matches 50 (24) 75 (34)
Sheet1 (3)
Comp -Slides
Data
HLA (2)
HLA
Data (Ph1-2+4Pt)
Competitors (2018)-Slide
Competitors (2018)
In the Pipeline Protein Kinase C delta (PKCδ) Inhibitors
30 of all human malignancies display activating RAS mutations Another 60 showing over-activity of Ras-signaling pathways
Ras has been termed ldquoundruggablerdquo (no one has been able to make a Ras inhibitor drug)
BriaCellrsquos novel proprietary PKCδ inhibitors have shown activity against multiple RAS transformed tumors Lung cancer Melanoma Breast cancer Neuroendocrine cancer Pancreatic cancer Colorectal cancer
This target has an attractive safety profile based on in vivo studies and knock out mouse studies
PKCδ inhibitors should qualify for an accelerated clinical development plan and regulatory pathway
Could be in clinic within 24 months
Cost-Effective Additional Shot-on-Goal and additional partnership opportunities
Early-Stage Preclinical Program
39
Protein Kinase C delta (PKCδ) Inhibitors
Activated PKCδ inhibits RAS degradation which in turn stimulates tumor growth
Koo et al Oncotarget 621328 2016
30 of all human malignancies display activating RASmutations with another 60 showing over-activity of Ras-signaling pathways
BriaCellrsquos novel proprietary PKCδ inhibitors have shownactivity against multiple RAS transformed tumors
This target has an attractive safety profile based on in vivostudies and knock out mouse studies
PKCδ also has potential activity as an immunotherapeuticby blocking TGFβ signaling
PKCδ inhibitors are applicable to specific niche tumor typeswhich provide an accelerated clinical development plan
Structural aspects of first generation inhibitor rottlerin and staurosporine (pan-PKC activator) were combined to create second generation inhibitor KAM1
Third generation inhibitors such as BJE6-106 have improved potency and selectivity Fourth generation inhibitors under development to optimize drug-like characteristics PKCδ inhibitors lack endothelial cell cytotoxicity amp PKCδ deficient mice develop normally and are fertile Potentially no marked intrinsic toxicity by inhibiting PKCδ
Mukai H Saeki T Shimada K Naito Y Matsubara N Nakanishi T Obaishi H Namiki M Sasaki Y Phase 1 combination study of eribulin mesylate with trastuzumab for advanced or recurrent human epidermal growth factor receptor 2 positive breast cancer Invest New Drugs 2015 Feb33(1)119-27
AstraZeneca
Lynparza (Olaparib) + Cediranib
PARP inhibitor + inhibitor of VEGF receptor tyrosine kinases
HR+ HER2- MBC
BC amp OC
2013
28 (8 BC)
3 for BC
Olaparib (a poly (ADP-ribose) polymerase (PARP) inhibitor) amp Cediranib (Vascular endothelial growth factor receptor (VEGFR) 1 2 and 3 tyrosine kinase inhibitor)3 at dose level (DL) 0 (cediranib 20mg olaparib 100mg) 3 at DL1 (cediranib 20mg olaparib 200mg) 7 at DL2 (cediranib 30mg olaparib 200mg) 6 at DL3 (cediranib 30mg olaparib 400mg)
Liu JF Tolaney SM Birrer M Fleming GF Buss MK Dahlberg SE Lee H Whalen C Tyburski K Winer E Ivy P Matulonis UA A Phase 1 trial of the poly(ADP-ribose) polymerase inhibitor olaparib (AZD2281) in combination with the anti-angiogenic cediranib (AZD2171) in recurrent epithelial ovarian or triple-negative breast cancer Eur J Cancer 2013 Sep49(14)2972-8
Reyon Pharmaceutical
VM206RY
Heterologous prime-boost with a truncated HER2 sequence
HER2+ Stage IIIampIV BC
2015
9
2 chemo
Plasmid DNA (pHM-GM-CSF expressing truncated HER2 amp GM-CSF) amp adenoviral vector (Ad-HM containing modified HER2) (2 4 and 8 mgpatientvisit) of pHM-GM-CSF 3x IM weeks 0 2 and 4 Ad-HM 3 times 109 virus particles at week 6
11 PR
4 pts showed 7 minor AEs
Unclear
Kim SB Ahn JH Kim J Jung KH A phase 1 study of a heterologous prime-boost vaccination involving a truncated HER2 sequence in patients with HER2-expressing breast cancer Mol Ther Methods Clin Dev 2015 Sep 30215031 doi 101038mtm201531 eCollection 2015
Rodon J Peacuterez-Fidalgo A Krop IE Burris H Guerrero-Zotano A Britten CD Becerra C Schellens J Richards DA Schuler M Abu-Khalaf M Johnson FM Ranson M Edenfield J Silva AP Hackl W Quadt C Demanse D Duval V Baselga J Phase 11b dose escalation and expansion study of BEZ235 a dual PI3KmTOR inhibitor in patients with advanced solid tumors including patients with advanced breast cancer Cancer Chemother Pharmacol 2018 Jun 7 doi 101007s00280-018-3610-z [Epub ahead of print]
Celgene (Abraxane)
Gemcitabine + Abraxane (nab-paclitaxel)
Chemo + Chemo
OC BC NSCLC amp Panc cancer + Lung OC BC Kaposi sarcoma
MBC
2016
9
Adjuvant chemo (100)chemo post-adjuvant (33)
Gem (nucleoside metabolic inhibitor 1250 mgm2) on days 1 and 8 nab-Pac (microtubule inhibitor) starting dose of 180 mgm2 (cohort 1) 220 mgm2 (cohort 2) and 260 mgm2 (cohort 3) on day 1 of the 21-day cycle using a 3 + 3 design
0
MTD not reached29 Gr3 Neutropenia59 Gr1 Peripheralneuropathy
Yoshitomi S Taira N Doihara H Mizoo T Nogami T Iwamoto T Motoki T Shien T Ogasawara Y Matsuoka J Tsuji H Mitsuhashi T A phase 1 dose-finding and pharmacokinetic study of gemcitabine with nab-paclitaxel in patients with metastatic breast cancer Cancer Chemother Pharmacol 2016 Aug78(2)289-94
Eli Lilly
Erbituxreg (cetuximab) + Taxane
EGFR inhibitor antineoplastic agent + Chemo
Headamp Neck Colorectal Cancer
TNBC
2007-2010
18
1 chemo
Cetuximab (epidermal growth factor receptor (EGFR) antagonist ) an initial loading dose of cetuximab 400 mgm2 followed by a weekly dose of 250 mgm2Paclitaxel (microtubule inhibitor) 80 mgm2 or Docetaxel at an initial dose of 30 mgm2 was administered weekly
56 CR 22 PR
83 Dermatologic toxicity11 Grade3+
Nechushtan H Vainer G Stainberg H Salmon AY Hamburger T Peretz T A phase 12 of a combination of cetuximab and taxane for triple negative breast cancer patients Breast 2014 Aug23(4)435-8
Polyphor
Balixafortide (POL6326) + eribulin
CXCR4 antagonist + tubulin-based antimitotic
Heavily pretreated Relapsed MBC
2014-2016
56
3rd line 3 chemo
3+3 dose escalation The highest dose was established as eribulin 14 mgmsup2 on days 2 and 9 and balixafortide 55 mgkg on days 1minus3 and 8minus10 of the 21-day cycle
30 PR
41 Gr34 Neutropenia11 Gr34 Leucopenia11 Gr34 Febrileneutropenia2 Related mortalities
Apr 2018 Fast Track for HER2-MBC who have failed 2prior regimens
Pernas S Martin M Kaufman PA Gil-Martin M Gomez Pardo P Lopez-Tarruella S Manso L Ciruelos E Perez-Fidalgo JA Hernando C Ademuyiwa FO Weilbaecher K Mayer I Pluard TJ Martinez Garcia M Vahdat L Perez-Garcia J Wach A Barker D Fung S Romagnoli B Cortes J Balixafortide plus eribulin in HER2-negative metastatic breast cancer a phase 1 single-arm dose-escalation trial Lancet Oncol 2018 Jun19(6)812-824
11 PRndashbut only + letrozole (No Resp on monotherapy)
61 Gr34 Neutropenia39 Gr34 Leucopenia
$933M in 1Q2018 $31B in 2017
Tamura K Mukai H Naito Y Yonemori K Kodaira M Tanabe Y Yamamoto N Osera S Sasaki M Mori Y Hashigaki S Nagasawa T Umeyama Y Yoshino T Phase I study of palbociclib a cyclin-dependent kinase 46 inhibitor in Japanese patients Cancer Sci 2016 Jun107(6)755-63 doi 101111cas12932 Epub 2016 May 11
Pfizer
Ibrancereg (palbociclib)
CDK 46 Inhibitor
HR+ HER2- MBC
Heavily pretreated Relapsed Metastatic Cancer
2004-2008
41 (5 BC)
chemo naiumlve (17) 1-2 (51)3 (29) 3+ (2)
Palbociclib 25-150 mg dose ranging
0
20 Gr34 Neutropenia23 Gr34 Leucopenia
$933M in 1Q2018 $31B in 2017
Flaherty KT Lorusso PM Demichele A Abramson VG Courtney R Randolph SS Shaik MN Wilner KD ODwyer PJ Schwartz GK Phase I dose-escalation trial of the oral cyclin-dependent kinase 46 inhibitor PD 0332991 administered using a 21-day schedule in patients with advanced cancer Clin Cancer Res 2012 Jan 1518(2)568-76 doi 1011581078-0432CCR-11-0509 Epub 2011 Nov 16
Novartis
Kisqalireg (ribociclib)
CDK 46 Inhibitors
Premenopausal HR+ HER2- MBC
Heavily pretreated Relapsed Metastatic Cancer
2016
132 (20 BC)
0-1 (25) 2-3 (42) 4+ (32)
Ribociclib 50 mg ranging up to 1200 mg dose escalation
23 PRndashincluded 1 in BC (5 of BC pts)
27 Gr34 Neutropenia17 Gr34 Leucopenia
Peak sales projected at $25B
Infante JR Cassier PA Gerecitano JF Witteveen PO Chugh R Ribrag V Chakraborty A Matano A Dobson JR Crystal AS Parasuraman S Shapiro GI A Phase I Study of the Cyclin-Dependent Kinase 46 Inhibitor Ribociclib (LEE011) in Patients with Advanced Solid Tumors and Lymphomas Clin Cancer Res 2016 Dec 122(23)5696-5705 Epub 2016 Aug 19
Eli Lilly
Verzenioreg (abemaciclib)
CDK 46 Inhibitors
HR+HER2minusMBC
Heavily pretreated Relapsed Metastatic Cancer
2016
12 (1 BC)
1 (312) 2 (212) 3+ (7)
Abemaciclib 100 mg ranging up to 200 mg dose escalation
17 PR (included 1 in BC)
17 Gr34 Neutropenia33 Gr34 Leucopenia
Peak sales projected at $2B
Fujiwara Y Tamura K Kondo S Tanabe Y Iwasa S Shimomura A Kitano S Ogasawara K Turner PK Mori J Asou H Chan EM Yamamoto N Phase 1 study of abemaciclib an inhibitor of CDK 4 and 6 as a single agent for Japanese patients with advanced cancer Cancer Chemother Pharmacol 2016 Aug78(2)281-8 doi 101007s00280-016-3085-8 Epub 2016 Jun 16
Mukai H Saeki T Shimada K Naito Y Matsubara N Nakanishi T Obaishi H Namiki M Sasaki Y Phase 1 combination study of eribulin mesylate with trastuzumab for advanced or recurrent human epidermal growth factor receptor 2 positive breast cancer Invest New Drugs 2015 Feb33(1)119-27
AstraZeneca
Lynparza (Olaparib)+ Cediranib
PARP inhibitor+ inhibitor of VEGF RTK
HR+ HER2- MBC
BC amp OC
13
28 (8 BC)
3 for BC
Olaparib (a poly (ADP-ribose) polymerase (PARP) inhibitor) amp Cediranib (Vascular endothelial growth factor receptor (VEGFR) 1 2 and 3 tyrosine kinase inhibitor)3 at dose level (DL) 0 (cediranib 20mg olaparib 100mg) 3 at DL1 (cediranib 20mg olaparib 200mg) 7 at DL2 (cediranib 30mg olaparib 200mg) 6 at DL3 (cediranib 30mg olaparib 400mg)
Liu JF Tolaney SM Birrer M Fleming GF Buss MK Dahlberg SE Lee H Whalen C Tyburski K Winer E Ivy P Matulonis UA A Phase 1 trial of the poly(ADP-ribose) polymerase inhibitor olaparib (AZD2281) in combination with the anti-angiogenic cediranib (AZD2171) in recurrent epithelial ovarian or triple-negative breast cancer Eur J Cancer 2013 Sep49(14)2972-8
ReyonPharma
VM206RY
Heterologous prime-boost with a truncated HER2 sequence
HER2+ Stg IIIampIV BC
15
9
2 chemo
Plasmid DNA (pHM-GM-CSF expressing truncated HER2 amp GM-CSF) amp adenoviral vector (Ad-HM containing modified HER2) (2 4 and 8 mgpatientvisit) of pHM-GM-CSF 3x IM weeks 0 2 and 4 Ad-HM 3 times 109 virus particles at week 6
11 PR
4 pts 7 minor AEs
Unclear
Kim SB Ahn JH Kim J Jung KH A phase 1 study of a heterologous prime-boost vaccination involving a truncated HER2 sequence in patients with HER2-expressing breast cancer Mol Ther Methods Clin Dev 2015 Sep 30215031 doi 101038mtm201531 eCollection 2015
Rodon J Peacuterez-Fidalgo A Krop IE Burris H Guerrero-Zotano A Britten CD Becerra C Schellens J Richards DA Schuler M Abu-Khalaf M Johnson FM Ranson M Edenfield J Silva AP Hackl W Quadt C Demanse D Duval V Baselga J Phase 11b dose escalation and expansion study of BEZ235 a dual PI3KmTOR inhibitor in patients with advanced solid tumors including patients with advanced breast cancer Cancer Chemother Pharmacol 2018 Jun 7 doi 101007s00280-018-3610-z [Epub ahead of print]
Celgene(Abraxane)
Gemcitabine + Abraxane (nab-paclitaxel)
Chemo+ Chemo
OC BC NSCLC PC + LC OC BC KS
MBC
16
9
Adjuv chemo (100)chemo post-adjuv (33)
Gem (nucleoside metabolic inhibitor 1250 mgm2) on days 1 and 8 nab-Pac (microtubule inhibitor) starting dose of 180 mgm2 (cohort 1) 220 mgm2 (cohort 2) and 260 mgm2 (cohort 3) on day 1 of the 21-day cycle using a 3 + 3 design
0
MTD not reached29 Gr3 Neutropenia59 Gr1 Peripheralneuropathy
Yoshitomi S Taira N Doihara H Mizoo T Nogami T Iwamoto T Motoki T Shien T Ogasawara Y Matsuoka J Tsuji H Mitsuhashi T A phase 1 dose-finding and pharmacokinetic study of gemcitabine with nab-paclitaxel in patients with metastatic breast cancer Cancer Chemother Pharmacol 2016 Aug78(2)289-94
Eli Lilly
Erbituxreg (cetuximab) + Taxane
EGFR inhibitor antineoplastic agent + Chemo
Head amp NeckColorectal
TNBC
07-10
18
1 chemo
Cetuximab (epidermal growth factor receptor (EGFR) antagonist ) an initial loading dose of cetuximab 400 mgm2 followed by a weekly dose of 250 mgm2Paclitaxel (microtubule inhibitor) 80 mgm2 or Docetaxel at an initial dose of 30 mgm2 was administered weekly
56 CR 22 PR
83 Dermatologic toxicity11 Grade3+
Nechushtan H Vainer G Stainberg H Salmon AY Hamburger T Peretz T A phase 12 of a combination of cetuximab and taxane for triple negative breast cancer patients Breast 2014 Aug23(4)435-8
Polyphor
Balixafortide (POL6326) + eribulin
CXCR4 antagonist + tubulin-based antimitotic
Heavily pretreatedRelapsed MBC
14-16
56
3rd line 3 chemo
3+3 dose escalation The highest dose was established as eribulin 14 mgmsup2 on days 2 and 9 and balixafortide 55 mgkg on days 1minus3 and 8minus10 of the 21-day cycle
30 PR
41 Gr34 Neutropenia11 Gr34 Leucopenia11 Gr34 Febrileneutropenia2 Related mortalities
42018 Fast Track (HER2-MBC failed 2 prior regimens)
Pernas S Martin M Kaufman PA Gil-Martin M Gomez Pardo P Lopez-Tarruella S Manso L Ciruelos E Perez-Fidalgo JA Hernando C Ademuyiwa FO Weilbaecher K Mayer I Pluard TJ Martinez Garcia M Vahdat L Perez-Garcia J Wach A Barker D Fung S Romagnoli B Cortes J Balixafortide plus eribulin in HER2-negative metastatic breast cancer a phase 1 single-arm dose-escalation trial Lancet Oncol 2018 Jun19(6)812-824
1 PRndashbut only + letrozoleNo Resp on monotherapy
61 Gr34 Neutropenia39 Gr34 Leucopenia
$933M (1Q18)$31B (2017)
Tamura K Mukai H Naito Y Yonemori K Kodaira M Tanabe Y Yamamoto N Osera S Sasaki M Mori Y Hashigaki S Nagasawa T Umeyama Y Yoshino T Phase I study of palbociclib a cyclin-dependent kinase 46 inhibitor in Japanese patients Cancer Sci 2016 Jun107(6)755-63 doi 101111cas12932 Epub 2016 May 11
Pfizer
Ibrancereg (palbociclib)
CDK 46 Inhibitor
HR+ HER2- MBC
Heavily pretreatedRelapsed Met Cancer
04-08
41 (5 BC)
chemo naiumlve (17)1-2(51) 3(29) 3+(2)
Palbociclib 25-150 mg dose ranging
0
20 Gr34 Neutropenia23 Gr34 Leucopenia
$933M (1Q18)$31B (2017)
Flaherty KT Lorusso PM Demichele A Abramson VG Courtney R Randolph SS Shaik MN Wilner KD ODwyer PJ Schwartz GK Phase I dose-escalation trial of the oral cyclin-dependent kinase 46 inhibitor PD 0332991 administered using a 21-day schedule in patients with advanced cancer Clin Cancer Res 2012 Jan 1518(2)568-76 doi 1011581078-0432CCR-11-0509 Epub 2011 Nov 16
Novartis
Kisqalireg (ribociclib)
CDK 46 Inhibitor
Premenopausal HR+ HER2- MBC
Heavily pretreatedRelapsed Met Cancer
16
132 (20 BC)
0-1 (25) 2-3 (42)4+ (32)
Ribociclib 50 mg ranging up to 1200 mg dose escalation
23 PR-included 1 BC (5 of BC pts)
27 Gr34 Neutropenia17 Gr34 Leucopenia
Peak sales est at $25B
Infante JR Cassier PA Gerecitano JF Witteveen PO Chugh R Ribrag V Chakraborty A Matano A Dobson JR Crystal AS Parasuraman S Shapiro GI A Phase I Study of the Cyclin-Dependent Kinase 46 Inhibitor Ribociclib (LEE011) in Patients with Advanced Solid Tumors and Lymphomas Clin Cancer Res 2016 Dec 122(23)5696-5705 Epub 2016 Aug 19
Eli Lilly
Verzenioreg (abemaciclib)
CDK 46 Inhibitor
HR+HER2minusMBC
Heavily pretreatedRelapsed Met Cancer
16
12 (1 BC)
1 (312) 2 (212) 3+(7)
Abemaciclib 100 mg ranging up to 200 mg dose escalation
17 PR (included 1 BC)
17 Gr34 Neutropenia33 Gr34 Leucopenia
Peak sales est at $2B
Fujiwara Y Tamura K Kondo S Tanabe Y Iwasa S Shimomura A Kitano S Ogasawara K Turner PK Mori J Asou H Chan EM Yamamoto N Phase 1 study of abemaciclib an inhibitor of CDK 4 and 6 as a single agent for Japanese patients with advanced cancer Cancer Chemother Pharmacol 2016 Aug78(2)281-8 doi 101007s00280-016-3085-8 Epub 2016 Jun 16
Mukai H Saeki T Shimada K Naito Y Matsubara N Nakanishi T Obaishi H Namiki M Sasaki Y Phase 1 combination study of eribulin mesylate with trastuzumab for advanced or recurrent human epidermal growth factor receptor 2 positive breast cancer Invest New Drugs 2015 Feb33(1)119-27
AstraZeneca
Lynparza (Olaparib) + Cediranib
PARP inhibitor + inhibitor of VEGF receptor tyrosine kinases
HR+ HER2- MBC
BC amp OC
2013
28 (8 BC)
3 for BC
Olaparib (a poly (ADP-ribose) polymerase (PARP) inhibitor) amp Cediranib (Vascular endothelial growth factor receptor (VEGFR) 1 2 and 3 tyrosine kinase inhibitor)3 at dose level (DL) 0 (cediranib 20mg olaparib 100mg) 3 at DL1 (cediranib 20mg olaparib 200mg) 7 at DL2 (cediranib 30mg olaparib 200mg) 6 at DL3 (cediranib 30mg olaparib 400mg)
Liu JF Tolaney SM Birrer M Fleming GF Buss MK Dahlberg SE Lee H Whalen C Tyburski K Winer E Ivy P Matulonis UA A Phase 1 trial of the poly(ADP-ribose) polymerase inhibitor olaparib (AZD2281) in combination with the anti-angiogenic cediranib (AZD2171) in recurrent epithelial ovarian or triple-negative breast cancer Eur J Cancer 2013 Sep49(14)2972-8
Reyon Pharmaceutical
VM206RY
Heterologous prime-boost with a truncated HER2 sequence
HER2+ Stage IIIampIV BC
2015
9
2 chemo
Plasmid DNA (pHM-GM-CSF expressing truncated HER2 amp GM-CSF) amp adenoviral vector (Ad-HM containing modified HER2) (2 4 and 8 mgpatientvisit) of pHM-GM-CSF 3x IM weeks 0 2 and 4 Ad-HM 3 times 109 virus particles at week 6
11 PR
4 pts showed 7 minor AEs
Unclear
Kim SB Ahn JH Kim J Jung KH A phase 1 study of a heterologous prime-boost vaccination involving a truncated HER2 sequence in patients with HER2-expressing breast cancer Mol Ther Methods Clin Dev 2015 Sep 30215031 doi 101038mtm201531 eCollection 2015
Rodon J Peacuterez-Fidalgo A Krop IE Burris H Guerrero-Zotano A Britten CD Becerra C Schellens J Richards DA Schuler M Abu-Khalaf M Johnson FM Ranson M Edenfield J Silva AP Hackl W Quadt C Demanse D Duval V Baselga J Phase 11b dose escalation and expansion study of BEZ235 a dual PI3KmTOR inhibitor in patients with advanced solid tumors including patients with advanced breast cancer Cancer Chemother Pharmacol 2018 Jun 7 doi 101007s00280-018-3610-z [Epub ahead of print]
Celgene (Abraxane)
Gemcitabine + Abraxane (nab-paclitaxel)
Chemo + Chemo
OC BC NSCLC amp Panc cancer + Lung OC BC Kaposi sarcoma
MBC
2016
9
Adjuvant chemo (100)chemo post-adjuvant (33)
Gem (nucleoside metabolic inhibitor 1250 mgm2) on days 1 and 8 nab-Pac (microtubule inhibitor) starting dose of 180 mgm2 (cohort 1) 220 mgm2 (cohort 2) and 260 mgm2 (cohort 3) on day 1 of the 21-day cycle using a 3 + 3 design
0
MTD not reached29 Gr3 Neutropenia59 Gr1 Peripheralneuropathy
Yoshitomi S Taira N Doihara H Mizoo T Nogami T Iwamoto T Motoki T Shien T Ogasawara Y Matsuoka J Tsuji H Mitsuhashi T A phase 1 dose-finding and pharmacokinetic study of gemcitabine with nab-paclitaxel in patients with metastatic breast cancer Cancer Chemother Pharmacol 2016 Aug78(2)289-94
Eli Lilly
Erbituxreg (cetuximab) + Taxane
EGFR inhibitor antineoplastic agent + Chemo
Headamp Neck Colorectal Cancer
TNBC
2007-2010
18
1 chemo
Cetuximab (epidermal growth factor receptor (EGFR) antagonist ) an initial loading dose of cetuximab 400 mgm2 followed by a weekly dose of 250 mgm2Paclitaxel (microtubule inhibitor) 80 mgm2 or Docetaxel at an initial dose of 30 mgm2 was administered weekly
56 CR 22 PR
83 Dermatologic toxicity11 Grade3+
Nechushtan H Vainer G Stainberg H Salmon AY Hamburger T Peretz T A phase 12 of a combination of cetuximab and taxane for triple negative breast cancer patients Breast 2014 Aug23(4)435-8
Polyphor
Balixafortide (POL6326) + eribulin
CXCR4 antagonist + tubulin-based antimitotic
Heavily pretreated Relapsed MBC
2014-2016
56
3rd line 3 chemo
3+3 dose escalation The highest dose was established as eribulin 14 mgmsup2 on days 2 and 9 and balixafortide 55 mgkg on days 1minus3 and 8minus10 of the 21-day cycle
30 PR
41 Gr34 Neutropenia11 Gr34 Leucopenia11 Gr34 Febrileneutropenia2 Related mortalities
Apr 2018 Fast Track for HER2-MBC who have failed 2prior regimens
Pernas S Martin M Kaufman PA Gil-Martin M Gomez Pardo P Lopez-Tarruella S Manso L Ciruelos E Perez-Fidalgo JA Hernando C Ademuyiwa FO Weilbaecher K Mayer I Pluard TJ Martinez Garcia M Vahdat L Perez-Garcia J Wach A Barker D Fung S Romagnoli B Cortes J Balixafortide plus eribulin in HER2-negative metastatic breast cancer a phase 1 single-arm dose-escalation trial Lancet Oncol 2018 Jun19(6)812-824
11 PRndashbut only + letrozole (No Resp on monotherapy)
61 Gr34 Neutropenia39 Gr34 Leucopenia
$933M in 1Q2018 $31B in 2017
Tamura K Mukai H Naito Y Yonemori K Kodaira M Tanabe Y Yamamoto N Osera S Sasaki M Mori Y Hashigaki S Nagasawa T Umeyama Y Yoshino T Phase I study of palbociclib a cyclin-dependent kinase 46 inhibitor in Japanese patients Cancer Sci 2016 Jun107(6)755-63 doi 101111cas12932 Epub 2016 May 11
Pfizer
Ibrancereg (palbociclib)
CDK 46 Inhibitor
HR+ HER2- MBC
Heavily pretreated Relapsed Metastatic Cancer
2004-2008
41 (5 BC)
chemo naiumlve (17) 1-2 (51)3 (29) 3+ (2)
Palbociclib 25-150 mg dose ranging
0
20 Gr34 Neutropenia23 Gr34 Leucopenia
$933M in 1Q2018 $31B in 2017
Flaherty KT Lorusso PM Demichele A Abramson VG Courtney R Randolph SS Shaik MN Wilner KD ODwyer PJ Schwartz GK Phase I dose-escalation trial of the oral cyclin-dependent kinase 46 inhibitor PD 0332991 administered using a 21-day schedule in patients with advanced cancer Clin Cancer Res 2012 Jan 1518(2)568-76 doi 1011581078-0432CCR-11-0509 Epub 2011 Nov 16
Novartis
Kisqalireg (ribociclib)
CDK 46 Inhibitors
Premenopausal HR+ HER2- MBC
Heavily pretreated Relapsed Metastatic Cancer
2016
132 (20 BC)
0-1 (25) 2-3 (42) 4+ (32)
Ribociclib 50 mg ranging up to 1200 mg dose escalation
23 PRndashincluded 1 in BC (5 of BC pts)
27 Gr34 Neutropenia17 Gr34 Leucopenia
Peak sales projected at $25B
Infante JR Cassier PA Gerecitano JF Witteveen PO Chugh R Ribrag V Chakraborty A Matano A Dobson JR Crystal AS Parasuraman S Shapiro GI A Phase I Study of the Cyclin-Dependent Kinase 46 Inhibitor Ribociclib (LEE011) in Patients with Advanced Solid Tumors and Lymphomas Clin Cancer Res 2016 Dec 122(23)5696-5705 Epub 2016 Aug 19
Eli Lilly
Verzenioreg (abemaciclib)
CDK 46 Inhibitors
HR+HER2minusMBC
Heavily pretreated Relapsed Metastatic Cancer
2016
12 (1 BC)
1 (312) 2 (212) 3+ (7)
Abemaciclib 100 mg ranging up to 200 mg dose escalation
17 PR (included 1 in BC)
17 Gr34 Neutropenia33 Gr34 Leucopenia
Peak sales projected at $2B
Fujiwara Y Tamura K Kondo S Tanabe Y Iwasa S Shimomura A Kitano S Ogasawara K Turner PK Mori J Asou H Chan EM Yamamoto N Phase 1 study of abemaciclib an inhibitor of CDK 4 and 6 as a single agent for Japanese patients with advanced cancer Cancer Chemother Pharmacol 2016 Aug78(2)281-8 doi 101007s00280-016-3085-8 Epub 2016 Jun 16
Mukai H Saeki T Shimada K Naito Y Matsubara N Nakanishi T Obaishi H Namiki M Sasaki Y Phase 1 combination study of eribulin mesylate with trastuzumab for advanced or recurrent human epidermal growth factor receptor 2 positive breast cancer Invest New Drugs 2015 Feb33(1)119-27
AstraZeneca
Lynparza (Olaparib)+ Cediranib
PARP inhibitor+ inhibitor of VEGF RTK
HR+ HER2- MBC
BC amp OC
13
28 (8 BC)
3 for BC
Olaparib (a poly (ADP-ribose) polymerase (PARP) inhibitor) amp Cediranib (Vascular endothelial growth factor receptor (VEGFR) 1 2 and 3 tyrosine kinase inhibitor)3 at dose level (DL) 0 (cediranib 20mg olaparib 100mg) 3 at DL1 (cediranib 20mg olaparib 200mg) 7 at DL2 (cediranib 30mg olaparib 200mg) 6 at DL3 (cediranib 30mg olaparib 400mg)
Liu JF Tolaney SM Birrer M Fleming GF Buss MK Dahlberg SE Lee H Whalen C Tyburski K Winer E Ivy P Matulonis UA A Phase 1 trial of the poly(ADP-ribose) polymerase inhibitor olaparib (AZD2281) in combination with the anti-angiogenic cediranib (AZD2171) in recurrent epithelial ovarian or triple-negative breast cancer Eur J Cancer 2013 Sep49(14)2972-8
ReyonPharma
VM206RY
Heterologous prime-boost with a truncated HER2 sequence
HER2+ Stg IIIampIV BC
15
9
2 chemo
Plasmid DNA (pHM-GM-CSF expressing truncated HER2 amp GM-CSF) amp adenoviral vector (Ad-HM containing modified HER2) (2 4 and 8 mgpatientvisit) of pHM-GM-CSF 3x IM weeks 0 2 and 4 Ad-HM 3 times 109 virus particles at week 6
11 PR
4 pts 7 minor AEs
Unclear
Kim SB Ahn JH Kim J Jung KH A phase 1 study of a heterologous prime-boost vaccination involving a truncated HER2 sequence in patients with HER2-expressing breast cancer Mol Ther Methods Clin Dev 2015 Sep 30215031 doi 101038mtm201531 eCollection 2015
Rodon J Peacuterez-Fidalgo A Krop IE Burris H Guerrero-Zotano A Britten CD Becerra C Schellens J Richards DA Schuler M Abu-Khalaf M Johnson FM Ranson M Edenfield J Silva AP Hackl W Quadt C Demanse D Duval V Baselga J Phase 11b dose escalation and expansion study of BEZ235 a dual PI3KmTOR inhibitor in patients with advanced solid tumors including patients with advanced breast cancer Cancer Chemother Pharmacol 2018 Jun 7 doi 101007s00280-018-3610-z [Epub ahead of print]
Celgene(Abraxane)
Gemcitabine + Abraxane (nab-paclitaxel)
Chemo+ Chemo
OC BC NSCLC PC + LC OC BC KS
MBC
16
9
Adjuv chemo (100)chemo post-adjuv (33)
Gem (nucleoside metabolic inhibitor 1250 mgm2) on days 1 and 8 nab-Pac (microtubule inhibitor) starting dose of 180 mgm2 (cohort 1) 220 mgm2 (cohort 2) and 260 mgm2 (cohort 3) on day 1 of the 21-day cycle using a 3 + 3 design
0
MTD not reached29 Gr3 Neutropenia59 Gr1 Peripheralneuropathy
Yoshitomi S Taira N Doihara H Mizoo T Nogami T Iwamoto T Motoki T Shien T Ogasawara Y Matsuoka J Tsuji H Mitsuhashi T A phase 1 dose-finding and pharmacokinetic study of gemcitabine with nab-paclitaxel in patients with metastatic breast cancer Cancer Chemother Pharmacol 2016 Aug78(2)289-94
Eli Lilly
Erbituxreg (cetuximab) + Taxane
EGFR inhibitor antineoplastic agent + Chemo
Head amp NeckColorectal
TNBC
07-10
18
1 chemo
Cetuximab (epidermal growth factor receptor (EGFR) antagonist ) an initial loading dose of cetuximab 400 mgm2 followed by a weekly dose of 250 mgm2Paclitaxel (microtubule inhibitor) 80 mgm2 or Docetaxel at an initial dose of 30 mgm2 was administered weekly
56 CR 22 PR
83 Dermatologic toxicity11 Grade3+
Nechushtan H Vainer G Stainberg H Salmon AY Hamburger T Peretz T A phase 12 of a combination of cetuximab and taxane for triple negative breast cancer patients Breast 2014 Aug23(4)435-8
Polyphor
Balixafortide (POL6326) + eribulin
CXCR4 antagonist + tubulin-based antimitotic
Heavily pretreatedRelapsed MBC
14-16
56
3rd line 3 chemo
3+3 dose escalation The highest dose was established as eribulin 14 mgmsup2 on days 2 and 9 and balixafortide 55 mgkg on days 1minus3 and 8minus10 of the 21-day cycle
30 PR
41 Gr34 Neutropenia11 Gr34 Leucopenia11 Gr34 Febrileneutropenia2 Related mortalities
42018 Fast Track (HER2-MBC failed 2 prior regimens)
Pernas S Martin M Kaufman PA Gil-Martin M Gomez Pardo P Lopez-Tarruella S Manso L Ciruelos E Perez-Fidalgo JA Hernando C Ademuyiwa FO Weilbaecher K Mayer I Pluard TJ Martinez Garcia M Vahdat L Perez-Garcia J Wach A Barker D Fung S Romagnoli B Cortes J Balixafortide plus eribulin in HER2-negative metastatic breast cancer a phase 1 single-arm dose-escalation trial Lancet Oncol 2018 Jun19(6)812-824
1 PRndashbut only + letrozoleNo Resp on monotherapy
61 Gr34 Neutropenia39 Gr34 Leucopenia
$933M (1Q18)$31B (2017)
Tamura K Mukai H Naito Y Yonemori K Kodaira M Tanabe Y Yamamoto N Osera S Sasaki M Mori Y Hashigaki S Nagasawa T Umeyama Y Yoshino T Phase I study of palbociclib a cyclin-dependent kinase 46 inhibitor in Japanese patients Cancer Sci 2016 Jun107(6)755-63 doi 101111cas12932 Epub 2016 May 11
Pfizer
Ibrancereg (palbociclib)
CDK 46 Inhibitor
HR+ HER2- MBC
Heavily pretreatedRelapsed Met Cancer
04-08
41 (5 BC)
chemo naiumlve (17)1-2(51) 3(29) 3+(2)
Palbociclib 25-150 mg dose ranging
0
20 Gr34 Neutropenia23 Gr34 Leucopenia
$933M (1Q18)$31B (2017)
Flaherty KT Lorusso PM Demichele A Abramson VG Courtney R Randolph SS Shaik MN Wilner KD ODwyer PJ Schwartz GK Phase I dose-escalation trial of the oral cyclin-dependent kinase 46 inhibitor PD 0332991 administered using a 21-day schedule in patients with advanced cancer Clin Cancer Res 2012 Jan 1518(2)568-76 doi 1011581078-0432CCR-11-0509 Epub 2011 Nov 16
Novartis
Kisqalireg (ribociclib)
CDK 46 Inhibitor
Premenopausal HR+ HER2- MBC
Heavily pretreatedRelapsed Met Cancer
16
132 (20 BC)
0-1 (25) 2-3 (42)4+ (32)
Ribociclib 50 mg ranging up to 1200 mg dose escalation
23 PR-included 1 BC (5 of BC pts)
27 Gr34 Neutropenia17 Gr34 Leucopenia
Peak sales est at $25B
Infante JR Cassier PA Gerecitano JF Witteveen PO Chugh R Ribrag V Chakraborty A Matano A Dobson JR Crystal AS Parasuraman S Shapiro GI A Phase I Study of the Cyclin-Dependent Kinase 46 Inhibitor Ribociclib (LEE011) in Patients with Advanced Solid Tumors and Lymphomas Clin Cancer Res 2016 Dec 122(23)5696-5705 Epub 2016 Aug 19
Eli Lilly
Verzenioreg (abemaciclib)
CDK 46 Inhibitor
HR+HER2minusMBC
Heavily pretreatedRelapsed Met Cancer
16
12 (1 BC)
1 (312) 2 (212) 3+(7)
Abemaciclib 100 mg ranging up to 200 mg dose escalation
17 PR (included 1 BC)
17 Gr34 Neutropenia33 Gr34 Leucopenia
Peak sales est at $2B
Fujiwara Y Tamura K Kondo S Tanabe Y Iwasa S Shimomura A Kitano S Ogasawara K Turner PK Mori J Asou H Chan EM Yamamoto N Phase 1 study of abemaciclib an inhibitor of CDK 4 and 6 as a single agent for Japanese patients with advanced cancer Cancer Chemother Pharmacol 2016 Aug78(2)281-8 doi 101007s00280-016-3085-8 Epub 2016 Jun 16
41 Gr34 Neutropenia11 Gr34 Leucopenia11 Gr34 Febrileneutropenia2 Related mortalities
30 PRs in combination with Halaven
Bria-IMTTM
20
Injection site reactions No related SAEs or SUSARs
Tumor vol darr ampor darr circul tumor cells)All Comers 21(419) 26(519)One or More HLA matches 27(415) 33(515)Two or More HLA matches 50 (24) 75 (34))
Drug
Technology
Approved for
Market (US)
Ibrance (palbociclib)
CDK 46 Inhibitor
HR+HER2- MBC in combination with fluvestrant or aromatase inhibitor
$933M in 1Q2018 $3126M in 2017
Kisqali (ribociclib)
CDK 46 Inhibitor
2017 HR+HER2- MBC in combination with fluvestrant or aromatase inhibitor
Peak sales projected at $25B
Verzenio (abemaciclib)
CDK 46 Inhibitor
2017 HR+HER2- MBC in combination with fluvestrant or aromatase inhibitor
Peak sales projected at $2B
Lynparza (olaparib)
Poly (ADP-ribose) polymerase (PARP) inhibitor
2017 ovarian amp breast cancer
$997M in 2017
Halaven (eribulin mesylate)
Tubulin-based antimitotic
2H2017 3rd line MBC amp liposarcoma
$181M in 2017
balixafortide
CXCR4 antagonist
Fast track designation in 2018 for HER2- MBC who have failed 2 prior regimens
Bria-IMTtrade Excellent Safety Data - To Date
To date Bria-IMTtrade has been dosed in 24 patients (4 in 2004-2005 20 in 2017-2018)
Interim Data (20 patients)-Ongoing Phase IIIa Study (2017-2018)
Bria-IMTtrade has been very well tolerated (ge60 doses given to date) The majority of adverse events (AEs) were limited to expected minor local irritation at the
injection sites No related grade gt3 or unexpected AEs No related serious AEs No serious unexpected related AEs Most patients who have dropped out did so due to worsening of their underlying disease
Based on the current study Bria-IMTtrade has an excellent safety profile
29
Bria-IMTtrade - Efficacy as Predicted
Interim Data (19 patients)-Ongoing Phase IIIa Study (2017-2018) amp Original Study (2004-2005)
PD-L1 expression on circulating cancer cells amp cancer-associated cells in 100 of patients (to date) Strong rationale for combination with checkpoint inhibitors like Keytruda
30
Bria-IMTtrade appears to be most effective in patients who match with Bria-IMT trade at 2 HLA loci (types) further supporting our ldquoHLA Matching Hypothesisrdquo and the development of Bria-OTS trade to cover 90 of the patient population
Combination with immune checkpoint inhibitors may induce a more potent anti-cancer response leading to our strategy of combination studies of Bria-IMT trade with Keytruda or Yervoy
Patients (n) HLA Match
Tumor Shrinkage
Biological Response
4 ge2 50 7515 ge1 27 334 0 0 0
Biological response includes tumor shrinkage or lower circulating cancer associated cells
The confirmatory Bria-IMTtrade monotherapy Phase IIa trial has completed enrollment Additional Support for the HLA-matching hypothesis has been obtained
Bria-IMTtrade Combination Therapy study with immune checkpoint inhibitors Keytrudareg if PD-L12 positive (ge1) Yervoyreg if PD-L12 negative (lt1) Accepting patients from the monotherapy study who develop progressive disease Also enrolling patients directly into this study to enhance experience with the combination In discussion with other pharmaceutical companies to evaluate additional combinations with other
immunotherapies
Bria-OTStrade Off-the-Shelf Personalized Targeted Immunotherapy Developing Bria-OTStrade to co-express GM-CSF and interferon-α Pre-manufacture additional HLA alleles ndash Total of 15 alleles (8 Class I and 7 Class II) Co-development of BriaDXtrade companion diagnostic for HLA typing Combination therapy clinical trial with immune checkpoint inhibitors for non-responders using
information from the Bria-IMTtrade Combination Therapy Study
33
Development Timeline ndash Breast Cancer
20192018 2020 2021
Phase IIIaBria-IMTtrade
Monotherapy
Currently Enrolling Phase IIaBria-IMTtrade + Checkpoint
Currently in discussions with potential partnersPhase II Bria-IMTtrade plus Additional Combinations (1Q19 4Q22)(eg PD-1 Inhibitor PD-L1 inhibitor anti-CTLA4 anti-GITR anti-OX40)
1Q 2Q 3Q 4Q
2023
Bria-OTStrade Off-The-Shelf Personalized ImmunotherapyMonotherapy and Potential Partnered Combo Therapy
(2H19 Ongoing)
Bria-OTStradeOff-the-Shelf Cell Line cGMP Manufacturing
and BriaDXtrade(1Q18 1Q19)
Registration Studies (1Q20 2H22)Bria-IMTtrade with Checkpoint InhibitorsBria-OTStrade +- Checkpoint Inhibitors
34
Immuno-oncology Deals
Recent deals of small biotechs with big pharma in immuno-oncology
35
Date PartnershipDevelopment stage at the time of the deal Deal size
07122018 Immatics-Genmab Preclinical Up to $28B
04042018 OSE Immunotherapeutics-Boehringer Ingelheim Preclinical Up to euro113B ($139B)
02092018 Pieris Pharmaceuticals-Seattle Genetics Preclinical Up to $123B
2142018 Nektar-BMS Ph III Up to $36B
01222018 Juno-Celgene Ph II $9B (Acquisition)
11142017 Loxo-Bayer Larotrectinib (Ph II) LOXO-195 (Ph III) Up to $155B
1032017 CytomX-Amgen Preclinical Up to $15B
03202017 CytomX--BMS Ph III Up to $36B
6282016 Xencor-Novartis Preclinical Up to $24B
Early Stage Clinical Studies (Comparison)
We compared the interim data of Ph IIIa study of Bria-IMTtrade in advanced breast cancer with thedata in the early stage clinical studies of recently approved breast cancer drugs and one fasttracked product candidate
Apples to apples comparison Early Stage Clinical Studies in oncology are typically done in patientswith no other therapeutic options Thus the patients have very advanced disease and response ratesare typically quite low
The patients in our Ph IIIa study have been heavily pre-treated (median 45 prior regimens)Some recent studies of relevance in breast cancer are noted in the following slides
36
Breast Cancer Market Opportunity
Drug Technology Approved for Market (US)Ibrance (palbociclib) CDK 46 Inhibitor HR+HER2- MBC in combination with
fluvestrant or aromatase inhibitor$933M in 1Q2018 $3126M in 2017
Kisqali (ribociclib) CDK 46 Inhibitor 2017 HR+HER2- MBC in combination with fluvestrant or aromatase inhibitor
Peak sales projected at $25B
Verzenio (abemaciclib) CDK 46 Inhibitor 2017 HR+HER2- MBC in combination with fluvestrant or aromatase inhibitor
balixafortide CXCR4 antagonist Fast track designation in 2018 for HER2- MBC who have failed 2 prior regimens
The market for breast cancer drugs is a multibillion dollar market with new drugs being approvedon an ongoing basis indicating the shortage of safe and effective treatments for this deadly disease
37
Competitors- Phase III Clinical Data Bria-IMTtrade shows superior safety and similar to superior efficacy data compared with those of the multi-billion dollar drugs when they were at a similar early stage of clinical development
Injection site reactions No related SAEs or SUSARs
Tumor vol darr ampor darr circul tumor cellsAll Comers 21(419) 26(519)One or More HLA matches 27(415) 33(515)Two or More HLA matches 50 (24) 75 (34)
Sheet1 (3)
Comp -Slides
Data
HLA (2)
HLA
Data (Ph1-2+4Pt)
Competitors (2018)-Slide
Competitors (2018)
In the Pipeline Protein Kinase C delta (PKCδ) Inhibitors
30 of all human malignancies display activating RAS mutations Another 60 showing over-activity of Ras-signaling pathways
Ras has been termed ldquoundruggablerdquo (no one has been able to make a Ras inhibitor drug)
BriaCellrsquos novel proprietary PKCδ inhibitors have shown activity against multiple RAS transformed tumors Lung cancer Melanoma Breast cancer Neuroendocrine cancer Pancreatic cancer Colorectal cancer
This target has an attractive safety profile based on in vivo studies and knock out mouse studies
PKCδ inhibitors should qualify for an accelerated clinical development plan and regulatory pathway
Could be in clinic within 24 months
Cost-Effective Additional Shot-on-Goal and additional partnership opportunities
Early-Stage Preclinical Program
39
Protein Kinase C delta (PKCδ) Inhibitors
Activated PKCδ inhibits RAS degradation which in turn stimulates tumor growth
Koo et al Oncotarget 621328 2016
30 of all human malignancies display activating RASmutations with another 60 showing over-activity of Ras-signaling pathways
BriaCellrsquos novel proprietary PKCδ inhibitors have shownactivity against multiple RAS transformed tumors
This target has an attractive safety profile based on in vivostudies and knock out mouse studies
PKCδ also has potential activity as an immunotherapeuticby blocking TGFβ signaling
PKCδ inhibitors are applicable to specific niche tumor typeswhich provide an accelerated clinical development plan
Structural aspects of first generation inhibitor rottlerin and staurosporine (pan-PKC activator) were combined to create second generation inhibitor KAM1
Third generation inhibitors such as BJE6-106 have improved potency and selectivity Fourth generation inhibitors under development to optimize drug-like characteristics PKCδ inhibitors lack endothelial cell cytotoxicity amp PKCδ deficient mice develop normally and are fertile Potentially no marked intrinsic toxicity by inhibiting PKCδ
Mukai H Saeki T Shimada K Naito Y Matsubara N Nakanishi T Obaishi H Namiki M Sasaki Y Phase 1 combination study of eribulin mesylate with trastuzumab for advanced or recurrent human epidermal growth factor receptor 2 positive breast cancer Invest New Drugs 2015 Feb33(1)119-27
AstraZeneca
Lynparza (Olaparib) + Cediranib
PARP inhibitor + inhibitor of VEGF receptor tyrosine kinases
HR+ HER2- MBC
BC amp OC
2013
28 (8 BC)
3 for BC
Olaparib (a poly (ADP-ribose) polymerase (PARP) inhibitor) amp Cediranib (Vascular endothelial growth factor receptor (VEGFR) 1 2 and 3 tyrosine kinase inhibitor)3 at dose level (DL) 0 (cediranib 20mg olaparib 100mg) 3 at DL1 (cediranib 20mg olaparib 200mg) 7 at DL2 (cediranib 30mg olaparib 200mg) 6 at DL3 (cediranib 30mg olaparib 400mg)
Liu JF Tolaney SM Birrer M Fleming GF Buss MK Dahlberg SE Lee H Whalen C Tyburski K Winer E Ivy P Matulonis UA A Phase 1 trial of the poly(ADP-ribose) polymerase inhibitor olaparib (AZD2281) in combination with the anti-angiogenic cediranib (AZD2171) in recurrent epithelial ovarian or triple-negative breast cancer Eur J Cancer 2013 Sep49(14)2972-8
Reyon Pharmaceutical
VM206RY
Heterologous prime-boost with a truncated HER2 sequence
HER2+ Stage IIIampIV BC
2015
9
2 chemo
Plasmid DNA (pHM-GM-CSF expressing truncated HER2 amp GM-CSF) amp adenoviral vector (Ad-HM containing modified HER2) (2 4 and 8 mgpatientvisit) of pHM-GM-CSF 3x IM weeks 0 2 and 4 Ad-HM 3 times 109 virus particles at week 6
11 PR
4 pts showed 7 minor AEs
Unclear
Kim SB Ahn JH Kim J Jung KH A phase 1 study of a heterologous prime-boost vaccination involving a truncated HER2 sequence in patients with HER2-expressing breast cancer Mol Ther Methods Clin Dev 2015 Sep 30215031 doi 101038mtm201531 eCollection 2015
Rodon J Peacuterez-Fidalgo A Krop IE Burris H Guerrero-Zotano A Britten CD Becerra C Schellens J Richards DA Schuler M Abu-Khalaf M Johnson FM Ranson M Edenfield J Silva AP Hackl W Quadt C Demanse D Duval V Baselga J Phase 11b dose escalation and expansion study of BEZ235 a dual PI3KmTOR inhibitor in patients with advanced solid tumors including patients with advanced breast cancer Cancer Chemother Pharmacol 2018 Jun 7 doi 101007s00280-018-3610-z [Epub ahead of print]
Celgene (Abraxane)
Gemcitabine + Abraxane (nab-paclitaxel)
Chemo + Chemo
OC BC NSCLC amp Panc cancer + Lung OC BC Kaposi sarcoma
MBC
2016
9
Adjuvant chemo (100)chemo post-adjuvant (33)
Gem (nucleoside metabolic inhibitor 1250 mgm2) on days 1 and 8 nab-Pac (microtubule inhibitor) starting dose of 180 mgm2 (cohort 1) 220 mgm2 (cohort 2) and 260 mgm2 (cohort 3) on day 1 of the 21-day cycle using a 3 + 3 design
0
MTD not reached29 Gr3 Neutropenia59 Gr1 Peripheralneuropathy
Yoshitomi S Taira N Doihara H Mizoo T Nogami T Iwamoto T Motoki T Shien T Ogasawara Y Matsuoka J Tsuji H Mitsuhashi T A phase 1 dose-finding and pharmacokinetic study of gemcitabine with nab-paclitaxel in patients with metastatic breast cancer Cancer Chemother Pharmacol 2016 Aug78(2)289-94
Eli Lilly
Erbituxreg (cetuximab) + Taxane
EGFR inhibitor antineoplastic agent + Chemo
Headamp Neck Colorectal Cancer
TNBC
2007-2010
18
1 chemo
Cetuximab (epidermal growth factor receptor (EGFR) antagonist ) an initial loading dose of cetuximab 400 mgm2 followed by a weekly dose of 250 mgm2Paclitaxel (microtubule inhibitor) 80 mgm2 or Docetaxel at an initial dose of 30 mgm2 was administered weekly
56 CR 22 PR
83 Dermatologic toxicity11 Grade3+
Nechushtan H Vainer G Stainberg H Salmon AY Hamburger T Peretz T A phase 12 of a combination of cetuximab and taxane for triple negative breast cancer patients Breast 2014 Aug23(4)435-8
Polyphor
Balixafortide (POL6326) + eribulin
CXCR4 antagonist + tubulin-based antimitotic
Heavily pretreated Relapsed MBC
2014-2016
56
3rd line 3 chemo
3+3 dose escalation The highest dose was established as eribulin 14 mgmsup2 on days 2 and 9 and balixafortide 55 mgkg on days 1minus3 and 8minus10 of the 21-day cycle
30 PR
41 Gr34 Neutropenia11 Gr34 Leucopenia11 Gr34 Febrileneutropenia2 Related mortalities
Apr 2018 Fast Track for HER2-MBC who have failed 2prior regimens
Pernas S Martin M Kaufman PA Gil-Martin M Gomez Pardo P Lopez-Tarruella S Manso L Ciruelos E Perez-Fidalgo JA Hernando C Ademuyiwa FO Weilbaecher K Mayer I Pluard TJ Martinez Garcia M Vahdat L Perez-Garcia J Wach A Barker D Fung S Romagnoli B Cortes J Balixafortide plus eribulin in HER2-negative metastatic breast cancer a phase 1 single-arm dose-escalation trial Lancet Oncol 2018 Jun19(6)812-824
11 PRndashbut only + letrozole (No Resp on monotherapy)
61 Gr34 Neutropenia39 Gr34 Leucopenia
$933M in 1Q2018 $31B in 2017
Tamura K Mukai H Naito Y Yonemori K Kodaira M Tanabe Y Yamamoto N Osera S Sasaki M Mori Y Hashigaki S Nagasawa T Umeyama Y Yoshino T Phase I study of palbociclib a cyclin-dependent kinase 46 inhibitor in Japanese patients Cancer Sci 2016 Jun107(6)755-63 doi 101111cas12932 Epub 2016 May 11
Pfizer
Ibrancereg (palbociclib)
CDK 46 Inhibitor
HR+ HER2- MBC
Heavily pretreated Relapsed Metastatic Cancer
2004-2008
41 (5 BC)
chemo naiumlve (17) 1-2 (51)3 (29) 3+ (2)
Palbociclib 25-150 mg dose ranging
0
20 Gr34 Neutropenia23 Gr34 Leucopenia
$933M in 1Q2018 $31B in 2017
Flaherty KT Lorusso PM Demichele A Abramson VG Courtney R Randolph SS Shaik MN Wilner KD ODwyer PJ Schwartz GK Phase I dose-escalation trial of the oral cyclin-dependent kinase 46 inhibitor PD 0332991 administered using a 21-day schedule in patients with advanced cancer Clin Cancer Res 2012 Jan 1518(2)568-76 doi 1011581078-0432CCR-11-0509 Epub 2011 Nov 16
Novartis
Kisqalireg (ribociclib)
CDK 46 Inhibitors
Premenopausal HR+ HER2- MBC
Heavily pretreated Relapsed Metastatic Cancer
2016
132 (20 BC)
0-1 (25) 2-3 (42) 4+ (32)
Ribociclib 50 mg ranging up to 1200 mg dose escalation
23 PRndashincluded 1 in BC (5 of BC pts)
27 Gr34 Neutropenia17 Gr34 Leucopenia
Peak sales projected at $25B
Infante JR Cassier PA Gerecitano JF Witteveen PO Chugh R Ribrag V Chakraborty A Matano A Dobson JR Crystal AS Parasuraman S Shapiro GI A Phase I Study of the Cyclin-Dependent Kinase 46 Inhibitor Ribociclib (LEE011) in Patients with Advanced Solid Tumors and Lymphomas Clin Cancer Res 2016 Dec 122(23)5696-5705 Epub 2016 Aug 19
Eli Lilly
Verzenioreg (abemaciclib)
CDK 46 Inhibitors
HR+HER2minusMBC
Heavily pretreated Relapsed Metastatic Cancer
2016
12 (1 BC)
1 (312) 2 (212) 3+ (7)
Abemaciclib 100 mg ranging up to 200 mg dose escalation
17 PR (included 1 in BC)
17 Gr34 Neutropenia33 Gr34 Leucopenia
Peak sales projected at $2B
Fujiwara Y Tamura K Kondo S Tanabe Y Iwasa S Shimomura A Kitano S Ogasawara K Turner PK Mori J Asou H Chan EM Yamamoto N Phase 1 study of abemaciclib an inhibitor of CDK 4 and 6 as a single agent for Japanese patients with advanced cancer Cancer Chemother Pharmacol 2016 Aug78(2)281-8 doi 101007s00280-016-3085-8 Epub 2016 Jun 16
Mukai H Saeki T Shimada K Naito Y Matsubara N Nakanishi T Obaishi H Namiki M Sasaki Y Phase 1 combination study of eribulin mesylate with trastuzumab for advanced or recurrent human epidermal growth factor receptor 2 positive breast cancer Invest New Drugs 2015 Feb33(1)119-27
AstraZeneca
Lynparza (Olaparib)+ Cediranib
PARP inhibitor+ inhibitor of VEGF RTK
HR+ HER2- MBC
BC amp OC
13
28 (8 BC)
3 for BC
Olaparib (a poly (ADP-ribose) polymerase (PARP) inhibitor) amp Cediranib (Vascular endothelial growth factor receptor (VEGFR) 1 2 and 3 tyrosine kinase inhibitor)3 at dose level (DL) 0 (cediranib 20mg olaparib 100mg) 3 at DL1 (cediranib 20mg olaparib 200mg) 7 at DL2 (cediranib 30mg olaparib 200mg) 6 at DL3 (cediranib 30mg olaparib 400mg)
Liu JF Tolaney SM Birrer M Fleming GF Buss MK Dahlberg SE Lee H Whalen C Tyburski K Winer E Ivy P Matulonis UA A Phase 1 trial of the poly(ADP-ribose) polymerase inhibitor olaparib (AZD2281) in combination with the anti-angiogenic cediranib (AZD2171) in recurrent epithelial ovarian or triple-negative breast cancer Eur J Cancer 2013 Sep49(14)2972-8
ReyonPharma
VM206RY
Heterologous prime-boost with a truncated HER2 sequence
HER2+ Stg IIIampIV BC
15
9
2 chemo
Plasmid DNA (pHM-GM-CSF expressing truncated HER2 amp GM-CSF) amp adenoviral vector (Ad-HM containing modified HER2) (2 4 and 8 mgpatientvisit) of pHM-GM-CSF 3x IM weeks 0 2 and 4 Ad-HM 3 times 109 virus particles at week 6
11 PR
4 pts 7 minor AEs
Unclear
Kim SB Ahn JH Kim J Jung KH A phase 1 study of a heterologous prime-boost vaccination involving a truncated HER2 sequence in patients with HER2-expressing breast cancer Mol Ther Methods Clin Dev 2015 Sep 30215031 doi 101038mtm201531 eCollection 2015
Rodon J Peacuterez-Fidalgo A Krop IE Burris H Guerrero-Zotano A Britten CD Becerra C Schellens J Richards DA Schuler M Abu-Khalaf M Johnson FM Ranson M Edenfield J Silva AP Hackl W Quadt C Demanse D Duval V Baselga J Phase 11b dose escalation and expansion study of BEZ235 a dual PI3KmTOR inhibitor in patients with advanced solid tumors including patients with advanced breast cancer Cancer Chemother Pharmacol 2018 Jun 7 doi 101007s00280-018-3610-z [Epub ahead of print]
Celgene(Abraxane)
Gemcitabine + Abraxane (nab-paclitaxel)
Chemo+ Chemo
OC BC NSCLC PC + LC OC BC KS
MBC
16
9
Adjuv chemo (100)chemo post-adjuv (33)
Gem (nucleoside metabolic inhibitor 1250 mgm2) on days 1 and 8 nab-Pac (microtubule inhibitor) starting dose of 180 mgm2 (cohort 1) 220 mgm2 (cohort 2) and 260 mgm2 (cohort 3) on day 1 of the 21-day cycle using a 3 + 3 design
0
MTD not reached29 Gr3 Neutropenia59 Gr1 Peripheralneuropathy
Yoshitomi S Taira N Doihara H Mizoo T Nogami T Iwamoto T Motoki T Shien T Ogasawara Y Matsuoka J Tsuji H Mitsuhashi T A phase 1 dose-finding and pharmacokinetic study of gemcitabine with nab-paclitaxel in patients with metastatic breast cancer Cancer Chemother Pharmacol 2016 Aug78(2)289-94
Eli Lilly
Erbituxreg (cetuximab) + Taxane
EGFR inhibitor antineoplastic agent + Chemo
Head amp NeckColorectal
TNBC
07-10
18
1 chemo
Cetuximab (epidermal growth factor receptor (EGFR) antagonist ) an initial loading dose of cetuximab 400 mgm2 followed by a weekly dose of 250 mgm2Paclitaxel (microtubule inhibitor) 80 mgm2 or Docetaxel at an initial dose of 30 mgm2 was administered weekly
56 CR 22 PR
83 Dermatologic toxicity11 Grade3+
Nechushtan H Vainer G Stainberg H Salmon AY Hamburger T Peretz T A phase 12 of a combination of cetuximab and taxane for triple negative breast cancer patients Breast 2014 Aug23(4)435-8
Polyphor
Balixafortide (POL6326) + eribulin
CXCR4 antagonist + tubulin-based antimitotic
Heavily pretreatedRelapsed MBC
14-16
56
3rd line 3 chemo
3+3 dose escalation The highest dose was established as eribulin 14 mgmsup2 on days 2 and 9 and balixafortide 55 mgkg on days 1minus3 and 8minus10 of the 21-day cycle
30 PR
41 Gr34 Neutropenia11 Gr34 Leucopenia11 Gr34 Febrileneutropenia2 Related mortalities
42018 Fast Track (HER2-MBC failed 2 prior regimens)
Pernas S Martin M Kaufman PA Gil-Martin M Gomez Pardo P Lopez-Tarruella S Manso L Ciruelos E Perez-Fidalgo JA Hernando C Ademuyiwa FO Weilbaecher K Mayer I Pluard TJ Martinez Garcia M Vahdat L Perez-Garcia J Wach A Barker D Fung S Romagnoli B Cortes J Balixafortide plus eribulin in HER2-negative metastatic breast cancer a phase 1 single-arm dose-escalation trial Lancet Oncol 2018 Jun19(6)812-824
1 PRndashbut only + letrozoleNo Resp on monotherapy
61 Gr34 Neutropenia39 Gr34 Leucopenia
$933M (1Q18)$31B (2017)
Tamura K Mukai H Naito Y Yonemori K Kodaira M Tanabe Y Yamamoto N Osera S Sasaki M Mori Y Hashigaki S Nagasawa T Umeyama Y Yoshino T Phase I study of palbociclib a cyclin-dependent kinase 46 inhibitor in Japanese patients Cancer Sci 2016 Jun107(6)755-63 doi 101111cas12932 Epub 2016 May 11
Pfizer
Ibrancereg (palbociclib)
CDK 46 Inhibitor
HR+ HER2- MBC
Heavily pretreatedRelapsed Met Cancer
04-08
41 (5 BC)
chemo naiumlve (17)1-2(51) 3(29) 3+(2)
Palbociclib 25-150 mg dose ranging
0
20 Gr34 Neutropenia23 Gr34 Leucopenia
$933M (1Q18)$31B (2017)
Flaherty KT Lorusso PM Demichele A Abramson VG Courtney R Randolph SS Shaik MN Wilner KD ODwyer PJ Schwartz GK Phase I dose-escalation trial of the oral cyclin-dependent kinase 46 inhibitor PD 0332991 administered using a 21-day schedule in patients with advanced cancer Clin Cancer Res 2012 Jan 1518(2)568-76 doi 1011581078-0432CCR-11-0509 Epub 2011 Nov 16
Novartis
Kisqalireg (ribociclib)
CDK 46 Inhibitor
Premenopausal HR+ HER2- MBC
Heavily pretreatedRelapsed Met Cancer
16
132 (20 BC)
0-1 (25) 2-3 (42)4+ (32)
Ribociclib 50 mg ranging up to 1200 mg dose escalation
23 PR-included 1 BC (5 of BC pts)
27 Gr34 Neutropenia17 Gr34 Leucopenia
Peak sales est at $25B
Infante JR Cassier PA Gerecitano JF Witteveen PO Chugh R Ribrag V Chakraborty A Matano A Dobson JR Crystal AS Parasuraman S Shapiro GI A Phase I Study of the Cyclin-Dependent Kinase 46 Inhibitor Ribociclib (LEE011) in Patients with Advanced Solid Tumors and Lymphomas Clin Cancer Res 2016 Dec 122(23)5696-5705 Epub 2016 Aug 19
Eli Lilly
Verzenioreg (abemaciclib)
CDK 46 Inhibitor
HR+HER2minusMBC
Heavily pretreatedRelapsed Met Cancer
16
12 (1 BC)
1 (312) 2 (212) 3+(7)
Abemaciclib 100 mg ranging up to 200 mg dose escalation
17 PR (included 1 BC)
17 Gr34 Neutropenia33 Gr34 Leucopenia
Peak sales est at $2B
Fujiwara Y Tamura K Kondo S Tanabe Y Iwasa S Shimomura A Kitano S Ogasawara K Turner PK Mori J Asou H Chan EM Yamamoto N Phase 1 study of abemaciclib an inhibitor of CDK 4 and 6 as a single agent for Japanese patients with advanced cancer Cancer Chemother Pharmacol 2016 Aug78(2)281-8 doi 101007s00280-016-3085-8 Epub 2016 Jun 16
Mukai H Saeki T Shimada K Naito Y Matsubara N Nakanishi T Obaishi H Namiki M Sasaki Y Phase 1 combination study of eribulin mesylate with trastuzumab for advanced or recurrent human epidermal growth factor receptor 2 positive breast cancer Invest New Drugs 2015 Feb33(1)119-27
AstraZeneca
Lynparza (Olaparib) + Cediranib
PARP inhibitor + inhibitor of VEGF receptor tyrosine kinases
HR+ HER2- MBC
BC amp OC
2013
28 (8 BC)
3 for BC
Olaparib (a poly (ADP-ribose) polymerase (PARP) inhibitor) amp Cediranib (Vascular endothelial growth factor receptor (VEGFR) 1 2 and 3 tyrosine kinase inhibitor)3 at dose level (DL) 0 (cediranib 20mg olaparib 100mg) 3 at DL1 (cediranib 20mg olaparib 200mg) 7 at DL2 (cediranib 30mg olaparib 200mg) 6 at DL3 (cediranib 30mg olaparib 400mg)
Liu JF Tolaney SM Birrer M Fleming GF Buss MK Dahlberg SE Lee H Whalen C Tyburski K Winer E Ivy P Matulonis UA A Phase 1 trial of the poly(ADP-ribose) polymerase inhibitor olaparib (AZD2281) in combination with the anti-angiogenic cediranib (AZD2171) in recurrent epithelial ovarian or triple-negative breast cancer Eur J Cancer 2013 Sep49(14)2972-8
Reyon Pharmaceutical
VM206RY
Heterologous prime-boost with a truncated HER2 sequence
HER2+ Stage IIIampIV BC
2015
9
2 chemo
Plasmid DNA (pHM-GM-CSF expressing truncated HER2 amp GM-CSF) amp adenoviral vector (Ad-HM containing modified HER2) (2 4 and 8 mgpatientvisit) of pHM-GM-CSF 3x IM weeks 0 2 and 4 Ad-HM 3 times 109 virus particles at week 6
11 PR
4 pts showed 7 minor AEs
Unclear
Kim SB Ahn JH Kim J Jung KH A phase 1 study of a heterologous prime-boost vaccination involving a truncated HER2 sequence in patients with HER2-expressing breast cancer Mol Ther Methods Clin Dev 2015 Sep 30215031 doi 101038mtm201531 eCollection 2015
Rodon J Peacuterez-Fidalgo A Krop IE Burris H Guerrero-Zotano A Britten CD Becerra C Schellens J Richards DA Schuler M Abu-Khalaf M Johnson FM Ranson M Edenfield J Silva AP Hackl W Quadt C Demanse D Duval V Baselga J Phase 11b dose escalation and expansion study of BEZ235 a dual PI3KmTOR inhibitor in patients with advanced solid tumors including patients with advanced breast cancer Cancer Chemother Pharmacol 2018 Jun 7 doi 101007s00280-018-3610-z [Epub ahead of print]
Celgene (Abraxane)
Gemcitabine + Abraxane (nab-paclitaxel)
Chemo + Chemo
OC BC NSCLC amp Panc cancer + Lung OC BC Kaposi sarcoma
MBC
2016
9
Adjuvant chemo (100)chemo post-adjuvant (33)
Gem (nucleoside metabolic inhibitor 1250 mgm2) on days 1 and 8 nab-Pac (microtubule inhibitor) starting dose of 180 mgm2 (cohort 1) 220 mgm2 (cohort 2) and 260 mgm2 (cohort 3) on day 1 of the 21-day cycle using a 3 + 3 design
0
MTD not reached29 Gr3 Neutropenia59 Gr1 Peripheralneuropathy
Yoshitomi S Taira N Doihara H Mizoo T Nogami T Iwamoto T Motoki T Shien T Ogasawara Y Matsuoka J Tsuji H Mitsuhashi T A phase 1 dose-finding and pharmacokinetic study of gemcitabine with nab-paclitaxel in patients with metastatic breast cancer Cancer Chemother Pharmacol 2016 Aug78(2)289-94
Eli Lilly
Erbituxreg (cetuximab) + Taxane
EGFR inhibitor antineoplastic agent + Chemo
Headamp Neck Colorectal Cancer
TNBC
2007-2010
18
1 chemo
Cetuximab (epidermal growth factor receptor (EGFR) antagonist ) an initial loading dose of cetuximab 400 mgm2 followed by a weekly dose of 250 mgm2Paclitaxel (microtubule inhibitor) 80 mgm2 or Docetaxel at an initial dose of 30 mgm2 was administered weekly
56 CR 22 PR
83 Dermatologic toxicity11 Grade3+
Nechushtan H Vainer G Stainberg H Salmon AY Hamburger T Peretz T A phase 12 of a combination of cetuximab and taxane for triple negative breast cancer patients Breast 2014 Aug23(4)435-8
Polyphor
Balixafortide (POL6326) + eribulin
CXCR4 antagonist + tubulin-based antimitotic
Heavily pretreated Relapsed MBC
2014-2016
56
3rd line 3 chemo
3+3 dose escalation The highest dose was established as eribulin 14 mgmsup2 on days 2 and 9 and balixafortide 55 mgkg on days 1minus3 and 8minus10 of the 21-day cycle
30 PR
41 Gr34 Neutropenia11 Gr34 Leucopenia11 Gr34 Febrileneutropenia2 Related mortalities
Apr 2018 Fast Track for HER2-MBC who have failed 2prior regimens
Pernas S Martin M Kaufman PA Gil-Martin M Gomez Pardo P Lopez-Tarruella S Manso L Ciruelos E Perez-Fidalgo JA Hernando C Ademuyiwa FO Weilbaecher K Mayer I Pluard TJ Martinez Garcia M Vahdat L Perez-Garcia J Wach A Barker D Fung S Romagnoli B Cortes J Balixafortide plus eribulin in HER2-negative metastatic breast cancer a phase 1 single-arm dose-escalation trial Lancet Oncol 2018 Jun19(6)812-824
11 PRndashbut only + letrozole (No Resp on monotherapy)
61 Gr34 Neutropenia39 Gr34 Leucopenia
$933M in 1Q2018 $31B in 2017
Tamura K Mukai H Naito Y Yonemori K Kodaira M Tanabe Y Yamamoto N Osera S Sasaki M Mori Y Hashigaki S Nagasawa T Umeyama Y Yoshino T Phase I study of palbociclib a cyclin-dependent kinase 46 inhibitor in Japanese patients Cancer Sci 2016 Jun107(6)755-63 doi 101111cas12932 Epub 2016 May 11
Pfizer
Ibrancereg (palbociclib)
CDK 46 Inhibitor
HR+ HER2- MBC
Heavily pretreated Relapsed Metastatic Cancer
2004-2008
41 (5 BC)
chemo naiumlve (17) 1-2 (51)3 (29) 3+ (2)
Palbociclib 25-150 mg dose ranging
0
20 Gr34 Neutropenia23 Gr34 Leucopenia
$933M in 1Q2018 $31B in 2017
Flaherty KT Lorusso PM Demichele A Abramson VG Courtney R Randolph SS Shaik MN Wilner KD ODwyer PJ Schwartz GK Phase I dose-escalation trial of the oral cyclin-dependent kinase 46 inhibitor PD 0332991 administered using a 21-day schedule in patients with advanced cancer Clin Cancer Res 2012 Jan 1518(2)568-76 doi 1011581078-0432CCR-11-0509 Epub 2011 Nov 16
Novartis
Kisqalireg (ribociclib)
CDK 46 Inhibitors
Premenopausal HR+ HER2- MBC
Heavily pretreated Relapsed Metastatic Cancer
2016
132 (20 BC)
0-1 (25) 2-3 (42) 4+ (32)
Ribociclib 50 mg ranging up to 1200 mg dose escalation
23 PRndashincluded 1 in BC (5 of BC pts)
27 Gr34 Neutropenia17 Gr34 Leucopenia
Peak sales projected at $25B
Infante JR Cassier PA Gerecitano JF Witteveen PO Chugh R Ribrag V Chakraborty A Matano A Dobson JR Crystal AS Parasuraman S Shapiro GI A Phase I Study of the Cyclin-Dependent Kinase 46 Inhibitor Ribociclib (LEE011) in Patients with Advanced Solid Tumors and Lymphomas Clin Cancer Res 2016 Dec 122(23)5696-5705 Epub 2016 Aug 19
Eli Lilly
Verzenioreg (abemaciclib)
CDK 46 Inhibitors
HR+HER2minusMBC
Heavily pretreated Relapsed Metastatic Cancer
2016
12 (1 BC)
1 (312) 2 (212) 3+ (7)
Abemaciclib 100 mg ranging up to 200 mg dose escalation
17 PR (included 1 in BC)
17 Gr34 Neutropenia33 Gr34 Leucopenia
Peak sales projected at $2B
Fujiwara Y Tamura K Kondo S Tanabe Y Iwasa S Shimomura A Kitano S Ogasawara K Turner PK Mori J Asou H Chan EM Yamamoto N Phase 1 study of abemaciclib an inhibitor of CDK 4 and 6 as a single agent for Japanese patients with advanced cancer Cancer Chemother Pharmacol 2016 Aug78(2)281-8 doi 101007s00280-016-3085-8 Epub 2016 Jun 16
Mukai H Saeki T Shimada K Naito Y Matsubara N Nakanishi T Obaishi H Namiki M Sasaki Y Phase 1 combination study of eribulin mesylate with trastuzumab for advanced or recurrent human epidermal growth factor receptor 2 positive breast cancer Invest New Drugs 2015 Feb33(1)119-27
AstraZeneca
Lynparza (Olaparib)+ Cediranib
PARP inhibitor+ inhibitor of VEGF RTK
HR+ HER2- MBC
BC amp OC
13
28 (8 BC)
3 for BC
Olaparib (a poly (ADP-ribose) polymerase (PARP) inhibitor) amp Cediranib (Vascular endothelial growth factor receptor (VEGFR) 1 2 and 3 tyrosine kinase inhibitor)3 at dose level (DL) 0 (cediranib 20mg olaparib 100mg) 3 at DL1 (cediranib 20mg olaparib 200mg) 7 at DL2 (cediranib 30mg olaparib 200mg) 6 at DL3 (cediranib 30mg olaparib 400mg)
Liu JF Tolaney SM Birrer M Fleming GF Buss MK Dahlberg SE Lee H Whalen C Tyburski K Winer E Ivy P Matulonis UA A Phase 1 trial of the poly(ADP-ribose) polymerase inhibitor olaparib (AZD2281) in combination with the anti-angiogenic cediranib (AZD2171) in recurrent epithelial ovarian or triple-negative breast cancer Eur J Cancer 2013 Sep49(14)2972-8
ReyonPharma
VM206RY
Heterologous prime-boost with a truncated HER2 sequence
HER2+ Stg IIIampIV BC
15
9
2 chemo
Plasmid DNA (pHM-GM-CSF expressing truncated HER2 amp GM-CSF) amp adenoviral vector (Ad-HM containing modified HER2) (2 4 and 8 mgpatientvisit) of pHM-GM-CSF 3x IM weeks 0 2 and 4 Ad-HM 3 times 109 virus particles at week 6
11 PR
4 pts 7 minor AEs
Unclear
Kim SB Ahn JH Kim J Jung KH A phase 1 study of a heterologous prime-boost vaccination involving a truncated HER2 sequence in patients with HER2-expressing breast cancer Mol Ther Methods Clin Dev 2015 Sep 30215031 doi 101038mtm201531 eCollection 2015
Rodon J Peacuterez-Fidalgo A Krop IE Burris H Guerrero-Zotano A Britten CD Becerra C Schellens J Richards DA Schuler M Abu-Khalaf M Johnson FM Ranson M Edenfield J Silva AP Hackl W Quadt C Demanse D Duval V Baselga J Phase 11b dose escalation and expansion study of BEZ235 a dual PI3KmTOR inhibitor in patients with advanced solid tumors including patients with advanced breast cancer Cancer Chemother Pharmacol 2018 Jun 7 doi 101007s00280-018-3610-z [Epub ahead of print]
Celgene(Abraxane)
Gemcitabine + Abraxane (nab-paclitaxel)
Chemo+ Chemo
OC BC NSCLC PC + LC OC BC KS
MBC
16
9
Adjuv chemo (100)chemo post-adjuv (33)
Gem (nucleoside metabolic inhibitor 1250 mgm2) on days 1 and 8 nab-Pac (microtubule inhibitor) starting dose of 180 mgm2 (cohort 1) 220 mgm2 (cohort 2) and 260 mgm2 (cohort 3) on day 1 of the 21-day cycle using a 3 + 3 design
0
MTD not reached29 Gr3 Neutropenia59 Gr1 Peripheralneuropathy
Yoshitomi S Taira N Doihara H Mizoo T Nogami T Iwamoto T Motoki T Shien T Ogasawara Y Matsuoka J Tsuji H Mitsuhashi T A phase 1 dose-finding and pharmacokinetic study of gemcitabine with nab-paclitaxel in patients with metastatic breast cancer Cancer Chemother Pharmacol 2016 Aug78(2)289-94
Eli Lilly
Erbituxreg (cetuximab) + Taxane
EGFR inhibitor antineoplastic agent + Chemo
Head amp NeckColorectal
TNBC
07-10
18
1 chemo
Cetuximab (epidermal growth factor receptor (EGFR) antagonist ) an initial loading dose of cetuximab 400 mgm2 followed by a weekly dose of 250 mgm2Paclitaxel (microtubule inhibitor) 80 mgm2 or Docetaxel at an initial dose of 30 mgm2 was administered weekly
56 CR 22 PR
83 Dermatologic toxicity11 Grade3+
Nechushtan H Vainer G Stainberg H Salmon AY Hamburger T Peretz T A phase 12 of a combination of cetuximab and taxane for triple negative breast cancer patients Breast 2014 Aug23(4)435-8
Polyphor
Balixafortide (POL6326) + eribulin
CXCR4 antagonist + tubulin-based antimitotic
Heavily pretreatedRelapsed MBC
14-16
56
3rd line 3 chemo
3+3 dose escalation The highest dose was established as eribulin 14 mgmsup2 on days 2 and 9 and balixafortide 55 mgkg on days 1minus3 and 8minus10 of the 21-day cycle
30 PR
41 Gr34 Neutropenia11 Gr34 Leucopenia11 Gr34 Febrileneutropenia2 Related mortalities
42018 Fast Track (HER2-MBC failed 2 prior regimens)
Pernas S Martin M Kaufman PA Gil-Martin M Gomez Pardo P Lopez-Tarruella S Manso L Ciruelos E Perez-Fidalgo JA Hernando C Ademuyiwa FO Weilbaecher K Mayer I Pluard TJ Martinez Garcia M Vahdat L Perez-Garcia J Wach A Barker D Fung S Romagnoli B Cortes J Balixafortide plus eribulin in HER2-negative metastatic breast cancer a phase 1 single-arm dose-escalation trial Lancet Oncol 2018 Jun19(6)812-824
1 PRndashbut only + letrozoleNo Resp on monotherapy
61 Gr34 Neutropenia39 Gr34 Leucopenia
$933M (1Q18)$31B (2017)
Tamura K Mukai H Naito Y Yonemori K Kodaira M Tanabe Y Yamamoto N Osera S Sasaki M Mori Y Hashigaki S Nagasawa T Umeyama Y Yoshino T Phase I study of palbociclib a cyclin-dependent kinase 46 inhibitor in Japanese patients Cancer Sci 2016 Jun107(6)755-63 doi 101111cas12932 Epub 2016 May 11
Pfizer
Ibrancereg (palbociclib)
CDK 46 Inhibitor
HR+ HER2- MBC
Heavily pretreatedRelapsed Met Cancer
04-08
41 (5 BC)
chemo naiumlve (17)1-2(51) 3(29) 3+(2)
Palbociclib 25-150 mg dose ranging
0
20 Gr34 Neutropenia23 Gr34 Leucopenia
$933M (1Q18)$31B (2017)
Flaherty KT Lorusso PM Demichele A Abramson VG Courtney R Randolph SS Shaik MN Wilner KD ODwyer PJ Schwartz GK Phase I dose-escalation trial of the oral cyclin-dependent kinase 46 inhibitor PD 0332991 administered using a 21-day schedule in patients with advanced cancer Clin Cancer Res 2012 Jan 1518(2)568-76 doi 1011581078-0432CCR-11-0509 Epub 2011 Nov 16
Novartis
Kisqalireg (ribociclib)
CDK 46 Inhibitor
Premenopausal HR+ HER2- MBC
Heavily pretreatedRelapsed Met Cancer
16
132 (20 BC)
0-1 (25) 2-3 (42)4+ (32)
Ribociclib 50 mg ranging up to 1200 mg dose escalation
23 PR-included 1 BC (5 of BC pts)
27 Gr34 Neutropenia17 Gr34 Leucopenia
Peak sales est at $25B
Infante JR Cassier PA Gerecitano JF Witteveen PO Chugh R Ribrag V Chakraborty A Matano A Dobson JR Crystal AS Parasuraman S Shapiro GI A Phase I Study of the Cyclin-Dependent Kinase 46 Inhibitor Ribociclib (LEE011) in Patients with Advanced Solid Tumors and Lymphomas Clin Cancer Res 2016 Dec 122(23)5696-5705 Epub 2016 Aug 19
Eli Lilly
Verzenioreg (abemaciclib)
CDK 46 Inhibitor
HR+HER2minusMBC
Heavily pretreatedRelapsed Met Cancer
16
12 (1 BC)
1 (312) 2 (212) 3+(7)
Abemaciclib 100 mg ranging up to 200 mg dose escalation
17 PR (included 1 BC)
17 Gr34 Neutropenia33 Gr34 Leucopenia
Peak sales est at $2B
Fujiwara Y Tamura K Kondo S Tanabe Y Iwasa S Shimomura A Kitano S Ogasawara K Turner PK Mori J Asou H Chan EM Yamamoto N Phase 1 study of abemaciclib an inhibitor of CDK 4 and 6 as a single agent for Japanese patients with advanced cancer Cancer Chemother Pharmacol 2016 Aug78(2)281-8 doi 101007s00280-016-3085-8 Epub 2016 Jun 16
41 Gr34 Neutropenia11 Gr34 Leucopenia11 Gr34 Febrileneutropenia2 Related mortalities
30 PRs in combination with Halaven
Bria-IMTTM
20
Injection site reactions No related SAEs or SUSARs
Tumor vol darr ampor darr circul tumor cells)All Comers 21(419) 26(519)One or More HLA matches 27(415) 33(515)Two or More HLA matches 50 (24) 75 (34))
Drug
Technology
Approved for
Market (US)
Ibrance (palbociclib)
CDK 46 Inhibitor
HR+HER2- MBC in combination with fluvestrant or aromatase inhibitor
$933M in 1Q2018 $3126M in 2017
Kisqali (ribociclib)
CDK 46 Inhibitor
2017 HR+HER2- MBC in combination with fluvestrant or aromatase inhibitor
Peak sales projected at $25B
Verzenio (abemaciclib)
CDK 46 Inhibitor
2017 HR+HER2- MBC in combination with fluvestrant or aromatase inhibitor
Peak sales projected at $2B
Lynparza (olaparib)
Poly (ADP-ribose) polymerase (PARP) inhibitor
2017 ovarian amp breast cancer
$997M in 2017
Halaven (eribulin mesylate)
Tubulin-based antimitotic
2H2017 3rd line MBC amp liposarcoma
$181M in 2017
balixafortide
CXCR4 antagonist
Fast track designation in 2018 for HER2- MBC who have failed 2 prior regimens
Bria-IMTtrade - Efficacy as Predicted
Interim Data (19 patients)-Ongoing Phase IIIa Study (2017-2018) amp Original Study (2004-2005)
PD-L1 expression on circulating cancer cells amp cancer-associated cells in 100 of patients (to date) Strong rationale for combination with checkpoint inhibitors like Keytruda
30
Bria-IMTtrade appears to be most effective in patients who match with Bria-IMT trade at 2 HLA loci (types) further supporting our ldquoHLA Matching Hypothesisrdquo and the development of Bria-OTS trade to cover 90 of the patient population
Combination with immune checkpoint inhibitors may induce a more potent anti-cancer response leading to our strategy of combination studies of Bria-IMT trade with Keytruda or Yervoy
Patients (n) HLA Match
Tumor Shrinkage
Biological Response
4 ge2 50 7515 ge1 27 334 0 0 0
Biological response includes tumor shrinkage or lower circulating cancer associated cells
The confirmatory Bria-IMTtrade monotherapy Phase IIa trial has completed enrollment Additional Support for the HLA-matching hypothesis has been obtained
Bria-IMTtrade Combination Therapy study with immune checkpoint inhibitors Keytrudareg if PD-L12 positive (ge1) Yervoyreg if PD-L12 negative (lt1) Accepting patients from the monotherapy study who develop progressive disease Also enrolling patients directly into this study to enhance experience with the combination In discussion with other pharmaceutical companies to evaluate additional combinations with other
immunotherapies
Bria-OTStrade Off-the-Shelf Personalized Targeted Immunotherapy Developing Bria-OTStrade to co-express GM-CSF and interferon-α Pre-manufacture additional HLA alleles ndash Total of 15 alleles (8 Class I and 7 Class II) Co-development of BriaDXtrade companion diagnostic for HLA typing Combination therapy clinical trial with immune checkpoint inhibitors for non-responders using
information from the Bria-IMTtrade Combination Therapy Study
33
Development Timeline ndash Breast Cancer
20192018 2020 2021
Phase IIIaBria-IMTtrade
Monotherapy
Currently Enrolling Phase IIaBria-IMTtrade + Checkpoint
Currently in discussions with potential partnersPhase II Bria-IMTtrade plus Additional Combinations (1Q19 4Q22)(eg PD-1 Inhibitor PD-L1 inhibitor anti-CTLA4 anti-GITR anti-OX40)
1Q 2Q 3Q 4Q
2023
Bria-OTStrade Off-The-Shelf Personalized ImmunotherapyMonotherapy and Potential Partnered Combo Therapy
(2H19 Ongoing)
Bria-OTStradeOff-the-Shelf Cell Line cGMP Manufacturing
and BriaDXtrade(1Q18 1Q19)
Registration Studies (1Q20 2H22)Bria-IMTtrade with Checkpoint InhibitorsBria-OTStrade +- Checkpoint Inhibitors
34
Immuno-oncology Deals
Recent deals of small biotechs with big pharma in immuno-oncology
35
Date PartnershipDevelopment stage at the time of the deal Deal size
07122018 Immatics-Genmab Preclinical Up to $28B
04042018 OSE Immunotherapeutics-Boehringer Ingelheim Preclinical Up to euro113B ($139B)
02092018 Pieris Pharmaceuticals-Seattle Genetics Preclinical Up to $123B
2142018 Nektar-BMS Ph III Up to $36B
01222018 Juno-Celgene Ph II $9B (Acquisition)
11142017 Loxo-Bayer Larotrectinib (Ph II) LOXO-195 (Ph III) Up to $155B
1032017 CytomX-Amgen Preclinical Up to $15B
03202017 CytomX--BMS Ph III Up to $36B
6282016 Xencor-Novartis Preclinical Up to $24B
Early Stage Clinical Studies (Comparison)
We compared the interim data of Ph IIIa study of Bria-IMTtrade in advanced breast cancer with thedata in the early stage clinical studies of recently approved breast cancer drugs and one fasttracked product candidate
Apples to apples comparison Early Stage Clinical Studies in oncology are typically done in patientswith no other therapeutic options Thus the patients have very advanced disease and response ratesare typically quite low
The patients in our Ph IIIa study have been heavily pre-treated (median 45 prior regimens)Some recent studies of relevance in breast cancer are noted in the following slides
36
Breast Cancer Market Opportunity
Drug Technology Approved for Market (US)Ibrance (palbociclib) CDK 46 Inhibitor HR+HER2- MBC in combination with
fluvestrant or aromatase inhibitor$933M in 1Q2018 $3126M in 2017
Kisqali (ribociclib) CDK 46 Inhibitor 2017 HR+HER2- MBC in combination with fluvestrant or aromatase inhibitor
Peak sales projected at $25B
Verzenio (abemaciclib) CDK 46 Inhibitor 2017 HR+HER2- MBC in combination with fluvestrant or aromatase inhibitor
balixafortide CXCR4 antagonist Fast track designation in 2018 for HER2- MBC who have failed 2 prior regimens
The market for breast cancer drugs is a multibillion dollar market with new drugs being approvedon an ongoing basis indicating the shortage of safe and effective treatments for this deadly disease
37
Competitors- Phase III Clinical Data Bria-IMTtrade shows superior safety and similar to superior efficacy data compared with those of the multi-billion dollar drugs when they were at a similar early stage of clinical development
Injection site reactions No related SAEs or SUSARs
Tumor vol darr ampor darr circul tumor cellsAll Comers 21(419) 26(519)One or More HLA matches 27(415) 33(515)Two or More HLA matches 50 (24) 75 (34)
Sheet1 (3)
Comp -Slides
Data
HLA (2)
HLA
Data (Ph1-2+4Pt)
Competitors (2018)-Slide
Competitors (2018)
In the Pipeline Protein Kinase C delta (PKCδ) Inhibitors
30 of all human malignancies display activating RAS mutations Another 60 showing over-activity of Ras-signaling pathways
Ras has been termed ldquoundruggablerdquo (no one has been able to make a Ras inhibitor drug)
BriaCellrsquos novel proprietary PKCδ inhibitors have shown activity against multiple RAS transformed tumors Lung cancer Melanoma Breast cancer Neuroendocrine cancer Pancreatic cancer Colorectal cancer
This target has an attractive safety profile based on in vivo studies and knock out mouse studies
PKCδ inhibitors should qualify for an accelerated clinical development plan and regulatory pathway
Could be in clinic within 24 months
Cost-Effective Additional Shot-on-Goal and additional partnership opportunities
Early-Stage Preclinical Program
39
Protein Kinase C delta (PKCδ) Inhibitors
Activated PKCδ inhibits RAS degradation which in turn stimulates tumor growth
Koo et al Oncotarget 621328 2016
30 of all human malignancies display activating RASmutations with another 60 showing over-activity of Ras-signaling pathways
BriaCellrsquos novel proprietary PKCδ inhibitors have shownactivity against multiple RAS transformed tumors
This target has an attractive safety profile based on in vivostudies and knock out mouse studies
PKCδ also has potential activity as an immunotherapeuticby blocking TGFβ signaling
PKCδ inhibitors are applicable to specific niche tumor typeswhich provide an accelerated clinical development plan
Structural aspects of first generation inhibitor rottlerin and staurosporine (pan-PKC activator) were combined to create second generation inhibitor KAM1
Third generation inhibitors such as BJE6-106 have improved potency and selectivity Fourth generation inhibitors under development to optimize drug-like characteristics PKCδ inhibitors lack endothelial cell cytotoxicity amp PKCδ deficient mice develop normally and are fertile Potentially no marked intrinsic toxicity by inhibiting PKCδ
Mukai H Saeki T Shimada K Naito Y Matsubara N Nakanishi T Obaishi H Namiki M Sasaki Y Phase 1 combination study of eribulin mesylate with trastuzumab for advanced or recurrent human epidermal growth factor receptor 2 positive breast cancer Invest New Drugs 2015 Feb33(1)119-27
AstraZeneca
Lynparza (Olaparib) + Cediranib
PARP inhibitor + inhibitor of VEGF receptor tyrosine kinases
HR+ HER2- MBC
BC amp OC
2013
28 (8 BC)
3 for BC
Olaparib (a poly (ADP-ribose) polymerase (PARP) inhibitor) amp Cediranib (Vascular endothelial growth factor receptor (VEGFR) 1 2 and 3 tyrosine kinase inhibitor)3 at dose level (DL) 0 (cediranib 20mg olaparib 100mg) 3 at DL1 (cediranib 20mg olaparib 200mg) 7 at DL2 (cediranib 30mg olaparib 200mg) 6 at DL3 (cediranib 30mg olaparib 400mg)
Liu JF Tolaney SM Birrer M Fleming GF Buss MK Dahlberg SE Lee H Whalen C Tyburski K Winer E Ivy P Matulonis UA A Phase 1 trial of the poly(ADP-ribose) polymerase inhibitor olaparib (AZD2281) in combination with the anti-angiogenic cediranib (AZD2171) in recurrent epithelial ovarian or triple-negative breast cancer Eur J Cancer 2013 Sep49(14)2972-8
Reyon Pharmaceutical
VM206RY
Heterologous prime-boost with a truncated HER2 sequence
HER2+ Stage IIIampIV BC
2015
9
2 chemo
Plasmid DNA (pHM-GM-CSF expressing truncated HER2 amp GM-CSF) amp adenoviral vector (Ad-HM containing modified HER2) (2 4 and 8 mgpatientvisit) of pHM-GM-CSF 3x IM weeks 0 2 and 4 Ad-HM 3 times 109 virus particles at week 6
11 PR
4 pts showed 7 minor AEs
Unclear
Kim SB Ahn JH Kim J Jung KH A phase 1 study of a heterologous prime-boost vaccination involving a truncated HER2 sequence in patients with HER2-expressing breast cancer Mol Ther Methods Clin Dev 2015 Sep 30215031 doi 101038mtm201531 eCollection 2015
Rodon J Peacuterez-Fidalgo A Krop IE Burris H Guerrero-Zotano A Britten CD Becerra C Schellens J Richards DA Schuler M Abu-Khalaf M Johnson FM Ranson M Edenfield J Silva AP Hackl W Quadt C Demanse D Duval V Baselga J Phase 11b dose escalation and expansion study of BEZ235 a dual PI3KmTOR inhibitor in patients with advanced solid tumors including patients with advanced breast cancer Cancer Chemother Pharmacol 2018 Jun 7 doi 101007s00280-018-3610-z [Epub ahead of print]
Celgene (Abraxane)
Gemcitabine + Abraxane (nab-paclitaxel)
Chemo + Chemo
OC BC NSCLC amp Panc cancer + Lung OC BC Kaposi sarcoma
MBC
2016
9
Adjuvant chemo (100)chemo post-adjuvant (33)
Gem (nucleoside metabolic inhibitor 1250 mgm2) on days 1 and 8 nab-Pac (microtubule inhibitor) starting dose of 180 mgm2 (cohort 1) 220 mgm2 (cohort 2) and 260 mgm2 (cohort 3) on day 1 of the 21-day cycle using a 3 + 3 design
0
MTD not reached29 Gr3 Neutropenia59 Gr1 Peripheralneuropathy
Yoshitomi S Taira N Doihara H Mizoo T Nogami T Iwamoto T Motoki T Shien T Ogasawara Y Matsuoka J Tsuji H Mitsuhashi T A phase 1 dose-finding and pharmacokinetic study of gemcitabine with nab-paclitaxel in patients with metastatic breast cancer Cancer Chemother Pharmacol 2016 Aug78(2)289-94
Eli Lilly
Erbituxreg (cetuximab) + Taxane
EGFR inhibitor antineoplastic agent + Chemo
Headamp Neck Colorectal Cancer
TNBC
2007-2010
18
1 chemo
Cetuximab (epidermal growth factor receptor (EGFR) antagonist ) an initial loading dose of cetuximab 400 mgm2 followed by a weekly dose of 250 mgm2Paclitaxel (microtubule inhibitor) 80 mgm2 or Docetaxel at an initial dose of 30 mgm2 was administered weekly
56 CR 22 PR
83 Dermatologic toxicity11 Grade3+
Nechushtan H Vainer G Stainberg H Salmon AY Hamburger T Peretz T A phase 12 of a combination of cetuximab and taxane for triple negative breast cancer patients Breast 2014 Aug23(4)435-8
Polyphor
Balixafortide (POL6326) + eribulin
CXCR4 antagonist + tubulin-based antimitotic
Heavily pretreated Relapsed MBC
2014-2016
56
3rd line 3 chemo
3+3 dose escalation The highest dose was established as eribulin 14 mgmsup2 on days 2 and 9 and balixafortide 55 mgkg on days 1minus3 and 8minus10 of the 21-day cycle
30 PR
41 Gr34 Neutropenia11 Gr34 Leucopenia11 Gr34 Febrileneutropenia2 Related mortalities
Apr 2018 Fast Track for HER2-MBC who have failed 2prior regimens
Pernas S Martin M Kaufman PA Gil-Martin M Gomez Pardo P Lopez-Tarruella S Manso L Ciruelos E Perez-Fidalgo JA Hernando C Ademuyiwa FO Weilbaecher K Mayer I Pluard TJ Martinez Garcia M Vahdat L Perez-Garcia J Wach A Barker D Fung S Romagnoli B Cortes J Balixafortide plus eribulin in HER2-negative metastatic breast cancer a phase 1 single-arm dose-escalation trial Lancet Oncol 2018 Jun19(6)812-824
11 PRndashbut only + letrozole (No Resp on monotherapy)
61 Gr34 Neutropenia39 Gr34 Leucopenia
$933M in 1Q2018 $31B in 2017
Tamura K Mukai H Naito Y Yonemori K Kodaira M Tanabe Y Yamamoto N Osera S Sasaki M Mori Y Hashigaki S Nagasawa T Umeyama Y Yoshino T Phase I study of palbociclib a cyclin-dependent kinase 46 inhibitor in Japanese patients Cancer Sci 2016 Jun107(6)755-63 doi 101111cas12932 Epub 2016 May 11
Pfizer
Ibrancereg (palbociclib)
CDK 46 Inhibitor
HR+ HER2- MBC
Heavily pretreated Relapsed Metastatic Cancer
2004-2008
41 (5 BC)
chemo naiumlve (17) 1-2 (51)3 (29) 3+ (2)
Palbociclib 25-150 mg dose ranging
0
20 Gr34 Neutropenia23 Gr34 Leucopenia
$933M in 1Q2018 $31B in 2017
Flaherty KT Lorusso PM Demichele A Abramson VG Courtney R Randolph SS Shaik MN Wilner KD ODwyer PJ Schwartz GK Phase I dose-escalation trial of the oral cyclin-dependent kinase 46 inhibitor PD 0332991 administered using a 21-day schedule in patients with advanced cancer Clin Cancer Res 2012 Jan 1518(2)568-76 doi 1011581078-0432CCR-11-0509 Epub 2011 Nov 16
Novartis
Kisqalireg (ribociclib)
CDK 46 Inhibitors
Premenopausal HR+ HER2- MBC
Heavily pretreated Relapsed Metastatic Cancer
2016
132 (20 BC)
0-1 (25) 2-3 (42) 4+ (32)
Ribociclib 50 mg ranging up to 1200 mg dose escalation
23 PRndashincluded 1 in BC (5 of BC pts)
27 Gr34 Neutropenia17 Gr34 Leucopenia
Peak sales projected at $25B
Infante JR Cassier PA Gerecitano JF Witteveen PO Chugh R Ribrag V Chakraborty A Matano A Dobson JR Crystal AS Parasuraman S Shapiro GI A Phase I Study of the Cyclin-Dependent Kinase 46 Inhibitor Ribociclib (LEE011) in Patients with Advanced Solid Tumors and Lymphomas Clin Cancer Res 2016 Dec 122(23)5696-5705 Epub 2016 Aug 19
Eli Lilly
Verzenioreg (abemaciclib)
CDK 46 Inhibitors
HR+HER2minusMBC
Heavily pretreated Relapsed Metastatic Cancer
2016
12 (1 BC)
1 (312) 2 (212) 3+ (7)
Abemaciclib 100 mg ranging up to 200 mg dose escalation
17 PR (included 1 in BC)
17 Gr34 Neutropenia33 Gr34 Leucopenia
Peak sales projected at $2B
Fujiwara Y Tamura K Kondo S Tanabe Y Iwasa S Shimomura A Kitano S Ogasawara K Turner PK Mori J Asou H Chan EM Yamamoto N Phase 1 study of abemaciclib an inhibitor of CDK 4 and 6 as a single agent for Japanese patients with advanced cancer Cancer Chemother Pharmacol 2016 Aug78(2)281-8 doi 101007s00280-016-3085-8 Epub 2016 Jun 16
Mukai H Saeki T Shimada K Naito Y Matsubara N Nakanishi T Obaishi H Namiki M Sasaki Y Phase 1 combination study of eribulin mesylate with trastuzumab for advanced or recurrent human epidermal growth factor receptor 2 positive breast cancer Invest New Drugs 2015 Feb33(1)119-27
AstraZeneca
Lynparza (Olaparib)+ Cediranib
PARP inhibitor+ inhibitor of VEGF RTK
HR+ HER2- MBC
BC amp OC
13
28 (8 BC)
3 for BC
Olaparib (a poly (ADP-ribose) polymerase (PARP) inhibitor) amp Cediranib (Vascular endothelial growth factor receptor (VEGFR) 1 2 and 3 tyrosine kinase inhibitor)3 at dose level (DL) 0 (cediranib 20mg olaparib 100mg) 3 at DL1 (cediranib 20mg olaparib 200mg) 7 at DL2 (cediranib 30mg olaparib 200mg) 6 at DL3 (cediranib 30mg olaparib 400mg)
Liu JF Tolaney SM Birrer M Fleming GF Buss MK Dahlberg SE Lee H Whalen C Tyburski K Winer E Ivy P Matulonis UA A Phase 1 trial of the poly(ADP-ribose) polymerase inhibitor olaparib (AZD2281) in combination with the anti-angiogenic cediranib (AZD2171) in recurrent epithelial ovarian or triple-negative breast cancer Eur J Cancer 2013 Sep49(14)2972-8
ReyonPharma
VM206RY
Heterologous prime-boost with a truncated HER2 sequence
HER2+ Stg IIIampIV BC
15
9
2 chemo
Plasmid DNA (pHM-GM-CSF expressing truncated HER2 amp GM-CSF) amp adenoviral vector (Ad-HM containing modified HER2) (2 4 and 8 mgpatientvisit) of pHM-GM-CSF 3x IM weeks 0 2 and 4 Ad-HM 3 times 109 virus particles at week 6
11 PR
4 pts 7 minor AEs
Unclear
Kim SB Ahn JH Kim J Jung KH A phase 1 study of a heterologous prime-boost vaccination involving a truncated HER2 sequence in patients with HER2-expressing breast cancer Mol Ther Methods Clin Dev 2015 Sep 30215031 doi 101038mtm201531 eCollection 2015
Rodon J Peacuterez-Fidalgo A Krop IE Burris H Guerrero-Zotano A Britten CD Becerra C Schellens J Richards DA Schuler M Abu-Khalaf M Johnson FM Ranson M Edenfield J Silva AP Hackl W Quadt C Demanse D Duval V Baselga J Phase 11b dose escalation and expansion study of BEZ235 a dual PI3KmTOR inhibitor in patients with advanced solid tumors including patients with advanced breast cancer Cancer Chemother Pharmacol 2018 Jun 7 doi 101007s00280-018-3610-z [Epub ahead of print]
Celgene(Abraxane)
Gemcitabine + Abraxane (nab-paclitaxel)
Chemo+ Chemo
OC BC NSCLC PC + LC OC BC KS
MBC
16
9
Adjuv chemo (100)chemo post-adjuv (33)
Gem (nucleoside metabolic inhibitor 1250 mgm2) on days 1 and 8 nab-Pac (microtubule inhibitor) starting dose of 180 mgm2 (cohort 1) 220 mgm2 (cohort 2) and 260 mgm2 (cohort 3) on day 1 of the 21-day cycle using a 3 + 3 design
0
MTD not reached29 Gr3 Neutropenia59 Gr1 Peripheralneuropathy
Yoshitomi S Taira N Doihara H Mizoo T Nogami T Iwamoto T Motoki T Shien T Ogasawara Y Matsuoka J Tsuji H Mitsuhashi T A phase 1 dose-finding and pharmacokinetic study of gemcitabine with nab-paclitaxel in patients with metastatic breast cancer Cancer Chemother Pharmacol 2016 Aug78(2)289-94
Eli Lilly
Erbituxreg (cetuximab) + Taxane
EGFR inhibitor antineoplastic agent + Chemo
Head amp NeckColorectal
TNBC
07-10
18
1 chemo
Cetuximab (epidermal growth factor receptor (EGFR) antagonist ) an initial loading dose of cetuximab 400 mgm2 followed by a weekly dose of 250 mgm2Paclitaxel (microtubule inhibitor) 80 mgm2 or Docetaxel at an initial dose of 30 mgm2 was administered weekly
56 CR 22 PR
83 Dermatologic toxicity11 Grade3+
Nechushtan H Vainer G Stainberg H Salmon AY Hamburger T Peretz T A phase 12 of a combination of cetuximab and taxane for triple negative breast cancer patients Breast 2014 Aug23(4)435-8
Polyphor
Balixafortide (POL6326) + eribulin
CXCR4 antagonist + tubulin-based antimitotic
Heavily pretreatedRelapsed MBC
14-16
56
3rd line 3 chemo
3+3 dose escalation The highest dose was established as eribulin 14 mgmsup2 on days 2 and 9 and balixafortide 55 mgkg on days 1minus3 and 8minus10 of the 21-day cycle
30 PR
41 Gr34 Neutropenia11 Gr34 Leucopenia11 Gr34 Febrileneutropenia2 Related mortalities
42018 Fast Track (HER2-MBC failed 2 prior regimens)
Pernas S Martin M Kaufman PA Gil-Martin M Gomez Pardo P Lopez-Tarruella S Manso L Ciruelos E Perez-Fidalgo JA Hernando C Ademuyiwa FO Weilbaecher K Mayer I Pluard TJ Martinez Garcia M Vahdat L Perez-Garcia J Wach A Barker D Fung S Romagnoli B Cortes J Balixafortide plus eribulin in HER2-negative metastatic breast cancer a phase 1 single-arm dose-escalation trial Lancet Oncol 2018 Jun19(6)812-824
1 PRndashbut only + letrozoleNo Resp on monotherapy
61 Gr34 Neutropenia39 Gr34 Leucopenia
$933M (1Q18)$31B (2017)
Tamura K Mukai H Naito Y Yonemori K Kodaira M Tanabe Y Yamamoto N Osera S Sasaki M Mori Y Hashigaki S Nagasawa T Umeyama Y Yoshino T Phase I study of palbociclib a cyclin-dependent kinase 46 inhibitor in Japanese patients Cancer Sci 2016 Jun107(6)755-63 doi 101111cas12932 Epub 2016 May 11
Pfizer
Ibrancereg (palbociclib)
CDK 46 Inhibitor
HR+ HER2- MBC
Heavily pretreatedRelapsed Met Cancer
04-08
41 (5 BC)
chemo naiumlve (17)1-2(51) 3(29) 3+(2)
Palbociclib 25-150 mg dose ranging
0
20 Gr34 Neutropenia23 Gr34 Leucopenia
$933M (1Q18)$31B (2017)
Flaherty KT Lorusso PM Demichele A Abramson VG Courtney R Randolph SS Shaik MN Wilner KD ODwyer PJ Schwartz GK Phase I dose-escalation trial of the oral cyclin-dependent kinase 46 inhibitor PD 0332991 administered using a 21-day schedule in patients with advanced cancer Clin Cancer Res 2012 Jan 1518(2)568-76 doi 1011581078-0432CCR-11-0509 Epub 2011 Nov 16
Novartis
Kisqalireg (ribociclib)
CDK 46 Inhibitor
Premenopausal HR+ HER2- MBC
Heavily pretreatedRelapsed Met Cancer
16
132 (20 BC)
0-1 (25) 2-3 (42)4+ (32)
Ribociclib 50 mg ranging up to 1200 mg dose escalation
23 PR-included 1 BC (5 of BC pts)
27 Gr34 Neutropenia17 Gr34 Leucopenia
Peak sales est at $25B
Infante JR Cassier PA Gerecitano JF Witteveen PO Chugh R Ribrag V Chakraborty A Matano A Dobson JR Crystal AS Parasuraman S Shapiro GI A Phase I Study of the Cyclin-Dependent Kinase 46 Inhibitor Ribociclib (LEE011) in Patients with Advanced Solid Tumors and Lymphomas Clin Cancer Res 2016 Dec 122(23)5696-5705 Epub 2016 Aug 19
Eli Lilly
Verzenioreg (abemaciclib)
CDK 46 Inhibitor
HR+HER2minusMBC
Heavily pretreatedRelapsed Met Cancer
16
12 (1 BC)
1 (312) 2 (212) 3+(7)
Abemaciclib 100 mg ranging up to 200 mg dose escalation
17 PR (included 1 BC)
17 Gr34 Neutropenia33 Gr34 Leucopenia
Peak sales est at $2B
Fujiwara Y Tamura K Kondo S Tanabe Y Iwasa S Shimomura A Kitano S Ogasawara K Turner PK Mori J Asou H Chan EM Yamamoto N Phase 1 study of abemaciclib an inhibitor of CDK 4 and 6 as a single agent for Japanese patients with advanced cancer Cancer Chemother Pharmacol 2016 Aug78(2)281-8 doi 101007s00280-016-3085-8 Epub 2016 Jun 16
Mukai H Saeki T Shimada K Naito Y Matsubara N Nakanishi T Obaishi H Namiki M Sasaki Y Phase 1 combination study of eribulin mesylate with trastuzumab for advanced or recurrent human epidermal growth factor receptor 2 positive breast cancer Invest New Drugs 2015 Feb33(1)119-27
AstraZeneca
Lynparza (Olaparib) + Cediranib
PARP inhibitor + inhibitor of VEGF receptor tyrosine kinases
HR+ HER2- MBC
BC amp OC
2013
28 (8 BC)
3 for BC
Olaparib (a poly (ADP-ribose) polymerase (PARP) inhibitor) amp Cediranib (Vascular endothelial growth factor receptor (VEGFR) 1 2 and 3 tyrosine kinase inhibitor)3 at dose level (DL) 0 (cediranib 20mg olaparib 100mg) 3 at DL1 (cediranib 20mg olaparib 200mg) 7 at DL2 (cediranib 30mg olaparib 200mg) 6 at DL3 (cediranib 30mg olaparib 400mg)
Liu JF Tolaney SM Birrer M Fleming GF Buss MK Dahlberg SE Lee H Whalen C Tyburski K Winer E Ivy P Matulonis UA A Phase 1 trial of the poly(ADP-ribose) polymerase inhibitor olaparib (AZD2281) in combination with the anti-angiogenic cediranib (AZD2171) in recurrent epithelial ovarian or triple-negative breast cancer Eur J Cancer 2013 Sep49(14)2972-8
Reyon Pharmaceutical
VM206RY
Heterologous prime-boost with a truncated HER2 sequence
HER2+ Stage IIIampIV BC
2015
9
2 chemo
Plasmid DNA (pHM-GM-CSF expressing truncated HER2 amp GM-CSF) amp adenoviral vector (Ad-HM containing modified HER2) (2 4 and 8 mgpatientvisit) of pHM-GM-CSF 3x IM weeks 0 2 and 4 Ad-HM 3 times 109 virus particles at week 6
11 PR
4 pts showed 7 minor AEs
Unclear
Kim SB Ahn JH Kim J Jung KH A phase 1 study of a heterologous prime-boost vaccination involving a truncated HER2 sequence in patients with HER2-expressing breast cancer Mol Ther Methods Clin Dev 2015 Sep 30215031 doi 101038mtm201531 eCollection 2015
Rodon J Peacuterez-Fidalgo A Krop IE Burris H Guerrero-Zotano A Britten CD Becerra C Schellens J Richards DA Schuler M Abu-Khalaf M Johnson FM Ranson M Edenfield J Silva AP Hackl W Quadt C Demanse D Duval V Baselga J Phase 11b dose escalation and expansion study of BEZ235 a dual PI3KmTOR inhibitor in patients with advanced solid tumors including patients with advanced breast cancer Cancer Chemother Pharmacol 2018 Jun 7 doi 101007s00280-018-3610-z [Epub ahead of print]
Celgene (Abraxane)
Gemcitabine + Abraxane (nab-paclitaxel)
Chemo + Chemo
OC BC NSCLC amp Panc cancer + Lung OC BC Kaposi sarcoma
MBC
2016
9
Adjuvant chemo (100)chemo post-adjuvant (33)
Gem (nucleoside metabolic inhibitor 1250 mgm2) on days 1 and 8 nab-Pac (microtubule inhibitor) starting dose of 180 mgm2 (cohort 1) 220 mgm2 (cohort 2) and 260 mgm2 (cohort 3) on day 1 of the 21-day cycle using a 3 + 3 design
0
MTD not reached29 Gr3 Neutropenia59 Gr1 Peripheralneuropathy
Yoshitomi S Taira N Doihara H Mizoo T Nogami T Iwamoto T Motoki T Shien T Ogasawara Y Matsuoka J Tsuji H Mitsuhashi T A phase 1 dose-finding and pharmacokinetic study of gemcitabine with nab-paclitaxel in patients with metastatic breast cancer Cancer Chemother Pharmacol 2016 Aug78(2)289-94
Eli Lilly
Erbituxreg (cetuximab) + Taxane
EGFR inhibitor antineoplastic agent + Chemo
Headamp Neck Colorectal Cancer
TNBC
2007-2010
18
1 chemo
Cetuximab (epidermal growth factor receptor (EGFR) antagonist ) an initial loading dose of cetuximab 400 mgm2 followed by a weekly dose of 250 mgm2Paclitaxel (microtubule inhibitor) 80 mgm2 or Docetaxel at an initial dose of 30 mgm2 was administered weekly
56 CR 22 PR
83 Dermatologic toxicity11 Grade3+
Nechushtan H Vainer G Stainberg H Salmon AY Hamburger T Peretz T A phase 12 of a combination of cetuximab and taxane for triple negative breast cancer patients Breast 2014 Aug23(4)435-8
Polyphor
Balixafortide (POL6326) + eribulin
CXCR4 antagonist + tubulin-based antimitotic
Heavily pretreated Relapsed MBC
2014-2016
56
3rd line 3 chemo
3+3 dose escalation The highest dose was established as eribulin 14 mgmsup2 on days 2 and 9 and balixafortide 55 mgkg on days 1minus3 and 8minus10 of the 21-day cycle
30 PR
41 Gr34 Neutropenia11 Gr34 Leucopenia11 Gr34 Febrileneutropenia2 Related mortalities
Apr 2018 Fast Track for HER2-MBC who have failed 2prior regimens
Pernas S Martin M Kaufman PA Gil-Martin M Gomez Pardo P Lopez-Tarruella S Manso L Ciruelos E Perez-Fidalgo JA Hernando C Ademuyiwa FO Weilbaecher K Mayer I Pluard TJ Martinez Garcia M Vahdat L Perez-Garcia J Wach A Barker D Fung S Romagnoli B Cortes J Balixafortide plus eribulin in HER2-negative metastatic breast cancer a phase 1 single-arm dose-escalation trial Lancet Oncol 2018 Jun19(6)812-824
11 PRndashbut only + letrozole (No Resp on monotherapy)
61 Gr34 Neutropenia39 Gr34 Leucopenia
$933M in 1Q2018 $31B in 2017
Tamura K Mukai H Naito Y Yonemori K Kodaira M Tanabe Y Yamamoto N Osera S Sasaki M Mori Y Hashigaki S Nagasawa T Umeyama Y Yoshino T Phase I study of palbociclib a cyclin-dependent kinase 46 inhibitor in Japanese patients Cancer Sci 2016 Jun107(6)755-63 doi 101111cas12932 Epub 2016 May 11
Pfizer
Ibrancereg (palbociclib)
CDK 46 Inhibitor
HR+ HER2- MBC
Heavily pretreated Relapsed Metastatic Cancer
2004-2008
41 (5 BC)
chemo naiumlve (17) 1-2 (51)3 (29) 3+ (2)
Palbociclib 25-150 mg dose ranging
0
20 Gr34 Neutropenia23 Gr34 Leucopenia
$933M in 1Q2018 $31B in 2017
Flaherty KT Lorusso PM Demichele A Abramson VG Courtney R Randolph SS Shaik MN Wilner KD ODwyer PJ Schwartz GK Phase I dose-escalation trial of the oral cyclin-dependent kinase 46 inhibitor PD 0332991 administered using a 21-day schedule in patients with advanced cancer Clin Cancer Res 2012 Jan 1518(2)568-76 doi 1011581078-0432CCR-11-0509 Epub 2011 Nov 16
Novartis
Kisqalireg (ribociclib)
CDK 46 Inhibitors
Premenopausal HR+ HER2- MBC
Heavily pretreated Relapsed Metastatic Cancer
2016
132 (20 BC)
0-1 (25) 2-3 (42) 4+ (32)
Ribociclib 50 mg ranging up to 1200 mg dose escalation
23 PRndashincluded 1 in BC (5 of BC pts)
27 Gr34 Neutropenia17 Gr34 Leucopenia
Peak sales projected at $25B
Infante JR Cassier PA Gerecitano JF Witteveen PO Chugh R Ribrag V Chakraborty A Matano A Dobson JR Crystal AS Parasuraman S Shapiro GI A Phase I Study of the Cyclin-Dependent Kinase 46 Inhibitor Ribociclib (LEE011) in Patients with Advanced Solid Tumors and Lymphomas Clin Cancer Res 2016 Dec 122(23)5696-5705 Epub 2016 Aug 19
Eli Lilly
Verzenioreg (abemaciclib)
CDK 46 Inhibitors
HR+HER2minusMBC
Heavily pretreated Relapsed Metastatic Cancer
2016
12 (1 BC)
1 (312) 2 (212) 3+ (7)
Abemaciclib 100 mg ranging up to 200 mg dose escalation
17 PR (included 1 in BC)
17 Gr34 Neutropenia33 Gr34 Leucopenia
Peak sales projected at $2B
Fujiwara Y Tamura K Kondo S Tanabe Y Iwasa S Shimomura A Kitano S Ogasawara K Turner PK Mori J Asou H Chan EM Yamamoto N Phase 1 study of abemaciclib an inhibitor of CDK 4 and 6 as a single agent for Japanese patients with advanced cancer Cancer Chemother Pharmacol 2016 Aug78(2)281-8 doi 101007s00280-016-3085-8 Epub 2016 Jun 16
Mukai H Saeki T Shimada K Naito Y Matsubara N Nakanishi T Obaishi H Namiki M Sasaki Y Phase 1 combination study of eribulin mesylate with trastuzumab for advanced or recurrent human epidermal growth factor receptor 2 positive breast cancer Invest New Drugs 2015 Feb33(1)119-27
AstraZeneca
Lynparza (Olaparib)+ Cediranib
PARP inhibitor+ inhibitor of VEGF RTK
HR+ HER2- MBC
BC amp OC
13
28 (8 BC)
3 for BC
Olaparib (a poly (ADP-ribose) polymerase (PARP) inhibitor) amp Cediranib (Vascular endothelial growth factor receptor (VEGFR) 1 2 and 3 tyrosine kinase inhibitor)3 at dose level (DL) 0 (cediranib 20mg olaparib 100mg) 3 at DL1 (cediranib 20mg olaparib 200mg) 7 at DL2 (cediranib 30mg olaparib 200mg) 6 at DL3 (cediranib 30mg olaparib 400mg)
Liu JF Tolaney SM Birrer M Fleming GF Buss MK Dahlberg SE Lee H Whalen C Tyburski K Winer E Ivy P Matulonis UA A Phase 1 trial of the poly(ADP-ribose) polymerase inhibitor olaparib (AZD2281) in combination with the anti-angiogenic cediranib (AZD2171) in recurrent epithelial ovarian or triple-negative breast cancer Eur J Cancer 2013 Sep49(14)2972-8
ReyonPharma
VM206RY
Heterologous prime-boost with a truncated HER2 sequence
HER2+ Stg IIIampIV BC
15
9
2 chemo
Plasmid DNA (pHM-GM-CSF expressing truncated HER2 amp GM-CSF) amp adenoviral vector (Ad-HM containing modified HER2) (2 4 and 8 mgpatientvisit) of pHM-GM-CSF 3x IM weeks 0 2 and 4 Ad-HM 3 times 109 virus particles at week 6
11 PR
4 pts 7 minor AEs
Unclear
Kim SB Ahn JH Kim J Jung KH A phase 1 study of a heterologous prime-boost vaccination involving a truncated HER2 sequence in patients with HER2-expressing breast cancer Mol Ther Methods Clin Dev 2015 Sep 30215031 doi 101038mtm201531 eCollection 2015
Rodon J Peacuterez-Fidalgo A Krop IE Burris H Guerrero-Zotano A Britten CD Becerra C Schellens J Richards DA Schuler M Abu-Khalaf M Johnson FM Ranson M Edenfield J Silva AP Hackl W Quadt C Demanse D Duval V Baselga J Phase 11b dose escalation and expansion study of BEZ235 a dual PI3KmTOR inhibitor in patients with advanced solid tumors including patients with advanced breast cancer Cancer Chemother Pharmacol 2018 Jun 7 doi 101007s00280-018-3610-z [Epub ahead of print]
Celgene(Abraxane)
Gemcitabine + Abraxane (nab-paclitaxel)
Chemo+ Chemo
OC BC NSCLC PC + LC OC BC KS
MBC
16
9
Adjuv chemo (100)chemo post-adjuv (33)
Gem (nucleoside metabolic inhibitor 1250 mgm2) on days 1 and 8 nab-Pac (microtubule inhibitor) starting dose of 180 mgm2 (cohort 1) 220 mgm2 (cohort 2) and 260 mgm2 (cohort 3) on day 1 of the 21-day cycle using a 3 + 3 design
0
MTD not reached29 Gr3 Neutropenia59 Gr1 Peripheralneuropathy
Yoshitomi S Taira N Doihara H Mizoo T Nogami T Iwamoto T Motoki T Shien T Ogasawara Y Matsuoka J Tsuji H Mitsuhashi T A phase 1 dose-finding and pharmacokinetic study of gemcitabine with nab-paclitaxel in patients with metastatic breast cancer Cancer Chemother Pharmacol 2016 Aug78(2)289-94
Eli Lilly
Erbituxreg (cetuximab) + Taxane
EGFR inhibitor antineoplastic agent + Chemo
Head amp NeckColorectal
TNBC
07-10
18
1 chemo
Cetuximab (epidermal growth factor receptor (EGFR) antagonist ) an initial loading dose of cetuximab 400 mgm2 followed by a weekly dose of 250 mgm2Paclitaxel (microtubule inhibitor) 80 mgm2 or Docetaxel at an initial dose of 30 mgm2 was administered weekly
56 CR 22 PR
83 Dermatologic toxicity11 Grade3+
Nechushtan H Vainer G Stainberg H Salmon AY Hamburger T Peretz T A phase 12 of a combination of cetuximab and taxane for triple negative breast cancer patients Breast 2014 Aug23(4)435-8
Polyphor
Balixafortide (POL6326) + eribulin
CXCR4 antagonist + tubulin-based antimitotic
Heavily pretreatedRelapsed MBC
14-16
56
3rd line 3 chemo
3+3 dose escalation The highest dose was established as eribulin 14 mgmsup2 on days 2 and 9 and balixafortide 55 mgkg on days 1minus3 and 8minus10 of the 21-day cycle
30 PR
41 Gr34 Neutropenia11 Gr34 Leucopenia11 Gr34 Febrileneutropenia2 Related mortalities
42018 Fast Track (HER2-MBC failed 2 prior regimens)
Pernas S Martin M Kaufman PA Gil-Martin M Gomez Pardo P Lopez-Tarruella S Manso L Ciruelos E Perez-Fidalgo JA Hernando C Ademuyiwa FO Weilbaecher K Mayer I Pluard TJ Martinez Garcia M Vahdat L Perez-Garcia J Wach A Barker D Fung S Romagnoli B Cortes J Balixafortide plus eribulin in HER2-negative metastatic breast cancer a phase 1 single-arm dose-escalation trial Lancet Oncol 2018 Jun19(6)812-824
1 PRndashbut only + letrozoleNo Resp on monotherapy
61 Gr34 Neutropenia39 Gr34 Leucopenia
$933M (1Q18)$31B (2017)
Tamura K Mukai H Naito Y Yonemori K Kodaira M Tanabe Y Yamamoto N Osera S Sasaki M Mori Y Hashigaki S Nagasawa T Umeyama Y Yoshino T Phase I study of palbociclib a cyclin-dependent kinase 46 inhibitor in Japanese patients Cancer Sci 2016 Jun107(6)755-63 doi 101111cas12932 Epub 2016 May 11
Pfizer
Ibrancereg (palbociclib)
CDK 46 Inhibitor
HR+ HER2- MBC
Heavily pretreatedRelapsed Met Cancer
04-08
41 (5 BC)
chemo naiumlve (17)1-2(51) 3(29) 3+(2)
Palbociclib 25-150 mg dose ranging
0
20 Gr34 Neutropenia23 Gr34 Leucopenia
$933M (1Q18)$31B (2017)
Flaherty KT Lorusso PM Demichele A Abramson VG Courtney R Randolph SS Shaik MN Wilner KD ODwyer PJ Schwartz GK Phase I dose-escalation trial of the oral cyclin-dependent kinase 46 inhibitor PD 0332991 administered using a 21-day schedule in patients with advanced cancer Clin Cancer Res 2012 Jan 1518(2)568-76 doi 1011581078-0432CCR-11-0509 Epub 2011 Nov 16
Novartis
Kisqalireg (ribociclib)
CDK 46 Inhibitor
Premenopausal HR+ HER2- MBC
Heavily pretreatedRelapsed Met Cancer
16
132 (20 BC)
0-1 (25) 2-3 (42)4+ (32)
Ribociclib 50 mg ranging up to 1200 mg dose escalation
23 PR-included 1 BC (5 of BC pts)
27 Gr34 Neutropenia17 Gr34 Leucopenia
Peak sales est at $25B
Infante JR Cassier PA Gerecitano JF Witteveen PO Chugh R Ribrag V Chakraborty A Matano A Dobson JR Crystal AS Parasuraman S Shapiro GI A Phase I Study of the Cyclin-Dependent Kinase 46 Inhibitor Ribociclib (LEE011) in Patients with Advanced Solid Tumors and Lymphomas Clin Cancer Res 2016 Dec 122(23)5696-5705 Epub 2016 Aug 19
Eli Lilly
Verzenioreg (abemaciclib)
CDK 46 Inhibitor
HR+HER2minusMBC
Heavily pretreatedRelapsed Met Cancer
16
12 (1 BC)
1 (312) 2 (212) 3+(7)
Abemaciclib 100 mg ranging up to 200 mg dose escalation
17 PR (included 1 BC)
17 Gr34 Neutropenia33 Gr34 Leucopenia
Peak sales est at $2B
Fujiwara Y Tamura K Kondo S Tanabe Y Iwasa S Shimomura A Kitano S Ogasawara K Turner PK Mori J Asou H Chan EM Yamamoto N Phase 1 study of abemaciclib an inhibitor of CDK 4 and 6 as a single agent for Japanese patients with advanced cancer Cancer Chemother Pharmacol 2016 Aug78(2)281-8 doi 101007s00280-016-3085-8 Epub 2016 Jun 16
The confirmatory Bria-IMTtrade monotherapy Phase IIa trial has completed enrollment Additional Support for the HLA-matching hypothesis has been obtained
Bria-IMTtrade Combination Therapy study with immune checkpoint inhibitors Keytrudareg if PD-L12 positive (ge1) Yervoyreg if PD-L12 negative (lt1) Accepting patients from the monotherapy study who develop progressive disease Also enrolling patients directly into this study to enhance experience with the combination In discussion with other pharmaceutical companies to evaluate additional combinations with other
immunotherapies
Bria-OTStrade Off-the-Shelf Personalized Targeted Immunotherapy Developing Bria-OTStrade to co-express GM-CSF and interferon-α Pre-manufacture additional HLA alleles ndash Total of 15 alleles (8 Class I and 7 Class II) Co-development of BriaDXtrade companion diagnostic for HLA typing Combination therapy clinical trial with immune checkpoint inhibitors for non-responders using
information from the Bria-IMTtrade Combination Therapy Study
33
Development Timeline ndash Breast Cancer
20192018 2020 2021
Phase IIIaBria-IMTtrade
Monotherapy
Currently Enrolling Phase IIaBria-IMTtrade + Checkpoint
Currently in discussions with potential partnersPhase II Bria-IMTtrade plus Additional Combinations (1Q19 4Q22)(eg PD-1 Inhibitor PD-L1 inhibitor anti-CTLA4 anti-GITR anti-OX40)
1Q 2Q 3Q 4Q
2023
Bria-OTStrade Off-The-Shelf Personalized ImmunotherapyMonotherapy and Potential Partnered Combo Therapy
(2H19 Ongoing)
Bria-OTStradeOff-the-Shelf Cell Line cGMP Manufacturing
and BriaDXtrade(1Q18 1Q19)
Registration Studies (1Q20 2H22)Bria-IMTtrade with Checkpoint InhibitorsBria-OTStrade +- Checkpoint Inhibitors
34
Immuno-oncology Deals
Recent deals of small biotechs with big pharma in immuno-oncology
35
Date PartnershipDevelopment stage at the time of the deal Deal size
07122018 Immatics-Genmab Preclinical Up to $28B
04042018 OSE Immunotherapeutics-Boehringer Ingelheim Preclinical Up to euro113B ($139B)
02092018 Pieris Pharmaceuticals-Seattle Genetics Preclinical Up to $123B
2142018 Nektar-BMS Ph III Up to $36B
01222018 Juno-Celgene Ph II $9B (Acquisition)
11142017 Loxo-Bayer Larotrectinib (Ph II) LOXO-195 (Ph III) Up to $155B
1032017 CytomX-Amgen Preclinical Up to $15B
03202017 CytomX--BMS Ph III Up to $36B
6282016 Xencor-Novartis Preclinical Up to $24B
Early Stage Clinical Studies (Comparison)
We compared the interim data of Ph IIIa study of Bria-IMTtrade in advanced breast cancer with thedata in the early stage clinical studies of recently approved breast cancer drugs and one fasttracked product candidate
Apples to apples comparison Early Stage Clinical Studies in oncology are typically done in patientswith no other therapeutic options Thus the patients have very advanced disease and response ratesare typically quite low
The patients in our Ph IIIa study have been heavily pre-treated (median 45 prior regimens)Some recent studies of relevance in breast cancer are noted in the following slides
36
Breast Cancer Market Opportunity
Drug Technology Approved for Market (US)Ibrance (palbociclib) CDK 46 Inhibitor HR+HER2- MBC in combination with
fluvestrant or aromatase inhibitor$933M in 1Q2018 $3126M in 2017
Kisqali (ribociclib) CDK 46 Inhibitor 2017 HR+HER2- MBC in combination with fluvestrant or aromatase inhibitor
Peak sales projected at $25B
Verzenio (abemaciclib) CDK 46 Inhibitor 2017 HR+HER2- MBC in combination with fluvestrant or aromatase inhibitor
balixafortide CXCR4 antagonist Fast track designation in 2018 for HER2- MBC who have failed 2 prior regimens
The market for breast cancer drugs is a multibillion dollar market with new drugs being approvedon an ongoing basis indicating the shortage of safe and effective treatments for this deadly disease
37
Competitors- Phase III Clinical Data Bria-IMTtrade shows superior safety and similar to superior efficacy data compared with those of the multi-billion dollar drugs when they were at a similar early stage of clinical development
Injection site reactions No related SAEs or SUSARs
Tumor vol darr ampor darr circul tumor cellsAll Comers 21(419) 26(519)One or More HLA matches 27(415) 33(515)Two or More HLA matches 50 (24) 75 (34)
Sheet1 (3)
Comp -Slides
Data
HLA (2)
HLA
Data (Ph1-2+4Pt)
Competitors (2018)-Slide
Competitors (2018)
In the Pipeline Protein Kinase C delta (PKCδ) Inhibitors
30 of all human malignancies display activating RAS mutations Another 60 showing over-activity of Ras-signaling pathways
Ras has been termed ldquoundruggablerdquo (no one has been able to make a Ras inhibitor drug)
BriaCellrsquos novel proprietary PKCδ inhibitors have shown activity against multiple RAS transformed tumors Lung cancer Melanoma Breast cancer Neuroendocrine cancer Pancreatic cancer Colorectal cancer
This target has an attractive safety profile based on in vivo studies and knock out mouse studies
PKCδ inhibitors should qualify for an accelerated clinical development plan and regulatory pathway
Could be in clinic within 24 months
Cost-Effective Additional Shot-on-Goal and additional partnership opportunities
Early-Stage Preclinical Program
39
Protein Kinase C delta (PKCδ) Inhibitors
Activated PKCδ inhibits RAS degradation which in turn stimulates tumor growth
Koo et al Oncotarget 621328 2016
30 of all human malignancies display activating RASmutations with another 60 showing over-activity of Ras-signaling pathways
BriaCellrsquos novel proprietary PKCδ inhibitors have shownactivity against multiple RAS transformed tumors
This target has an attractive safety profile based on in vivostudies and knock out mouse studies
PKCδ also has potential activity as an immunotherapeuticby blocking TGFβ signaling
PKCδ inhibitors are applicable to specific niche tumor typeswhich provide an accelerated clinical development plan
Structural aspects of first generation inhibitor rottlerin and staurosporine (pan-PKC activator) were combined to create second generation inhibitor KAM1
Third generation inhibitors such as BJE6-106 have improved potency and selectivity Fourth generation inhibitors under development to optimize drug-like characteristics PKCδ inhibitors lack endothelial cell cytotoxicity amp PKCδ deficient mice develop normally and are fertile Potentially no marked intrinsic toxicity by inhibiting PKCδ
Mukai H Saeki T Shimada K Naito Y Matsubara N Nakanishi T Obaishi H Namiki M Sasaki Y Phase 1 combination study of eribulin mesylate with trastuzumab for advanced or recurrent human epidermal growth factor receptor 2 positive breast cancer Invest New Drugs 2015 Feb33(1)119-27
AstraZeneca
Lynparza (Olaparib) + Cediranib
PARP inhibitor + inhibitor of VEGF receptor tyrosine kinases
HR+ HER2- MBC
BC amp OC
2013
28 (8 BC)
3 for BC
Olaparib (a poly (ADP-ribose) polymerase (PARP) inhibitor) amp Cediranib (Vascular endothelial growth factor receptor (VEGFR) 1 2 and 3 tyrosine kinase inhibitor)3 at dose level (DL) 0 (cediranib 20mg olaparib 100mg) 3 at DL1 (cediranib 20mg olaparib 200mg) 7 at DL2 (cediranib 30mg olaparib 200mg) 6 at DL3 (cediranib 30mg olaparib 400mg)
Liu JF Tolaney SM Birrer M Fleming GF Buss MK Dahlberg SE Lee H Whalen C Tyburski K Winer E Ivy P Matulonis UA A Phase 1 trial of the poly(ADP-ribose) polymerase inhibitor olaparib (AZD2281) in combination with the anti-angiogenic cediranib (AZD2171) in recurrent epithelial ovarian or triple-negative breast cancer Eur J Cancer 2013 Sep49(14)2972-8
Reyon Pharmaceutical
VM206RY
Heterologous prime-boost with a truncated HER2 sequence
HER2+ Stage IIIampIV BC
2015
9
2 chemo
Plasmid DNA (pHM-GM-CSF expressing truncated HER2 amp GM-CSF) amp adenoviral vector (Ad-HM containing modified HER2) (2 4 and 8 mgpatientvisit) of pHM-GM-CSF 3x IM weeks 0 2 and 4 Ad-HM 3 times 109 virus particles at week 6
11 PR
4 pts showed 7 minor AEs
Unclear
Kim SB Ahn JH Kim J Jung KH A phase 1 study of a heterologous prime-boost vaccination involving a truncated HER2 sequence in patients with HER2-expressing breast cancer Mol Ther Methods Clin Dev 2015 Sep 30215031 doi 101038mtm201531 eCollection 2015
Rodon J Peacuterez-Fidalgo A Krop IE Burris H Guerrero-Zotano A Britten CD Becerra C Schellens J Richards DA Schuler M Abu-Khalaf M Johnson FM Ranson M Edenfield J Silva AP Hackl W Quadt C Demanse D Duval V Baselga J Phase 11b dose escalation and expansion study of BEZ235 a dual PI3KmTOR inhibitor in patients with advanced solid tumors including patients with advanced breast cancer Cancer Chemother Pharmacol 2018 Jun 7 doi 101007s00280-018-3610-z [Epub ahead of print]
Celgene (Abraxane)
Gemcitabine + Abraxane (nab-paclitaxel)
Chemo + Chemo
OC BC NSCLC amp Panc cancer + Lung OC BC Kaposi sarcoma
MBC
2016
9
Adjuvant chemo (100)chemo post-adjuvant (33)
Gem (nucleoside metabolic inhibitor 1250 mgm2) on days 1 and 8 nab-Pac (microtubule inhibitor) starting dose of 180 mgm2 (cohort 1) 220 mgm2 (cohort 2) and 260 mgm2 (cohort 3) on day 1 of the 21-day cycle using a 3 + 3 design
0
MTD not reached29 Gr3 Neutropenia59 Gr1 Peripheralneuropathy
Yoshitomi S Taira N Doihara H Mizoo T Nogami T Iwamoto T Motoki T Shien T Ogasawara Y Matsuoka J Tsuji H Mitsuhashi T A phase 1 dose-finding and pharmacokinetic study of gemcitabine with nab-paclitaxel in patients with metastatic breast cancer Cancer Chemother Pharmacol 2016 Aug78(2)289-94
Eli Lilly
Erbituxreg (cetuximab) + Taxane
EGFR inhibitor antineoplastic agent + Chemo
Headamp Neck Colorectal Cancer
TNBC
2007-2010
18
1 chemo
Cetuximab (epidermal growth factor receptor (EGFR) antagonist ) an initial loading dose of cetuximab 400 mgm2 followed by a weekly dose of 250 mgm2Paclitaxel (microtubule inhibitor) 80 mgm2 or Docetaxel at an initial dose of 30 mgm2 was administered weekly
56 CR 22 PR
83 Dermatologic toxicity11 Grade3+
Nechushtan H Vainer G Stainberg H Salmon AY Hamburger T Peretz T A phase 12 of a combination of cetuximab and taxane for triple negative breast cancer patients Breast 2014 Aug23(4)435-8
Polyphor
Balixafortide (POL6326) + eribulin
CXCR4 antagonist + tubulin-based antimitotic
Heavily pretreated Relapsed MBC
2014-2016
56
3rd line 3 chemo
3+3 dose escalation The highest dose was established as eribulin 14 mgmsup2 on days 2 and 9 and balixafortide 55 mgkg on days 1minus3 and 8minus10 of the 21-day cycle
30 PR
41 Gr34 Neutropenia11 Gr34 Leucopenia11 Gr34 Febrileneutropenia2 Related mortalities
Apr 2018 Fast Track for HER2-MBC who have failed 2prior regimens
Pernas S Martin M Kaufman PA Gil-Martin M Gomez Pardo P Lopez-Tarruella S Manso L Ciruelos E Perez-Fidalgo JA Hernando C Ademuyiwa FO Weilbaecher K Mayer I Pluard TJ Martinez Garcia M Vahdat L Perez-Garcia J Wach A Barker D Fung S Romagnoli B Cortes J Balixafortide plus eribulin in HER2-negative metastatic breast cancer a phase 1 single-arm dose-escalation trial Lancet Oncol 2018 Jun19(6)812-824
11 PRndashbut only + letrozole (No Resp on monotherapy)
61 Gr34 Neutropenia39 Gr34 Leucopenia
$933M in 1Q2018 $31B in 2017
Tamura K Mukai H Naito Y Yonemori K Kodaira M Tanabe Y Yamamoto N Osera S Sasaki M Mori Y Hashigaki S Nagasawa T Umeyama Y Yoshino T Phase I study of palbociclib a cyclin-dependent kinase 46 inhibitor in Japanese patients Cancer Sci 2016 Jun107(6)755-63 doi 101111cas12932 Epub 2016 May 11
Pfizer
Ibrancereg (palbociclib)
CDK 46 Inhibitor
HR+ HER2- MBC
Heavily pretreated Relapsed Metastatic Cancer
2004-2008
41 (5 BC)
chemo naiumlve (17) 1-2 (51)3 (29) 3+ (2)
Palbociclib 25-150 mg dose ranging
0
20 Gr34 Neutropenia23 Gr34 Leucopenia
$933M in 1Q2018 $31B in 2017
Flaherty KT Lorusso PM Demichele A Abramson VG Courtney R Randolph SS Shaik MN Wilner KD ODwyer PJ Schwartz GK Phase I dose-escalation trial of the oral cyclin-dependent kinase 46 inhibitor PD 0332991 administered using a 21-day schedule in patients with advanced cancer Clin Cancer Res 2012 Jan 1518(2)568-76 doi 1011581078-0432CCR-11-0509 Epub 2011 Nov 16
Novartis
Kisqalireg (ribociclib)
CDK 46 Inhibitors
Premenopausal HR+ HER2- MBC
Heavily pretreated Relapsed Metastatic Cancer
2016
132 (20 BC)
0-1 (25) 2-3 (42) 4+ (32)
Ribociclib 50 mg ranging up to 1200 mg dose escalation
23 PRndashincluded 1 in BC (5 of BC pts)
27 Gr34 Neutropenia17 Gr34 Leucopenia
Peak sales projected at $25B
Infante JR Cassier PA Gerecitano JF Witteveen PO Chugh R Ribrag V Chakraborty A Matano A Dobson JR Crystal AS Parasuraman S Shapiro GI A Phase I Study of the Cyclin-Dependent Kinase 46 Inhibitor Ribociclib (LEE011) in Patients with Advanced Solid Tumors and Lymphomas Clin Cancer Res 2016 Dec 122(23)5696-5705 Epub 2016 Aug 19
Eli Lilly
Verzenioreg (abemaciclib)
CDK 46 Inhibitors
HR+HER2minusMBC
Heavily pretreated Relapsed Metastatic Cancer
2016
12 (1 BC)
1 (312) 2 (212) 3+ (7)
Abemaciclib 100 mg ranging up to 200 mg dose escalation
17 PR (included 1 in BC)
17 Gr34 Neutropenia33 Gr34 Leucopenia
Peak sales projected at $2B
Fujiwara Y Tamura K Kondo S Tanabe Y Iwasa S Shimomura A Kitano S Ogasawara K Turner PK Mori J Asou H Chan EM Yamamoto N Phase 1 study of abemaciclib an inhibitor of CDK 4 and 6 as a single agent for Japanese patients with advanced cancer Cancer Chemother Pharmacol 2016 Aug78(2)281-8 doi 101007s00280-016-3085-8 Epub 2016 Jun 16
Mukai H Saeki T Shimada K Naito Y Matsubara N Nakanishi T Obaishi H Namiki M Sasaki Y Phase 1 combination study of eribulin mesylate with trastuzumab for advanced or recurrent human epidermal growth factor receptor 2 positive breast cancer Invest New Drugs 2015 Feb33(1)119-27
AstraZeneca
Lynparza (Olaparib)+ Cediranib
PARP inhibitor+ inhibitor of VEGF RTK
HR+ HER2- MBC
BC amp OC
13
28 (8 BC)
3 for BC
Olaparib (a poly (ADP-ribose) polymerase (PARP) inhibitor) amp Cediranib (Vascular endothelial growth factor receptor (VEGFR) 1 2 and 3 tyrosine kinase inhibitor)3 at dose level (DL) 0 (cediranib 20mg olaparib 100mg) 3 at DL1 (cediranib 20mg olaparib 200mg) 7 at DL2 (cediranib 30mg olaparib 200mg) 6 at DL3 (cediranib 30mg olaparib 400mg)
Liu JF Tolaney SM Birrer M Fleming GF Buss MK Dahlberg SE Lee H Whalen C Tyburski K Winer E Ivy P Matulonis UA A Phase 1 trial of the poly(ADP-ribose) polymerase inhibitor olaparib (AZD2281) in combination with the anti-angiogenic cediranib (AZD2171) in recurrent epithelial ovarian or triple-negative breast cancer Eur J Cancer 2013 Sep49(14)2972-8
ReyonPharma
VM206RY
Heterologous prime-boost with a truncated HER2 sequence
HER2+ Stg IIIampIV BC
15
9
2 chemo
Plasmid DNA (pHM-GM-CSF expressing truncated HER2 amp GM-CSF) amp adenoviral vector (Ad-HM containing modified HER2) (2 4 and 8 mgpatientvisit) of pHM-GM-CSF 3x IM weeks 0 2 and 4 Ad-HM 3 times 109 virus particles at week 6
11 PR
4 pts 7 minor AEs
Unclear
Kim SB Ahn JH Kim J Jung KH A phase 1 study of a heterologous prime-boost vaccination involving a truncated HER2 sequence in patients with HER2-expressing breast cancer Mol Ther Methods Clin Dev 2015 Sep 30215031 doi 101038mtm201531 eCollection 2015
Rodon J Peacuterez-Fidalgo A Krop IE Burris H Guerrero-Zotano A Britten CD Becerra C Schellens J Richards DA Schuler M Abu-Khalaf M Johnson FM Ranson M Edenfield J Silva AP Hackl W Quadt C Demanse D Duval V Baselga J Phase 11b dose escalation and expansion study of BEZ235 a dual PI3KmTOR inhibitor in patients with advanced solid tumors including patients with advanced breast cancer Cancer Chemother Pharmacol 2018 Jun 7 doi 101007s00280-018-3610-z [Epub ahead of print]
Celgene(Abraxane)
Gemcitabine + Abraxane (nab-paclitaxel)
Chemo+ Chemo
OC BC NSCLC PC + LC OC BC KS
MBC
16
9
Adjuv chemo (100)chemo post-adjuv (33)
Gem (nucleoside metabolic inhibitor 1250 mgm2) on days 1 and 8 nab-Pac (microtubule inhibitor) starting dose of 180 mgm2 (cohort 1) 220 mgm2 (cohort 2) and 260 mgm2 (cohort 3) on day 1 of the 21-day cycle using a 3 + 3 design
0
MTD not reached29 Gr3 Neutropenia59 Gr1 Peripheralneuropathy
Yoshitomi S Taira N Doihara H Mizoo T Nogami T Iwamoto T Motoki T Shien T Ogasawara Y Matsuoka J Tsuji H Mitsuhashi T A phase 1 dose-finding and pharmacokinetic study of gemcitabine with nab-paclitaxel in patients with metastatic breast cancer Cancer Chemother Pharmacol 2016 Aug78(2)289-94
Eli Lilly
Erbituxreg (cetuximab) + Taxane
EGFR inhibitor antineoplastic agent + Chemo
Head amp NeckColorectal
TNBC
07-10
18
1 chemo
Cetuximab (epidermal growth factor receptor (EGFR) antagonist ) an initial loading dose of cetuximab 400 mgm2 followed by a weekly dose of 250 mgm2Paclitaxel (microtubule inhibitor) 80 mgm2 or Docetaxel at an initial dose of 30 mgm2 was administered weekly
56 CR 22 PR
83 Dermatologic toxicity11 Grade3+
Nechushtan H Vainer G Stainberg H Salmon AY Hamburger T Peretz T A phase 12 of a combination of cetuximab and taxane for triple negative breast cancer patients Breast 2014 Aug23(4)435-8
Polyphor
Balixafortide (POL6326) + eribulin
CXCR4 antagonist + tubulin-based antimitotic
Heavily pretreatedRelapsed MBC
14-16
56
3rd line 3 chemo
3+3 dose escalation The highest dose was established as eribulin 14 mgmsup2 on days 2 and 9 and balixafortide 55 mgkg on days 1minus3 and 8minus10 of the 21-day cycle
30 PR
41 Gr34 Neutropenia11 Gr34 Leucopenia11 Gr34 Febrileneutropenia2 Related mortalities
42018 Fast Track (HER2-MBC failed 2 prior regimens)
Pernas S Martin M Kaufman PA Gil-Martin M Gomez Pardo P Lopez-Tarruella S Manso L Ciruelos E Perez-Fidalgo JA Hernando C Ademuyiwa FO Weilbaecher K Mayer I Pluard TJ Martinez Garcia M Vahdat L Perez-Garcia J Wach A Barker D Fung S Romagnoli B Cortes J Balixafortide plus eribulin in HER2-negative metastatic breast cancer a phase 1 single-arm dose-escalation trial Lancet Oncol 2018 Jun19(6)812-824
1 PRndashbut only + letrozoleNo Resp on monotherapy
61 Gr34 Neutropenia39 Gr34 Leucopenia
$933M (1Q18)$31B (2017)
Tamura K Mukai H Naito Y Yonemori K Kodaira M Tanabe Y Yamamoto N Osera S Sasaki M Mori Y Hashigaki S Nagasawa T Umeyama Y Yoshino T Phase I study of palbociclib a cyclin-dependent kinase 46 inhibitor in Japanese patients Cancer Sci 2016 Jun107(6)755-63 doi 101111cas12932 Epub 2016 May 11
Pfizer
Ibrancereg (palbociclib)
CDK 46 Inhibitor
HR+ HER2- MBC
Heavily pretreatedRelapsed Met Cancer
04-08
41 (5 BC)
chemo naiumlve (17)1-2(51) 3(29) 3+(2)
Palbociclib 25-150 mg dose ranging
0
20 Gr34 Neutropenia23 Gr34 Leucopenia
$933M (1Q18)$31B (2017)
Flaherty KT Lorusso PM Demichele A Abramson VG Courtney R Randolph SS Shaik MN Wilner KD ODwyer PJ Schwartz GK Phase I dose-escalation trial of the oral cyclin-dependent kinase 46 inhibitor PD 0332991 administered using a 21-day schedule in patients with advanced cancer Clin Cancer Res 2012 Jan 1518(2)568-76 doi 1011581078-0432CCR-11-0509 Epub 2011 Nov 16
Novartis
Kisqalireg (ribociclib)
CDK 46 Inhibitor
Premenopausal HR+ HER2- MBC
Heavily pretreatedRelapsed Met Cancer
16
132 (20 BC)
0-1 (25) 2-3 (42)4+ (32)
Ribociclib 50 mg ranging up to 1200 mg dose escalation
23 PR-included 1 BC (5 of BC pts)
27 Gr34 Neutropenia17 Gr34 Leucopenia
Peak sales est at $25B
Infante JR Cassier PA Gerecitano JF Witteveen PO Chugh R Ribrag V Chakraborty A Matano A Dobson JR Crystal AS Parasuraman S Shapiro GI A Phase I Study of the Cyclin-Dependent Kinase 46 Inhibitor Ribociclib (LEE011) in Patients with Advanced Solid Tumors and Lymphomas Clin Cancer Res 2016 Dec 122(23)5696-5705 Epub 2016 Aug 19
Eli Lilly
Verzenioreg (abemaciclib)
CDK 46 Inhibitor
HR+HER2minusMBC
Heavily pretreatedRelapsed Met Cancer
16
12 (1 BC)
1 (312) 2 (212) 3+(7)
Abemaciclib 100 mg ranging up to 200 mg dose escalation
17 PR (included 1 BC)
17 Gr34 Neutropenia33 Gr34 Leucopenia
Peak sales est at $2B
Fujiwara Y Tamura K Kondo S Tanabe Y Iwasa S Shimomura A Kitano S Ogasawara K Turner PK Mori J Asou H Chan EM Yamamoto N Phase 1 study of abemaciclib an inhibitor of CDK 4 and 6 as a single agent for Japanese patients with advanced cancer Cancer Chemother Pharmacol 2016 Aug78(2)281-8 doi 101007s00280-016-3085-8 Epub 2016 Jun 16
The confirmatory Bria-IMTtrade monotherapy Phase IIa trial has completed enrollment Additional Support for the HLA-matching hypothesis has been obtained
Bria-IMTtrade Combination Therapy study with immune checkpoint inhibitors Keytrudareg if PD-L12 positive (ge1) Yervoyreg if PD-L12 negative (lt1) Accepting patients from the monotherapy study who develop progressive disease Also enrolling patients directly into this study to enhance experience with the combination In discussion with other pharmaceutical companies to evaluate additional combinations with other
immunotherapies
Bria-OTStrade Off-the-Shelf Personalized Targeted Immunotherapy Developing Bria-OTStrade to co-express GM-CSF and interferon-α Pre-manufacture additional HLA alleles ndash Total of 15 alleles (8 Class I and 7 Class II) Co-development of BriaDXtrade companion diagnostic for HLA typing Combination therapy clinical trial with immune checkpoint inhibitors for non-responders using
information from the Bria-IMTtrade Combination Therapy Study
33
Development Timeline ndash Breast Cancer
20192018 2020 2021
Phase IIIaBria-IMTtrade
Monotherapy
Currently Enrolling Phase IIaBria-IMTtrade + Checkpoint
Currently in discussions with potential partnersPhase II Bria-IMTtrade plus Additional Combinations (1Q19 4Q22)(eg PD-1 Inhibitor PD-L1 inhibitor anti-CTLA4 anti-GITR anti-OX40)
1Q 2Q 3Q 4Q
2023
Bria-OTStrade Off-The-Shelf Personalized ImmunotherapyMonotherapy and Potential Partnered Combo Therapy
(2H19 Ongoing)
Bria-OTStradeOff-the-Shelf Cell Line cGMP Manufacturing
and BriaDXtrade(1Q18 1Q19)
Registration Studies (1Q20 2H22)Bria-IMTtrade with Checkpoint InhibitorsBria-OTStrade +- Checkpoint Inhibitors
34
Immuno-oncology Deals
Recent deals of small biotechs with big pharma in immuno-oncology
35
Date PartnershipDevelopment stage at the time of the deal Deal size
07122018 Immatics-Genmab Preclinical Up to $28B
04042018 OSE Immunotherapeutics-Boehringer Ingelheim Preclinical Up to euro113B ($139B)
02092018 Pieris Pharmaceuticals-Seattle Genetics Preclinical Up to $123B
2142018 Nektar-BMS Ph III Up to $36B
01222018 Juno-Celgene Ph II $9B (Acquisition)
11142017 Loxo-Bayer Larotrectinib (Ph II) LOXO-195 (Ph III) Up to $155B
1032017 CytomX-Amgen Preclinical Up to $15B
03202017 CytomX--BMS Ph III Up to $36B
6282016 Xencor-Novartis Preclinical Up to $24B
Early Stage Clinical Studies (Comparison)
We compared the interim data of Ph IIIa study of Bria-IMTtrade in advanced breast cancer with thedata in the early stage clinical studies of recently approved breast cancer drugs and one fasttracked product candidate
Apples to apples comparison Early Stage Clinical Studies in oncology are typically done in patientswith no other therapeutic options Thus the patients have very advanced disease and response ratesare typically quite low
The patients in our Ph IIIa study have been heavily pre-treated (median 45 prior regimens)Some recent studies of relevance in breast cancer are noted in the following slides
36
Breast Cancer Market Opportunity
Drug Technology Approved for Market (US)Ibrance (palbociclib) CDK 46 Inhibitor HR+HER2- MBC in combination with
fluvestrant or aromatase inhibitor$933M in 1Q2018 $3126M in 2017
Kisqali (ribociclib) CDK 46 Inhibitor 2017 HR+HER2- MBC in combination with fluvestrant or aromatase inhibitor
Peak sales projected at $25B
Verzenio (abemaciclib) CDK 46 Inhibitor 2017 HR+HER2- MBC in combination with fluvestrant or aromatase inhibitor
balixafortide CXCR4 antagonist Fast track designation in 2018 for HER2- MBC who have failed 2 prior regimens
The market for breast cancer drugs is a multibillion dollar market with new drugs being approvedon an ongoing basis indicating the shortage of safe and effective treatments for this deadly disease
37
Competitors- Phase III Clinical Data Bria-IMTtrade shows superior safety and similar to superior efficacy data compared with those of the multi-billion dollar drugs when they were at a similar early stage of clinical development
Injection site reactions No related SAEs or SUSARs
Tumor vol darr ampor darr circul tumor cellsAll Comers 21(419) 26(519)One or More HLA matches 27(415) 33(515)Two or More HLA matches 50 (24) 75 (34)
Sheet1 (3)
Comp -Slides
Data
HLA (2)
HLA
Data (Ph1-2+4Pt)
Competitors (2018)-Slide
Competitors (2018)
In the Pipeline Protein Kinase C delta (PKCδ) Inhibitors
30 of all human malignancies display activating RAS mutations Another 60 showing over-activity of Ras-signaling pathways
Ras has been termed ldquoundruggablerdquo (no one has been able to make a Ras inhibitor drug)
BriaCellrsquos novel proprietary PKCδ inhibitors have shown activity against multiple RAS transformed tumors Lung cancer Melanoma Breast cancer Neuroendocrine cancer Pancreatic cancer Colorectal cancer
This target has an attractive safety profile based on in vivo studies and knock out mouse studies
PKCδ inhibitors should qualify for an accelerated clinical development plan and regulatory pathway
Could be in clinic within 24 months
Cost-Effective Additional Shot-on-Goal and additional partnership opportunities
Early-Stage Preclinical Program
39
Protein Kinase C delta (PKCδ) Inhibitors
Activated PKCδ inhibits RAS degradation which in turn stimulates tumor growth
Koo et al Oncotarget 621328 2016
30 of all human malignancies display activating RASmutations with another 60 showing over-activity of Ras-signaling pathways
BriaCellrsquos novel proprietary PKCδ inhibitors have shownactivity against multiple RAS transformed tumors
This target has an attractive safety profile based on in vivostudies and knock out mouse studies
PKCδ also has potential activity as an immunotherapeuticby blocking TGFβ signaling
PKCδ inhibitors are applicable to specific niche tumor typeswhich provide an accelerated clinical development plan
Structural aspects of first generation inhibitor rottlerin and staurosporine (pan-PKC activator) were combined to create second generation inhibitor KAM1
Third generation inhibitors such as BJE6-106 have improved potency and selectivity Fourth generation inhibitors under development to optimize drug-like characteristics PKCδ inhibitors lack endothelial cell cytotoxicity amp PKCδ deficient mice develop normally and are fertile Potentially no marked intrinsic toxicity by inhibiting PKCδ
Mukai H Saeki T Shimada K Naito Y Matsubara N Nakanishi T Obaishi H Namiki M Sasaki Y Phase 1 combination study of eribulin mesylate with trastuzumab for advanced or recurrent human epidermal growth factor receptor 2 positive breast cancer Invest New Drugs 2015 Feb33(1)119-27
AstraZeneca
Lynparza (Olaparib) + Cediranib
PARP inhibitor + inhibitor of VEGF receptor tyrosine kinases
HR+ HER2- MBC
BC amp OC
2013
28 (8 BC)
3 for BC
Olaparib (a poly (ADP-ribose) polymerase (PARP) inhibitor) amp Cediranib (Vascular endothelial growth factor receptor (VEGFR) 1 2 and 3 tyrosine kinase inhibitor)3 at dose level (DL) 0 (cediranib 20mg olaparib 100mg) 3 at DL1 (cediranib 20mg olaparib 200mg) 7 at DL2 (cediranib 30mg olaparib 200mg) 6 at DL3 (cediranib 30mg olaparib 400mg)
Liu JF Tolaney SM Birrer M Fleming GF Buss MK Dahlberg SE Lee H Whalen C Tyburski K Winer E Ivy P Matulonis UA A Phase 1 trial of the poly(ADP-ribose) polymerase inhibitor olaparib (AZD2281) in combination with the anti-angiogenic cediranib (AZD2171) in recurrent epithelial ovarian or triple-negative breast cancer Eur J Cancer 2013 Sep49(14)2972-8
Reyon Pharmaceutical
VM206RY
Heterologous prime-boost with a truncated HER2 sequence
HER2+ Stage IIIampIV BC
2015
9
2 chemo
Plasmid DNA (pHM-GM-CSF expressing truncated HER2 amp GM-CSF) amp adenoviral vector (Ad-HM containing modified HER2) (2 4 and 8 mgpatientvisit) of pHM-GM-CSF 3x IM weeks 0 2 and 4 Ad-HM 3 times 109 virus particles at week 6
11 PR
4 pts showed 7 minor AEs
Unclear
Kim SB Ahn JH Kim J Jung KH A phase 1 study of a heterologous prime-boost vaccination involving a truncated HER2 sequence in patients with HER2-expressing breast cancer Mol Ther Methods Clin Dev 2015 Sep 30215031 doi 101038mtm201531 eCollection 2015
Rodon J Peacuterez-Fidalgo A Krop IE Burris H Guerrero-Zotano A Britten CD Becerra C Schellens J Richards DA Schuler M Abu-Khalaf M Johnson FM Ranson M Edenfield J Silva AP Hackl W Quadt C Demanse D Duval V Baselga J Phase 11b dose escalation and expansion study of BEZ235 a dual PI3KmTOR inhibitor in patients with advanced solid tumors including patients with advanced breast cancer Cancer Chemother Pharmacol 2018 Jun 7 doi 101007s00280-018-3610-z [Epub ahead of print]
Celgene (Abraxane)
Gemcitabine + Abraxane (nab-paclitaxel)
Chemo + Chemo
OC BC NSCLC amp Panc cancer + Lung OC BC Kaposi sarcoma
MBC
2016
9
Adjuvant chemo (100)chemo post-adjuvant (33)
Gem (nucleoside metabolic inhibitor 1250 mgm2) on days 1 and 8 nab-Pac (microtubule inhibitor) starting dose of 180 mgm2 (cohort 1) 220 mgm2 (cohort 2) and 260 mgm2 (cohort 3) on day 1 of the 21-day cycle using a 3 + 3 design
0
MTD not reached29 Gr3 Neutropenia59 Gr1 Peripheralneuropathy
Yoshitomi S Taira N Doihara H Mizoo T Nogami T Iwamoto T Motoki T Shien T Ogasawara Y Matsuoka J Tsuji H Mitsuhashi T A phase 1 dose-finding and pharmacokinetic study of gemcitabine with nab-paclitaxel in patients with metastatic breast cancer Cancer Chemother Pharmacol 2016 Aug78(2)289-94
Eli Lilly
Erbituxreg (cetuximab) + Taxane
EGFR inhibitor antineoplastic agent + Chemo
Headamp Neck Colorectal Cancer
TNBC
2007-2010
18
1 chemo
Cetuximab (epidermal growth factor receptor (EGFR) antagonist ) an initial loading dose of cetuximab 400 mgm2 followed by a weekly dose of 250 mgm2Paclitaxel (microtubule inhibitor) 80 mgm2 or Docetaxel at an initial dose of 30 mgm2 was administered weekly
56 CR 22 PR
83 Dermatologic toxicity11 Grade3+
Nechushtan H Vainer G Stainberg H Salmon AY Hamburger T Peretz T A phase 12 of a combination of cetuximab and taxane for triple negative breast cancer patients Breast 2014 Aug23(4)435-8
Polyphor
Balixafortide (POL6326) + eribulin
CXCR4 antagonist + tubulin-based antimitotic
Heavily pretreated Relapsed MBC
2014-2016
56
3rd line 3 chemo
3+3 dose escalation The highest dose was established as eribulin 14 mgmsup2 on days 2 and 9 and balixafortide 55 mgkg on days 1minus3 and 8minus10 of the 21-day cycle
30 PR
41 Gr34 Neutropenia11 Gr34 Leucopenia11 Gr34 Febrileneutropenia2 Related mortalities
Apr 2018 Fast Track for HER2-MBC who have failed 2prior regimens
Pernas S Martin M Kaufman PA Gil-Martin M Gomez Pardo P Lopez-Tarruella S Manso L Ciruelos E Perez-Fidalgo JA Hernando C Ademuyiwa FO Weilbaecher K Mayer I Pluard TJ Martinez Garcia M Vahdat L Perez-Garcia J Wach A Barker D Fung S Romagnoli B Cortes J Balixafortide plus eribulin in HER2-negative metastatic breast cancer a phase 1 single-arm dose-escalation trial Lancet Oncol 2018 Jun19(6)812-824
11 PRndashbut only + letrozole (No Resp on monotherapy)
61 Gr34 Neutropenia39 Gr34 Leucopenia
$933M in 1Q2018 $31B in 2017
Tamura K Mukai H Naito Y Yonemori K Kodaira M Tanabe Y Yamamoto N Osera S Sasaki M Mori Y Hashigaki S Nagasawa T Umeyama Y Yoshino T Phase I study of palbociclib a cyclin-dependent kinase 46 inhibitor in Japanese patients Cancer Sci 2016 Jun107(6)755-63 doi 101111cas12932 Epub 2016 May 11
Pfizer
Ibrancereg (palbociclib)
CDK 46 Inhibitor
HR+ HER2- MBC
Heavily pretreated Relapsed Metastatic Cancer
2004-2008
41 (5 BC)
chemo naiumlve (17) 1-2 (51)3 (29) 3+ (2)
Palbociclib 25-150 mg dose ranging
0
20 Gr34 Neutropenia23 Gr34 Leucopenia
$933M in 1Q2018 $31B in 2017
Flaherty KT Lorusso PM Demichele A Abramson VG Courtney R Randolph SS Shaik MN Wilner KD ODwyer PJ Schwartz GK Phase I dose-escalation trial of the oral cyclin-dependent kinase 46 inhibitor PD 0332991 administered using a 21-day schedule in patients with advanced cancer Clin Cancer Res 2012 Jan 1518(2)568-76 doi 1011581078-0432CCR-11-0509 Epub 2011 Nov 16
Novartis
Kisqalireg (ribociclib)
CDK 46 Inhibitors
Premenopausal HR+ HER2- MBC
Heavily pretreated Relapsed Metastatic Cancer
2016
132 (20 BC)
0-1 (25) 2-3 (42) 4+ (32)
Ribociclib 50 mg ranging up to 1200 mg dose escalation
23 PRndashincluded 1 in BC (5 of BC pts)
27 Gr34 Neutropenia17 Gr34 Leucopenia
Peak sales projected at $25B
Infante JR Cassier PA Gerecitano JF Witteveen PO Chugh R Ribrag V Chakraborty A Matano A Dobson JR Crystal AS Parasuraman S Shapiro GI A Phase I Study of the Cyclin-Dependent Kinase 46 Inhibitor Ribociclib (LEE011) in Patients with Advanced Solid Tumors and Lymphomas Clin Cancer Res 2016 Dec 122(23)5696-5705 Epub 2016 Aug 19
Eli Lilly
Verzenioreg (abemaciclib)
CDK 46 Inhibitors
HR+HER2minusMBC
Heavily pretreated Relapsed Metastatic Cancer
2016
12 (1 BC)
1 (312) 2 (212) 3+ (7)
Abemaciclib 100 mg ranging up to 200 mg dose escalation
17 PR (included 1 in BC)
17 Gr34 Neutropenia33 Gr34 Leucopenia
Peak sales projected at $2B
Fujiwara Y Tamura K Kondo S Tanabe Y Iwasa S Shimomura A Kitano S Ogasawara K Turner PK Mori J Asou H Chan EM Yamamoto N Phase 1 study of abemaciclib an inhibitor of CDK 4 and 6 as a single agent for Japanese patients with advanced cancer Cancer Chemother Pharmacol 2016 Aug78(2)281-8 doi 101007s00280-016-3085-8 Epub 2016 Jun 16
Mukai H Saeki T Shimada K Naito Y Matsubara N Nakanishi T Obaishi H Namiki M Sasaki Y Phase 1 combination study of eribulin mesylate with trastuzumab for advanced or recurrent human epidermal growth factor receptor 2 positive breast cancer Invest New Drugs 2015 Feb33(1)119-27
AstraZeneca
Lynparza (Olaparib)+ Cediranib
PARP inhibitor+ inhibitor of VEGF RTK
HR+ HER2- MBC
BC amp OC
13
28 (8 BC)
3 for BC
Olaparib (a poly (ADP-ribose) polymerase (PARP) inhibitor) amp Cediranib (Vascular endothelial growth factor receptor (VEGFR) 1 2 and 3 tyrosine kinase inhibitor)3 at dose level (DL) 0 (cediranib 20mg olaparib 100mg) 3 at DL1 (cediranib 20mg olaparib 200mg) 7 at DL2 (cediranib 30mg olaparib 200mg) 6 at DL3 (cediranib 30mg olaparib 400mg)
Liu JF Tolaney SM Birrer M Fleming GF Buss MK Dahlberg SE Lee H Whalen C Tyburski K Winer E Ivy P Matulonis UA A Phase 1 trial of the poly(ADP-ribose) polymerase inhibitor olaparib (AZD2281) in combination with the anti-angiogenic cediranib (AZD2171) in recurrent epithelial ovarian or triple-negative breast cancer Eur J Cancer 2013 Sep49(14)2972-8
ReyonPharma
VM206RY
Heterologous prime-boost with a truncated HER2 sequence
HER2+ Stg IIIampIV BC
15
9
2 chemo
Plasmid DNA (pHM-GM-CSF expressing truncated HER2 amp GM-CSF) amp adenoviral vector (Ad-HM containing modified HER2) (2 4 and 8 mgpatientvisit) of pHM-GM-CSF 3x IM weeks 0 2 and 4 Ad-HM 3 times 109 virus particles at week 6
11 PR
4 pts 7 minor AEs
Unclear
Kim SB Ahn JH Kim J Jung KH A phase 1 study of a heterologous prime-boost vaccination involving a truncated HER2 sequence in patients with HER2-expressing breast cancer Mol Ther Methods Clin Dev 2015 Sep 30215031 doi 101038mtm201531 eCollection 2015
Rodon J Peacuterez-Fidalgo A Krop IE Burris H Guerrero-Zotano A Britten CD Becerra C Schellens J Richards DA Schuler M Abu-Khalaf M Johnson FM Ranson M Edenfield J Silva AP Hackl W Quadt C Demanse D Duval V Baselga J Phase 11b dose escalation and expansion study of BEZ235 a dual PI3KmTOR inhibitor in patients with advanced solid tumors including patients with advanced breast cancer Cancer Chemother Pharmacol 2018 Jun 7 doi 101007s00280-018-3610-z [Epub ahead of print]
Celgene(Abraxane)
Gemcitabine + Abraxane (nab-paclitaxel)
Chemo+ Chemo
OC BC NSCLC PC + LC OC BC KS
MBC
16
9
Adjuv chemo (100)chemo post-adjuv (33)
Gem (nucleoside metabolic inhibitor 1250 mgm2) on days 1 and 8 nab-Pac (microtubule inhibitor) starting dose of 180 mgm2 (cohort 1) 220 mgm2 (cohort 2) and 260 mgm2 (cohort 3) on day 1 of the 21-day cycle using a 3 + 3 design
0
MTD not reached29 Gr3 Neutropenia59 Gr1 Peripheralneuropathy
Yoshitomi S Taira N Doihara H Mizoo T Nogami T Iwamoto T Motoki T Shien T Ogasawara Y Matsuoka J Tsuji H Mitsuhashi T A phase 1 dose-finding and pharmacokinetic study of gemcitabine with nab-paclitaxel in patients with metastatic breast cancer Cancer Chemother Pharmacol 2016 Aug78(2)289-94
Eli Lilly
Erbituxreg (cetuximab) + Taxane
EGFR inhibitor antineoplastic agent + Chemo
Head amp NeckColorectal
TNBC
07-10
18
1 chemo
Cetuximab (epidermal growth factor receptor (EGFR) antagonist ) an initial loading dose of cetuximab 400 mgm2 followed by a weekly dose of 250 mgm2Paclitaxel (microtubule inhibitor) 80 mgm2 or Docetaxel at an initial dose of 30 mgm2 was administered weekly
56 CR 22 PR
83 Dermatologic toxicity11 Grade3+
Nechushtan H Vainer G Stainberg H Salmon AY Hamburger T Peretz T A phase 12 of a combination of cetuximab and taxane for triple negative breast cancer patients Breast 2014 Aug23(4)435-8
Polyphor
Balixafortide (POL6326) + eribulin
CXCR4 antagonist + tubulin-based antimitotic
Heavily pretreatedRelapsed MBC
14-16
56
3rd line 3 chemo
3+3 dose escalation The highest dose was established as eribulin 14 mgmsup2 on days 2 and 9 and balixafortide 55 mgkg on days 1minus3 and 8minus10 of the 21-day cycle
30 PR
41 Gr34 Neutropenia11 Gr34 Leucopenia11 Gr34 Febrileneutropenia2 Related mortalities
42018 Fast Track (HER2-MBC failed 2 prior regimens)
Pernas S Martin M Kaufman PA Gil-Martin M Gomez Pardo P Lopez-Tarruella S Manso L Ciruelos E Perez-Fidalgo JA Hernando C Ademuyiwa FO Weilbaecher K Mayer I Pluard TJ Martinez Garcia M Vahdat L Perez-Garcia J Wach A Barker D Fung S Romagnoli B Cortes J Balixafortide plus eribulin in HER2-negative metastatic breast cancer a phase 1 single-arm dose-escalation trial Lancet Oncol 2018 Jun19(6)812-824
1 PRndashbut only + letrozoleNo Resp on monotherapy
61 Gr34 Neutropenia39 Gr34 Leucopenia
$933M (1Q18)$31B (2017)
Tamura K Mukai H Naito Y Yonemori K Kodaira M Tanabe Y Yamamoto N Osera S Sasaki M Mori Y Hashigaki S Nagasawa T Umeyama Y Yoshino T Phase I study of palbociclib a cyclin-dependent kinase 46 inhibitor in Japanese patients Cancer Sci 2016 Jun107(6)755-63 doi 101111cas12932 Epub 2016 May 11
Pfizer
Ibrancereg (palbociclib)
CDK 46 Inhibitor
HR+ HER2- MBC
Heavily pretreatedRelapsed Met Cancer
04-08
41 (5 BC)
chemo naiumlve (17)1-2(51) 3(29) 3+(2)
Palbociclib 25-150 mg dose ranging
0
20 Gr34 Neutropenia23 Gr34 Leucopenia
$933M (1Q18)$31B (2017)
Flaherty KT Lorusso PM Demichele A Abramson VG Courtney R Randolph SS Shaik MN Wilner KD ODwyer PJ Schwartz GK Phase I dose-escalation trial of the oral cyclin-dependent kinase 46 inhibitor PD 0332991 administered using a 21-day schedule in patients with advanced cancer Clin Cancer Res 2012 Jan 1518(2)568-76 doi 1011581078-0432CCR-11-0509 Epub 2011 Nov 16
Novartis
Kisqalireg (ribociclib)
CDK 46 Inhibitor
Premenopausal HR+ HER2- MBC
Heavily pretreatedRelapsed Met Cancer
16
132 (20 BC)
0-1 (25) 2-3 (42)4+ (32)
Ribociclib 50 mg ranging up to 1200 mg dose escalation
23 PR-included 1 BC (5 of BC pts)
27 Gr34 Neutropenia17 Gr34 Leucopenia
Peak sales est at $25B
Infante JR Cassier PA Gerecitano JF Witteveen PO Chugh R Ribrag V Chakraborty A Matano A Dobson JR Crystal AS Parasuraman S Shapiro GI A Phase I Study of the Cyclin-Dependent Kinase 46 Inhibitor Ribociclib (LEE011) in Patients with Advanced Solid Tumors and Lymphomas Clin Cancer Res 2016 Dec 122(23)5696-5705 Epub 2016 Aug 19
Eli Lilly
Verzenioreg (abemaciclib)
CDK 46 Inhibitor
HR+HER2minusMBC
Heavily pretreatedRelapsed Met Cancer
16
12 (1 BC)
1 (312) 2 (212) 3+(7)
Abemaciclib 100 mg ranging up to 200 mg dose escalation
17 PR (included 1 BC)
17 Gr34 Neutropenia33 Gr34 Leucopenia
Peak sales est at $2B
Fujiwara Y Tamura K Kondo S Tanabe Y Iwasa S Shimomura A Kitano S Ogasawara K Turner PK Mori J Asou H Chan EM Yamamoto N Phase 1 study of abemaciclib an inhibitor of CDK 4 and 6 as a single agent for Japanese patients with advanced cancer Cancer Chemother Pharmacol 2016 Aug78(2)281-8 doi 101007s00280-016-3085-8 Epub 2016 Jun 16
41 Gr34 Neutropenia11 Gr34 Leucopenia11 Gr34 Febrileneutropenia2 Related mortalities
30 PRs in combination with Halaven
Bria-IMTTM
24 (safety)19 (efficacy)
Injection site reactions No related SAEs or SUSARs
Tumor vol darr ampor darr circul tumor cellsAll Comers 21(419) 26(519)One or More HLA matches 27(415) 33(515)Two or More HLA matches 50 (24) 75 (34)
Drug
Technology
Approved for
Market (US)
Ibrance (palbociclib)
CDK 46 Inhibitor
HR+HER2- MBC in combination with fluvestrant or aromatase inhibitor
$933M in 1Q2018 $3126M in 2017
Kisqali (ribociclib)
CDK 46 Inhibitor
2017 HR+HER2- MBC in combination with fluvestrant or aromatase inhibitor
Peak sales projected at $25B
Verzenio (abemaciclib)
CDK 46 Inhibitor
2017 HR+HER2- MBC in combination with fluvestrant or aromatase inhibitor
Peak sales projected at $2B
Lynparza (olaparib)
Poly (ADP-ribose) polymerase (PARP) inhibitor
2017 ovarian amp breast cancer
$997M in 2017
Halaven (eribulin mesylate)
Tubulin-based antimitotic
2H2017 3rd line MBC amp liposarcoma
$181M in 2017
balixafortide
CXCR4 antagonist
Fast track designation in 2018 for HER2- MBC who have failed 2 prior regimens
Clinical Development Strategy
The confirmatory Bria-IMTtrade monotherapy Phase IIa trial has completed enrollment Additional Support for the HLA-matching hypothesis has been obtained
Bria-IMTtrade Combination Therapy study with immune checkpoint inhibitors Keytrudareg if PD-L12 positive (ge1) Yervoyreg if PD-L12 negative (lt1) Accepting patients from the monotherapy study who develop progressive disease Also enrolling patients directly into this study to enhance experience with the combination In discussion with other pharmaceutical companies to evaluate additional combinations with other
immunotherapies
Bria-OTStrade Off-the-Shelf Personalized Targeted Immunotherapy Developing Bria-OTStrade to co-express GM-CSF and interferon-α Pre-manufacture additional HLA alleles ndash Total of 15 alleles (8 Class I and 7 Class II) Co-development of BriaDXtrade companion diagnostic for HLA typing Combination therapy clinical trial with immune checkpoint inhibitors for non-responders using
information from the Bria-IMTtrade Combination Therapy Study
33
Development Timeline ndash Breast Cancer
20192018 2020 2021
Phase IIIaBria-IMTtrade
Monotherapy
Currently Enrolling Phase IIaBria-IMTtrade + Checkpoint
Currently in discussions with potential partnersPhase II Bria-IMTtrade plus Additional Combinations (1Q19 4Q22)(eg PD-1 Inhibitor PD-L1 inhibitor anti-CTLA4 anti-GITR anti-OX40)
1Q 2Q 3Q 4Q
2023
Bria-OTStrade Off-The-Shelf Personalized ImmunotherapyMonotherapy and Potential Partnered Combo Therapy
(2H19 Ongoing)
Bria-OTStradeOff-the-Shelf Cell Line cGMP Manufacturing
and BriaDXtrade(1Q18 1Q19)
Registration Studies (1Q20 2H22)Bria-IMTtrade with Checkpoint InhibitorsBria-OTStrade +- Checkpoint Inhibitors
34
Immuno-oncology Deals
Recent deals of small biotechs with big pharma in immuno-oncology
35
Date PartnershipDevelopment stage at the time of the deal Deal size
07122018 Immatics-Genmab Preclinical Up to $28B
04042018 OSE Immunotherapeutics-Boehringer Ingelheim Preclinical Up to euro113B ($139B)
02092018 Pieris Pharmaceuticals-Seattle Genetics Preclinical Up to $123B
2142018 Nektar-BMS Ph III Up to $36B
01222018 Juno-Celgene Ph II $9B (Acquisition)
11142017 Loxo-Bayer Larotrectinib (Ph II) LOXO-195 (Ph III) Up to $155B
1032017 CytomX-Amgen Preclinical Up to $15B
03202017 CytomX--BMS Ph III Up to $36B
6282016 Xencor-Novartis Preclinical Up to $24B
Early Stage Clinical Studies (Comparison)
We compared the interim data of Ph IIIa study of Bria-IMTtrade in advanced breast cancer with thedata in the early stage clinical studies of recently approved breast cancer drugs and one fasttracked product candidate
Apples to apples comparison Early Stage Clinical Studies in oncology are typically done in patientswith no other therapeutic options Thus the patients have very advanced disease and response ratesare typically quite low
The patients in our Ph IIIa study have been heavily pre-treated (median 45 prior regimens)Some recent studies of relevance in breast cancer are noted in the following slides
36
Breast Cancer Market Opportunity
Drug Technology Approved for Market (US)Ibrance (palbociclib) CDK 46 Inhibitor HR+HER2- MBC in combination with
fluvestrant or aromatase inhibitor$933M in 1Q2018 $3126M in 2017
Kisqali (ribociclib) CDK 46 Inhibitor 2017 HR+HER2- MBC in combination with fluvestrant or aromatase inhibitor
Peak sales projected at $25B
Verzenio (abemaciclib) CDK 46 Inhibitor 2017 HR+HER2- MBC in combination with fluvestrant or aromatase inhibitor
balixafortide CXCR4 antagonist Fast track designation in 2018 for HER2- MBC who have failed 2 prior regimens
The market for breast cancer drugs is a multibillion dollar market with new drugs being approvedon an ongoing basis indicating the shortage of safe and effective treatments for this deadly disease
37
Competitors- Phase III Clinical Data Bria-IMTtrade shows superior safety and similar to superior efficacy data compared with those of the multi-billion dollar drugs when they were at a similar early stage of clinical development
Injection site reactions No related SAEs or SUSARs
Tumor vol darr ampor darr circul tumor cellsAll Comers 21(419) 26(519)One or More HLA matches 27(415) 33(515)Two or More HLA matches 50 (24) 75 (34)
Sheet1 (3)
Comp -Slides
Data
HLA (2)
HLA
Data (Ph1-2+4Pt)
Competitors (2018)-Slide
Competitors (2018)
In the Pipeline Protein Kinase C delta (PKCδ) Inhibitors
30 of all human malignancies display activating RAS mutations Another 60 showing over-activity of Ras-signaling pathways
Ras has been termed ldquoundruggablerdquo (no one has been able to make a Ras inhibitor drug)
BriaCellrsquos novel proprietary PKCδ inhibitors have shown activity against multiple RAS transformed tumors Lung cancer Melanoma Breast cancer Neuroendocrine cancer Pancreatic cancer Colorectal cancer
This target has an attractive safety profile based on in vivo studies and knock out mouse studies
PKCδ inhibitors should qualify for an accelerated clinical development plan and regulatory pathway
Could be in clinic within 24 months
Cost-Effective Additional Shot-on-Goal and additional partnership opportunities
Early-Stage Preclinical Program
39
Protein Kinase C delta (PKCδ) Inhibitors
Activated PKCδ inhibits RAS degradation which in turn stimulates tumor growth
Koo et al Oncotarget 621328 2016
30 of all human malignancies display activating RASmutations with another 60 showing over-activity of Ras-signaling pathways
BriaCellrsquos novel proprietary PKCδ inhibitors have shownactivity against multiple RAS transformed tumors
This target has an attractive safety profile based on in vivostudies and knock out mouse studies
PKCδ also has potential activity as an immunotherapeuticby blocking TGFβ signaling
PKCδ inhibitors are applicable to specific niche tumor typeswhich provide an accelerated clinical development plan
Structural aspects of first generation inhibitor rottlerin and staurosporine (pan-PKC activator) were combined to create second generation inhibitor KAM1
Third generation inhibitors such as BJE6-106 have improved potency and selectivity Fourth generation inhibitors under development to optimize drug-like characteristics PKCδ inhibitors lack endothelial cell cytotoxicity amp PKCδ deficient mice develop normally and are fertile Potentially no marked intrinsic toxicity by inhibiting PKCδ
Mukai H Saeki T Shimada K Naito Y Matsubara N Nakanishi T Obaishi H Namiki M Sasaki Y Phase 1 combination study of eribulin mesylate with trastuzumab for advanced or recurrent human epidermal growth factor receptor 2 positive breast cancer Invest New Drugs 2015 Feb33(1)119-27
AstraZeneca
Lynparza (Olaparib) + Cediranib
PARP inhibitor + inhibitor of VEGF receptor tyrosine kinases
HR+ HER2- MBC
BC amp OC
2013
28 (8 BC)
3 for BC
Olaparib (a poly (ADP-ribose) polymerase (PARP) inhibitor) amp Cediranib (Vascular endothelial growth factor receptor (VEGFR) 1 2 and 3 tyrosine kinase inhibitor)3 at dose level (DL) 0 (cediranib 20mg olaparib 100mg) 3 at DL1 (cediranib 20mg olaparib 200mg) 7 at DL2 (cediranib 30mg olaparib 200mg) 6 at DL3 (cediranib 30mg olaparib 400mg)
Liu JF Tolaney SM Birrer M Fleming GF Buss MK Dahlberg SE Lee H Whalen C Tyburski K Winer E Ivy P Matulonis UA A Phase 1 trial of the poly(ADP-ribose) polymerase inhibitor olaparib (AZD2281) in combination with the anti-angiogenic cediranib (AZD2171) in recurrent epithelial ovarian or triple-negative breast cancer Eur J Cancer 2013 Sep49(14)2972-8
Reyon Pharmaceutical
VM206RY
Heterologous prime-boost with a truncated HER2 sequence
HER2+ Stage IIIampIV BC
2015
9
2 chemo
Plasmid DNA (pHM-GM-CSF expressing truncated HER2 amp GM-CSF) amp adenoviral vector (Ad-HM containing modified HER2) (2 4 and 8 mgpatientvisit) of pHM-GM-CSF 3x IM weeks 0 2 and 4 Ad-HM 3 times 109 virus particles at week 6
11 PR
4 pts showed 7 minor AEs
Unclear
Kim SB Ahn JH Kim J Jung KH A phase 1 study of a heterologous prime-boost vaccination involving a truncated HER2 sequence in patients with HER2-expressing breast cancer Mol Ther Methods Clin Dev 2015 Sep 30215031 doi 101038mtm201531 eCollection 2015
Rodon J Peacuterez-Fidalgo A Krop IE Burris H Guerrero-Zotano A Britten CD Becerra C Schellens J Richards DA Schuler M Abu-Khalaf M Johnson FM Ranson M Edenfield J Silva AP Hackl W Quadt C Demanse D Duval V Baselga J Phase 11b dose escalation and expansion study of BEZ235 a dual PI3KmTOR inhibitor in patients with advanced solid tumors including patients with advanced breast cancer Cancer Chemother Pharmacol 2018 Jun 7 doi 101007s00280-018-3610-z [Epub ahead of print]
Celgene (Abraxane)
Gemcitabine + Abraxane (nab-paclitaxel)
Chemo + Chemo
OC BC NSCLC amp Panc cancer + Lung OC BC Kaposi sarcoma
MBC
2016
9
Adjuvant chemo (100)chemo post-adjuvant (33)
Gem (nucleoside metabolic inhibitor 1250 mgm2) on days 1 and 8 nab-Pac (microtubule inhibitor) starting dose of 180 mgm2 (cohort 1) 220 mgm2 (cohort 2) and 260 mgm2 (cohort 3) on day 1 of the 21-day cycle using a 3 + 3 design
0
MTD not reached29 Gr3 Neutropenia59 Gr1 Peripheralneuropathy
Yoshitomi S Taira N Doihara H Mizoo T Nogami T Iwamoto T Motoki T Shien T Ogasawara Y Matsuoka J Tsuji H Mitsuhashi T A phase 1 dose-finding and pharmacokinetic study of gemcitabine with nab-paclitaxel in patients with metastatic breast cancer Cancer Chemother Pharmacol 2016 Aug78(2)289-94
Eli Lilly
Erbituxreg (cetuximab) + Taxane
EGFR inhibitor antineoplastic agent + Chemo
Headamp Neck Colorectal Cancer
TNBC
2007-2010
18
1 chemo
Cetuximab (epidermal growth factor receptor (EGFR) antagonist ) an initial loading dose of cetuximab 400 mgm2 followed by a weekly dose of 250 mgm2Paclitaxel (microtubule inhibitor) 80 mgm2 or Docetaxel at an initial dose of 30 mgm2 was administered weekly
56 CR 22 PR
83 Dermatologic toxicity11 Grade3+
Nechushtan H Vainer G Stainberg H Salmon AY Hamburger T Peretz T A phase 12 of a combination of cetuximab and taxane for triple negative breast cancer patients Breast 2014 Aug23(4)435-8
Polyphor
Balixafortide (POL6326) + eribulin
CXCR4 antagonist + tubulin-based antimitotic
Heavily pretreated Relapsed MBC
2014-2016
56
3rd line 3 chemo
3+3 dose escalation The highest dose was established as eribulin 14 mgmsup2 on days 2 and 9 and balixafortide 55 mgkg on days 1minus3 and 8minus10 of the 21-day cycle
30 PR
41 Gr34 Neutropenia11 Gr34 Leucopenia11 Gr34 Febrileneutropenia2 Related mortalities
Apr 2018 Fast Track for HER2-MBC who have failed 2prior regimens
Pernas S Martin M Kaufman PA Gil-Martin M Gomez Pardo P Lopez-Tarruella S Manso L Ciruelos E Perez-Fidalgo JA Hernando C Ademuyiwa FO Weilbaecher K Mayer I Pluard TJ Martinez Garcia M Vahdat L Perez-Garcia J Wach A Barker D Fung S Romagnoli B Cortes J Balixafortide plus eribulin in HER2-negative metastatic breast cancer a phase 1 single-arm dose-escalation trial Lancet Oncol 2018 Jun19(6)812-824
11 PRndashbut only + letrozole (No Resp on monotherapy)
61 Gr34 Neutropenia39 Gr34 Leucopenia
$933M in 1Q2018 $31B in 2017
Tamura K Mukai H Naito Y Yonemori K Kodaira M Tanabe Y Yamamoto N Osera S Sasaki M Mori Y Hashigaki S Nagasawa T Umeyama Y Yoshino T Phase I study of palbociclib a cyclin-dependent kinase 46 inhibitor in Japanese patients Cancer Sci 2016 Jun107(6)755-63 doi 101111cas12932 Epub 2016 May 11
Pfizer
Ibrancereg (palbociclib)
CDK 46 Inhibitor
HR+ HER2- MBC
Heavily pretreated Relapsed Metastatic Cancer
2004-2008
41 (5 BC)
chemo naiumlve (17) 1-2 (51)3 (29) 3+ (2)
Palbociclib 25-150 mg dose ranging
0
20 Gr34 Neutropenia23 Gr34 Leucopenia
$933M in 1Q2018 $31B in 2017
Flaherty KT Lorusso PM Demichele A Abramson VG Courtney R Randolph SS Shaik MN Wilner KD ODwyer PJ Schwartz GK Phase I dose-escalation trial of the oral cyclin-dependent kinase 46 inhibitor PD 0332991 administered using a 21-day schedule in patients with advanced cancer Clin Cancer Res 2012 Jan 1518(2)568-76 doi 1011581078-0432CCR-11-0509 Epub 2011 Nov 16
Novartis
Kisqalireg (ribociclib)
CDK 46 Inhibitors
Premenopausal HR+ HER2- MBC
Heavily pretreated Relapsed Metastatic Cancer
2016
132 (20 BC)
0-1 (25) 2-3 (42) 4+ (32)
Ribociclib 50 mg ranging up to 1200 mg dose escalation
23 PRndashincluded 1 in BC (5 of BC pts)
27 Gr34 Neutropenia17 Gr34 Leucopenia
Peak sales projected at $25B
Infante JR Cassier PA Gerecitano JF Witteveen PO Chugh R Ribrag V Chakraborty A Matano A Dobson JR Crystal AS Parasuraman S Shapiro GI A Phase I Study of the Cyclin-Dependent Kinase 46 Inhibitor Ribociclib (LEE011) in Patients with Advanced Solid Tumors and Lymphomas Clin Cancer Res 2016 Dec 122(23)5696-5705 Epub 2016 Aug 19
Eli Lilly
Verzenioreg (abemaciclib)
CDK 46 Inhibitors
HR+HER2minusMBC
Heavily pretreated Relapsed Metastatic Cancer
2016
12 (1 BC)
1 (312) 2 (212) 3+ (7)
Abemaciclib 100 mg ranging up to 200 mg dose escalation
17 PR (included 1 in BC)
17 Gr34 Neutropenia33 Gr34 Leucopenia
Peak sales projected at $2B
Fujiwara Y Tamura K Kondo S Tanabe Y Iwasa S Shimomura A Kitano S Ogasawara K Turner PK Mori J Asou H Chan EM Yamamoto N Phase 1 study of abemaciclib an inhibitor of CDK 4 and 6 as a single agent for Japanese patients with advanced cancer Cancer Chemother Pharmacol 2016 Aug78(2)281-8 doi 101007s00280-016-3085-8 Epub 2016 Jun 16
Mukai H Saeki T Shimada K Naito Y Matsubara N Nakanishi T Obaishi H Namiki M Sasaki Y Phase 1 combination study of eribulin mesylate with trastuzumab for advanced or recurrent human epidermal growth factor receptor 2 positive breast cancer Invest New Drugs 2015 Feb33(1)119-27
AstraZeneca
Lynparza (Olaparib)+ Cediranib
PARP inhibitor+ inhibitor of VEGF RTK
HR+ HER2- MBC
BC amp OC
13
28 (8 BC)
3 for BC
Olaparib (a poly (ADP-ribose) polymerase (PARP) inhibitor) amp Cediranib (Vascular endothelial growth factor receptor (VEGFR) 1 2 and 3 tyrosine kinase inhibitor)3 at dose level (DL) 0 (cediranib 20mg olaparib 100mg) 3 at DL1 (cediranib 20mg olaparib 200mg) 7 at DL2 (cediranib 30mg olaparib 200mg) 6 at DL3 (cediranib 30mg olaparib 400mg)
Liu JF Tolaney SM Birrer M Fleming GF Buss MK Dahlberg SE Lee H Whalen C Tyburski K Winer E Ivy P Matulonis UA A Phase 1 trial of the poly(ADP-ribose) polymerase inhibitor olaparib (AZD2281) in combination with the anti-angiogenic cediranib (AZD2171) in recurrent epithelial ovarian or triple-negative breast cancer Eur J Cancer 2013 Sep49(14)2972-8
ReyonPharma
VM206RY
Heterologous prime-boost with a truncated HER2 sequence
HER2+ Stg IIIampIV BC
15
9
2 chemo
Plasmid DNA (pHM-GM-CSF expressing truncated HER2 amp GM-CSF) amp adenoviral vector (Ad-HM containing modified HER2) (2 4 and 8 mgpatientvisit) of pHM-GM-CSF 3x IM weeks 0 2 and 4 Ad-HM 3 times 109 virus particles at week 6
11 PR
4 pts 7 minor AEs
Unclear
Kim SB Ahn JH Kim J Jung KH A phase 1 study of a heterologous prime-boost vaccination involving a truncated HER2 sequence in patients with HER2-expressing breast cancer Mol Ther Methods Clin Dev 2015 Sep 30215031 doi 101038mtm201531 eCollection 2015
Rodon J Peacuterez-Fidalgo A Krop IE Burris H Guerrero-Zotano A Britten CD Becerra C Schellens J Richards DA Schuler M Abu-Khalaf M Johnson FM Ranson M Edenfield J Silva AP Hackl W Quadt C Demanse D Duval V Baselga J Phase 11b dose escalation and expansion study of BEZ235 a dual PI3KmTOR inhibitor in patients with advanced solid tumors including patients with advanced breast cancer Cancer Chemother Pharmacol 2018 Jun 7 doi 101007s00280-018-3610-z [Epub ahead of print]
Celgene(Abraxane)
Gemcitabine + Abraxane (nab-paclitaxel)
Chemo+ Chemo
OC BC NSCLC PC + LC OC BC KS
MBC
16
9
Adjuv chemo (100)chemo post-adjuv (33)
Gem (nucleoside metabolic inhibitor 1250 mgm2) on days 1 and 8 nab-Pac (microtubule inhibitor) starting dose of 180 mgm2 (cohort 1) 220 mgm2 (cohort 2) and 260 mgm2 (cohort 3) on day 1 of the 21-day cycle using a 3 + 3 design
0
MTD not reached29 Gr3 Neutropenia59 Gr1 Peripheralneuropathy
Yoshitomi S Taira N Doihara H Mizoo T Nogami T Iwamoto T Motoki T Shien T Ogasawara Y Matsuoka J Tsuji H Mitsuhashi T A phase 1 dose-finding and pharmacokinetic study of gemcitabine with nab-paclitaxel in patients with metastatic breast cancer Cancer Chemother Pharmacol 2016 Aug78(2)289-94
Eli Lilly
Erbituxreg (cetuximab) + Taxane
EGFR inhibitor antineoplastic agent + Chemo
Head amp NeckColorectal
TNBC
07-10
18
1 chemo
Cetuximab (epidermal growth factor receptor (EGFR) antagonist ) an initial loading dose of cetuximab 400 mgm2 followed by a weekly dose of 250 mgm2Paclitaxel (microtubule inhibitor) 80 mgm2 or Docetaxel at an initial dose of 30 mgm2 was administered weekly
56 CR 22 PR
83 Dermatologic toxicity11 Grade3+
Nechushtan H Vainer G Stainberg H Salmon AY Hamburger T Peretz T A phase 12 of a combination of cetuximab and taxane for triple negative breast cancer patients Breast 2014 Aug23(4)435-8
Polyphor
Balixafortide (POL6326) + eribulin
CXCR4 antagonist + tubulin-based antimitotic
Heavily pretreatedRelapsed MBC
14-16
56
3rd line 3 chemo
3+3 dose escalation The highest dose was established as eribulin 14 mgmsup2 on days 2 and 9 and balixafortide 55 mgkg on days 1minus3 and 8minus10 of the 21-day cycle
30 PR
41 Gr34 Neutropenia11 Gr34 Leucopenia11 Gr34 Febrileneutropenia2 Related mortalities
42018 Fast Track (HER2-MBC failed 2 prior regimens)
Pernas S Martin M Kaufman PA Gil-Martin M Gomez Pardo P Lopez-Tarruella S Manso L Ciruelos E Perez-Fidalgo JA Hernando C Ademuyiwa FO Weilbaecher K Mayer I Pluard TJ Martinez Garcia M Vahdat L Perez-Garcia J Wach A Barker D Fung S Romagnoli B Cortes J Balixafortide plus eribulin in HER2-negative metastatic breast cancer a phase 1 single-arm dose-escalation trial Lancet Oncol 2018 Jun19(6)812-824
1 PRndashbut only + letrozoleNo Resp on monotherapy
61 Gr34 Neutropenia39 Gr34 Leucopenia
$933M (1Q18)$31B (2017)
Tamura K Mukai H Naito Y Yonemori K Kodaira M Tanabe Y Yamamoto N Osera S Sasaki M Mori Y Hashigaki S Nagasawa T Umeyama Y Yoshino T Phase I study of palbociclib a cyclin-dependent kinase 46 inhibitor in Japanese patients Cancer Sci 2016 Jun107(6)755-63 doi 101111cas12932 Epub 2016 May 11
Pfizer
Ibrancereg (palbociclib)
CDK 46 Inhibitor
HR+ HER2- MBC
Heavily pretreatedRelapsed Met Cancer
04-08
41 (5 BC)
chemo naiumlve (17)1-2(51) 3(29) 3+(2)
Palbociclib 25-150 mg dose ranging
0
20 Gr34 Neutropenia23 Gr34 Leucopenia
$933M (1Q18)$31B (2017)
Flaherty KT Lorusso PM Demichele A Abramson VG Courtney R Randolph SS Shaik MN Wilner KD ODwyer PJ Schwartz GK Phase I dose-escalation trial of the oral cyclin-dependent kinase 46 inhibitor PD 0332991 administered using a 21-day schedule in patients with advanced cancer Clin Cancer Res 2012 Jan 1518(2)568-76 doi 1011581078-0432CCR-11-0509 Epub 2011 Nov 16
Novartis
Kisqalireg (ribociclib)
CDK 46 Inhibitor
Premenopausal HR+ HER2- MBC
Heavily pretreatedRelapsed Met Cancer
16
132 (20 BC)
0-1 (25) 2-3 (42)4+ (32)
Ribociclib 50 mg ranging up to 1200 mg dose escalation
23 PR-included 1 BC (5 of BC pts)
27 Gr34 Neutropenia17 Gr34 Leucopenia
Peak sales est at $25B
Infante JR Cassier PA Gerecitano JF Witteveen PO Chugh R Ribrag V Chakraborty A Matano A Dobson JR Crystal AS Parasuraman S Shapiro GI A Phase I Study of the Cyclin-Dependent Kinase 46 Inhibitor Ribociclib (LEE011) in Patients with Advanced Solid Tumors and Lymphomas Clin Cancer Res 2016 Dec 122(23)5696-5705 Epub 2016 Aug 19
Eli Lilly
Verzenioreg (abemaciclib)
CDK 46 Inhibitor
HR+HER2minusMBC
Heavily pretreatedRelapsed Met Cancer
16
12 (1 BC)
1 (312) 2 (212) 3+(7)
Abemaciclib 100 mg ranging up to 200 mg dose escalation
17 PR (included 1 BC)
17 Gr34 Neutropenia33 Gr34 Leucopenia
Peak sales est at $2B
Fujiwara Y Tamura K Kondo S Tanabe Y Iwasa S Shimomura A Kitano S Ogasawara K Turner PK Mori J Asou H Chan EM Yamamoto N Phase 1 study of abemaciclib an inhibitor of CDK 4 and 6 as a single agent for Japanese patients with advanced cancer Cancer Chemother Pharmacol 2016 Aug78(2)281-8 doi 101007s00280-016-3085-8 Epub 2016 Jun 16
Currently in discussions with potential partnersPhase II Bria-IMTtrade plus Additional Combinations (1Q19 4Q22)(eg PD-1 Inhibitor PD-L1 inhibitor anti-CTLA4 anti-GITR anti-OX40)
1Q 2Q 3Q 4Q
2023
Bria-OTStrade Off-The-Shelf Personalized ImmunotherapyMonotherapy and Potential Partnered Combo Therapy
(2H19 Ongoing)
Bria-OTStradeOff-the-Shelf Cell Line cGMP Manufacturing
and BriaDXtrade(1Q18 1Q19)
Registration Studies (1Q20 2H22)Bria-IMTtrade with Checkpoint InhibitorsBria-OTStrade +- Checkpoint Inhibitors
34
Immuno-oncology Deals
Recent deals of small biotechs with big pharma in immuno-oncology
35
Date PartnershipDevelopment stage at the time of the deal Deal size
07122018 Immatics-Genmab Preclinical Up to $28B
04042018 OSE Immunotherapeutics-Boehringer Ingelheim Preclinical Up to euro113B ($139B)
02092018 Pieris Pharmaceuticals-Seattle Genetics Preclinical Up to $123B
2142018 Nektar-BMS Ph III Up to $36B
01222018 Juno-Celgene Ph II $9B (Acquisition)
11142017 Loxo-Bayer Larotrectinib (Ph II) LOXO-195 (Ph III) Up to $155B
1032017 CytomX-Amgen Preclinical Up to $15B
03202017 CytomX--BMS Ph III Up to $36B
6282016 Xencor-Novartis Preclinical Up to $24B
Early Stage Clinical Studies (Comparison)
We compared the interim data of Ph IIIa study of Bria-IMTtrade in advanced breast cancer with thedata in the early stage clinical studies of recently approved breast cancer drugs and one fasttracked product candidate
Apples to apples comparison Early Stage Clinical Studies in oncology are typically done in patientswith no other therapeutic options Thus the patients have very advanced disease and response ratesare typically quite low
The patients in our Ph IIIa study have been heavily pre-treated (median 45 prior regimens)Some recent studies of relevance in breast cancer are noted in the following slides
36
Breast Cancer Market Opportunity
Drug Technology Approved for Market (US)Ibrance (palbociclib) CDK 46 Inhibitor HR+HER2- MBC in combination with
fluvestrant or aromatase inhibitor$933M in 1Q2018 $3126M in 2017
Kisqali (ribociclib) CDK 46 Inhibitor 2017 HR+HER2- MBC in combination with fluvestrant or aromatase inhibitor
Peak sales projected at $25B
Verzenio (abemaciclib) CDK 46 Inhibitor 2017 HR+HER2- MBC in combination with fluvestrant or aromatase inhibitor
balixafortide CXCR4 antagonist Fast track designation in 2018 for HER2- MBC who have failed 2 prior regimens
The market for breast cancer drugs is a multibillion dollar market with new drugs being approvedon an ongoing basis indicating the shortage of safe and effective treatments for this deadly disease
37
Competitors- Phase III Clinical Data Bria-IMTtrade shows superior safety and similar to superior efficacy data compared with those of the multi-billion dollar drugs when they were at a similar early stage of clinical development
Injection site reactions No related SAEs or SUSARs
Tumor vol darr ampor darr circul tumor cellsAll Comers 21(419) 26(519)One or More HLA matches 27(415) 33(515)Two or More HLA matches 50 (24) 75 (34)
Sheet1 (3)
Comp -Slides
Data
HLA (2)
HLA
Data (Ph1-2+4Pt)
Competitors (2018)-Slide
Competitors (2018)
In the Pipeline Protein Kinase C delta (PKCδ) Inhibitors
30 of all human malignancies display activating RAS mutations Another 60 showing over-activity of Ras-signaling pathways
Ras has been termed ldquoundruggablerdquo (no one has been able to make a Ras inhibitor drug)
BriaCellrsquos novel proprietary PKCδ inhibitors have shown activity against multiple RAS transformed tumors Lung cancer Melanoma Breast cancer Neuroendocrine cancer Pancreatic cancer Colorectal cancer
This target has an attractive safety profile based on in vivo studies and knock out mouse studies
PKCδ inhibitors should qualify for an accelerated clinical development plan and regulatory pathway
Could be in clinic within 24 months
Cost-Effective Additional Shot-on-Goal and additional partnership opportunities
Early-Stage Preclinical Program
39
Protein Kinase C delta (PKCδ) Inhibitors
Activated PKCδ inhibits RAS degradation which in turn stimulates tumor growth
Koo et al Oncotarget 621328 2016
30 of all human malignancies display activating RASmutations with another 60 showing over-activity of Ras-signaling pathways
BriaCellrsquos novel proprietary PKCδ inhibitors have shownactivity against multiple RAS transformed tumors
This target has an attractive safety profile based on in vivostudies and knock out mouse studies
PKCδ also has potential activity as an immunotherapeuticby blocking TGFβ signaling
PKCδ inhibitors are applicable to specific niche tumor typeswhich provide an accelerated clinical development plan
Structural aspects of first generation inhibitor rottlerin and staurosporine (pan-PKC activator) were combined to create second generation inhibitor KAM1
Third generation inhibitors such as BJE6-106 have improved potency and selectivity Fourth generation inhibitors under development to optimize drug-like characteristics PKCδ inhibitors lack endothelial cell cytotoxicity amp PKCδ deficient mice develop normally and are fertile Potentially no marked intrinsic toxicity by inhibiting PKCδ
Mukai H Saeki T Shimada K Naito Y Matsubara N Nakanishi T Obaishi H Namiki M Sasaki Y Phase 1 combination study of eribulin mesylate with trastuzumab for advanced or recurrent human epidermal growth factor receptor 2 positive breast cancer Invest New Drugs 2015 Feb33(1)119-27
AstraZeneca
Lynparza (Olaparib) + Cediranib
PARP inhibitor + inhibitor of VEGF receptor tyrosine kinases
HR+ HER2- MBC
BC amp OC
2013
28 (8 BC)
3 for BC
Olaparib (a poly (ADP-ribose) polymerase (PARP) inhibitor) amp Cediranib (Vascular endothelial growth factor receptor (VEGFR) 1 2 and 3 tyrosine kinase inhibitor)3 at dose level (DL) 0 (cediranib 20mg olaparib 100mg) 3 at DL1 (cediranib 20mg olaparib 200mg) 7 at DL2 (cediranib 30mg olaparib 200mg) 6 at DL3 (cediranib 30mg olaparib 400mg)
Liu JF Tolaney SM Birrer M Fleming GF Buss MK Dahlberg SE Lee H Whalen C Tyburski K Winer E Ivy P Matulonis UA A Phase 1 trial of the poly(ADP-ribose) polymerase inhibitor olaparib (AZD2281) in combination with the anti-angiogenic cediranib (AZD2171) in recurrent epithelial ovarian or triple-negative breast cancer Eur J Cancer 2013 Sep49(14)2972-8
Reyon Pharmaceutical
VM206RY
Heterologous prime-boost with a truncated HER2 sequence
HER2+ Stage IIIampIV BC
2015
9
2 chemo
Plasmid DNA (pHM-GM-CSF expressing truncated HER2 amp GM-CSF) amp adenoviral vector (Ad-HM containing modified HER2) (2 4 and 8 mgpatientvisit) of pHM-GM-CSF 3x IM weeks 0 2 and 4 Ad-HM 3 times 109 virus particles at week 6
11 PR
4 pts showed 7 minor AEs
Unclear
Kim SB Ahn JH Kim J Jung KH A phase 1 study of a heterologous prime-boost vaccination involving a truncated HER2 sequence in patients with HER2-expressing breast cancer Mol Ther Methods Clin Dev 2015 Sep 30215031 doi 101038mtm201531 eCollection 2015
Rodon J Peacuterez-Fidalgo A Krop IE Burris H Guerrero-Zotano A Britten CD Becerra C Schellens J Richards DA Schuler M Abu-Khalaf M Johnson FM Ranson M Edenfield J Silva AP Hackl W Quadt C Demanse D Duval V Baselga J Phase 11b dose escalation and expansion study of BEZ235 a dual PI3KmTOR inhibitor in patients with advanced solid tumors including patients with advanced breast cancer Cancer Chemother Pharmacol 2018 Jun 7 doi 101007s00280-018-3610-z [Epub ahead of print]
Celgene (Abraxane)
Gemcitabine + Abraxane (nab-paclitaxel)
Chemo + Chemo
OC BC NSCLC amp Panc cancer + Lung OC BC Kaposi sarcoma
MBC
2016
9
Adjuvant chemo (100)chemo post-adjuvant (33)
Gem (nucleoside metabolic inhibitor 1250 mgm2) on days 1 and 8 nab-Pac (microtubule inhibitor) starting dose of 180 mgm2 (cohort 1) 220 mgm2 (cohort 2) and 260 mgm2 (cohort 3) on day 1 of the 21-day cycle using a 3 + 3 design
0
MTD not reached29 Gr3 Neutropenia59 Gr1 Peripheralneuropathy
Yoshitomi S Taira N Doihara H Mizoo T Nogami T Iwamoto T Motoki T Shien T Ogasawara Y Matsuoka J Tsuji H Mitsuhashi T A phase 1 dose-finding and pharmacokinetic study of gemcitabine with nab-paclitaxel in patients with metastatic breast cancer Cancer Chemother Pharmacol 2016 Aug78(2)289-94
Eli Lilly
Erbituxreg (cetuximab) + Taxane
EGFR inhibitor antineoplastic agent + Chemo
Headamp Neck Colorectal Cancer
TNBC
2007-2010
18
1 chemo
Cetuximab (epidermal growth factor receptor (EGFR) antagonist ) an initial loading dose of cetuximab 400 mgm2 followed by a weekly dose of 250 mgm2Paclitaxel (microtubule inhibitor) 80 mgm2 or Docetaxel at an initial dose of 30 mgm2 was administered weekly
56 CR 22 PR
83 Dermatologic toxicity11 Grade3+
Nechushtan H Vainer G Stainberg H Salmon AY Hamburger T Peretz T A phase 12 of a combination of cetuximab and taxane for triple negative breast cancer patients Breast 2014 Aug23(4)435-8
Polyphor
Balixafortide (POL6326) + eribulin
CXCR4 antagonist + tubulin-based antimitotic
Heavily pretreated Relapsed MBC
2014-2016
56
3rd line 3 chemo
3+3 dose escalation The highest dose was established as eribulin 14 mgmsup2 on days 2 and 9 and balixafortide 55 mgkg on days 1minus3 and 8minus10 of the 21-day cycle
30 PR
41 Gr34 Neutropenia11 Gr34 Leucopenia11 Gr34 Febrileneutropenia2 Related mortalities
Apr 2018 Fast Track for HER2-MBC who have failed 2prior regimens
Pernas S Martin M Kaufman PA Gil-Martin M Gomez Pardo P Lopez-Tarruella S Manso L Ciruelos E Perez-Fidalgo JA Hernando C Ademuyiwa FO Weilbaecher K Mayer I Pluard TJ Martinez Garcia M Vahdat L Perez-Garcia J Wach A Barker D Fung S Romagnoli B Cortes J Balixafortide plus eribulin in HER2-negative metastatic breast cancer a phase 1 single-arm dose-escalation trial Lancet Oncol 2018 Jun19(6)812-824
11 PRndashbut only + letrozole (No Resp on monotherapy)
61 Gr34 Neutropenia39 Gr34 Leucopenia
$933M in 1Q2018 $31B in 2017
Tamura K Mukai H Naito Y Yonemori K Kodaira M Tanabe Y Yamamoto N Osera S Sasaki M Mori Y Hashigaki S Nagasawa T Umeyama Y Yoshino T Phase I study of palbociclib a cyclin-dependent kinase 46 inhibitor in Japanese patients Cancer Sci 2016 Jun107(6)755-63 doi 101111cas12932 Epub 2016 May 11
Pfizer
Ibrancereg (palbociclib)
CDK 46 Inhibitor
HR+ HER2- MBC
Heavily pretreated Relapsed Metastatic Cancer
2004-2008
41 (5 BC)
chemo naiumlve (17) 1-2 (51)3 (29) 3+ (2)
Palbociclib 25-150 mg dose ranging
0
20 Gr34 Neutropenia23 Gr34 Leucopenia
$933M in 1Q2018 $31B in 2017
Flaherty KT Lorusso PM Demichele A Abramson VG Courtney R Randolph SS Shaik MN Wilner KD ODwyer PJ Schwartz GK Phase I dose-escalation trial of the oral cyclin-dependent kinase 46 inhibitor PD 0332991 administered using a 21-day schedule in patients with advanced cancer Clin Cancer Res 2012 Jan 1518(2)568-76 doi 1011581078-0432CCR-11-0509 Epub 2011 Nov 16
Novartis
Kisqalireg (ribociclib)
CDK 46 Inhibitors
Premenopausal HR+ HER2- MBC
Heavily pretreated Relapsed Metastatic Cancer
2016
132 (20 BC)
0-1 (25) 2-3 (42) 4+ (32)
Ribociclib 50 mg ranging up to 1200 mg dose escalation
23 PRndashincluded 1 in BC (5 of BC pts)
27 Gr34 Neutropenia17 Gr34 Leucopenia
Peak sales projected at $25B
Infante JR Cassier PA Gerecitano JF Witteveen PO Chugh R Ribrag V Chakraborty A Matano A Dobson JR Crystal AS Parasuraman S Shapiro GI A Phase I Study of the Cyclin-Dependent Kinase 46 Inhibitor Ribociclib (LEE011) in Patients with Advanced Solid Tumors and Lymphomas Clin Cancer Res 2016 Dec 122(23)5696-5705 Epub 2016 Aug 19
Eli Lilly
Verzenioreg (abemaciclib)
CDK 46 Inhibitors
HR+HER2minusMBC
Heavily pretreated Relapsed Metastatic Cancer
2016
12 (1 BC)
1 (312) 2 (212) 3+ (7)
Abemaciclib 100 mg ranging up to 200 mg dose escalation
17 PR (included 1 in BC)
17 Gr34 Neutropenia33 Gr34 Leucopenia
Peak sales projected at $2B
Fujiwara Y Tamura K Kondo S Tanabe Y Iwasa S Shimomura A Kitano S Ogasawara K Turner PK Mori J Asou H Chan EM Yamamoto N Phase 1 study of abemaciclib an inhibitor of CDK 4 and 6 as a single agent for Japanese patients with advanced cancer Cancer Chemother Pharmacol 2016 Aug78(2)281-8 doi 101007s00280-016-3085-8 Epub 2016 Jun 16
Mukai H Saeki T Shimada K Naito Y Matsubara N Nakanishi T Obaishi H Namiki M Sasaki Y Phase 1 combination study of eribulin mesylate with trastuzumab for advanced or recurrent human epidermal growth factor receptor 2 positive breast cancer Invest New Drugs 2015 Feb33(1)119-27
AstraZeneca
Lynparza (Olaparib)+ Cediranib
PARP inhibitor+ inhibitor of VEGF RTK
HR+ HER2- MBC
BC amp OC
13
28 (8 BC)
3 for BC
Olaparib (a poly (ADP-ribose) polymerase (PARP) inhibitor) amp Cediranib (Vascular endothelial growth factor receptor (VEGFR) 1 2 and 3 tyrosine kinase inhibitor)3 at dose level (DL) 0 (cediranib 20mg olaparib 100mg) 3 at DL1 (cediranib 20mg olaparib 200mg) 7 at DL2 (cediranib 30mg olaparib 200mg) 6 at DL3 (cediranib 30mg olaparib 400mg)
Liu JF Tolaney SM Birrer M Fleming GF Buss MK Dahlberg SE Lee H Whalen C Tyburski K Winer E Ivy P Matulonis UA A Phase 1 trial of the poly(ADP-ribose) polymerase inhibitor olaparib (AZD2281) in combination with the anti-angiogenic cediranib (AZD2171) in recurrent epithelial ovarian or triple-negative breast cancer Eur J Cancer 2013 Sep49(14)2972-8
ReyonPharma
VM206RY
Heterologous prime-boost with a truncated HER2 sequence
HER2+ Stg IIIampIV BC
15
9
2 chemo
Plasmid DNA (pHM-GM-CSF expressing truncated HER2 amp GM-CSF) amp adenoviral vector (Ad-HM containing modified HER2) (2 4 and 8 mgpatientvisit) of pHM-GM-CSF 3x IM weeks 0 2 and 4 Ad-HM 3 times 109 virus particles at week 6
11 PR
4 pts 7 minor AEs
Unclear
Kim SB Ahn JH Kim J Jung KH A phase 1 study of a heterologous prime-boost vaccination involving a truncated HER2 sequence in patients with HER2-expressing breast cancer Mol Ther Methods Clin Dev 2015 Sep 30215031 doi 101038mtm201531 eCollection 2015
Rodon J Peacuterez-Fidalgo A Krop IE Burris H Guerrero-Zotano A Britten CD Becerra C Schellens J Richards DA Schuler M Abu-Khalaf M Johnson FM Ranson M Edenfield J Silva AP Hackl W Quadt C Demanse D Duval V Baselga J Phase 11b dose escalation and expansion study of BEZ235 a dual PI3KmTOR inhibitor in patients with advanced solid tumors including patients with advanced breast cancer Cancer Chemother Pharmacol 2018 Jun 7 doi 101007s00280-018-3610-z [Epub ahead of print]
Celgene(Abraxane)
Gemcitabine + Abraxane (nab-paclitaxel)
Chemo+ Chemo
OC BC NSCLC PC + LC OC BC KS
MBC
16
9
Adjuv chemo (100)chemo post-adjuv (33)
Gem (nucleoside metabolic inhibitor 1250 mgm2) on days 1 and 8 nab-Pac (microtubule inhibitor) starting dose of 180 mgm2 (cohort 1) 220 mgm2 (cohort 2) and 260 mgm2 (cohort 3) on day 1 of the 21-day cycle using a 3 + 3 design
0
MTD not reached29 Gr3 Neutropenia59 Gr1 Peripheralneuropathy
Yoshitomi S Taira N Doihara H Mizoo T Nogami T Iwamoto T Motoki T Shien T Ogasawara Y Matsuoka J Tsuji H Mitsuhashi T A phase 1 dose-finding and pharmacokinetic study of gemcitabine with nab-paclitaxel in patients with metastatic breast cancer Cancer Chemother Pharmacol 2016 Aug78(2)289-94
Eli Lilly
Erbituxreg (cetuximab) + Taxane
EGFR inhibitor antineoplastic agent + Chemo
Head amp NeckColorectal
TNBC
07-10
18
1 chemo
Cetuximab (epidermal growth factor receptor (EGFR) antagonist ) an initial loading dose of cetuximab 400 mgm2 followed by a weekly dose of 250 mgm2Paclitaxel (microtubule inhibitor) 80 mgm2 or Docetaxel at an initial dose of 30 mgm2 was administered weekly
56 CR 22 PR
83 Dermatologic toxicity11 Grade3+
Nechushtan H Vainer G Stainberg H Salmon AY Hamburger T Peretz T A phase 12 of a combination of cetuximab and taxane for triple negative breast cancer patients Breast 2014 Aug23(4)435-8
Polyphor
Balixafortide (POL6326) + eribulin
CXCR4 antagonist + tubulin-based antimitotic
Heavily pretreatedRelapsed MBC
14-16
56
3rd line 3 chemo
3+3 dose escalation The highest dose was established as eribulin 14 mgmsup2 on days 2 and 9 and balixafortide 55 mgkg on days 1minus3 and 8minus10 of the 21-day cycle
30 PR
41 Gr34 Neutropenia11 Gr34 Leucopenia11 Gr34 Febrileneutropenia2 Related mortalities
42018 Fast Track (HER2-MBC failed 2 prior regimens)
Pernas S Martin M Kaufman PA Gil-Martin M Gomez Pardo P Lopez-Tarruella S Manso L Ciruelos E Perez-Fidalgo JA Hernando C Ademuyiwa FO Weilbaecher K Mayer I Pluard TJ Martinez Garcia M Vahdat L Perez-Garcia J Wach A Barker D Fung S Romagnoli B Cortes J Balixafortide plus eribulin in HER2-negative metastatic breast cancer a phase 1 single-arm dose-escalation trial Lancet Oncol 2018 Jun19(6)812-824
1 PRndashbut only + letrozoleNo Resp on monotherapy
61 Gr34 Neutropenia39 Gr34 Leucopenia
$933M (1Q18)$31B (2017)
Tamura K Mukai H Naito Y Yonemori K Kodaira M Tanabe Y Yamamoto N Osera S Sasaki M Mori Y Hashigaki S Nagasawa T Umeyama Y Yoshino T Phase I study of palbociclib a cyclin-dependent kinase 46 inhibitor in Japanese patients Cancer Sci 2016 Jun107(6)755-63 doi 101111cas12932 Epub 2016 May 11
Pfizer
Ibrancereg (palbociclib)
CDK 46 Inhibitor
HR+ HER2- MBC
Heavily pretreatedRelapsed Met Cancer
04-08
41 (5 BC)
chemo naiumlve (17)1-2(51) 3(29) 3+(2)
Palbociclib 25-150 mg dose ranging
0
20 Gr34 Neutropenia23 Gr34 Leucopenia
$933M (1Q18)$31B (2017)
Flaherty KT Lorusso PM Demichele A Abramson VG Courtney R Randolph SS Shaik MN Wilner KD ODwyer PJ Schwartz GK Phase I dose-escalation trial of the oral cyclin-dependent kinase 46 inhibitor PD 0332991 administered using a 21-day schedule in patients with advanced cancer Clin Cancer Res 2012 Jan 1518(2)568-76 doi 1011581078-0432CCR-11-0509 Epub 2011 Nov 16
Novartis
Kisqalireg (ribociclib)
CDK 46 Inhibitor
Premenopausal HR+ HER2- MBC
Heavily pretreatedRelapsed Met Cancer
16
132 (20 BC)
0-1 (25) 2-3 (42)4+ (32)
Ribociclib 50 mg ranging up to 1200 mg dose escalation
23 PR-included 1 BC (5 of BC pts)
27 Gr34 Neutropenia17 Gr34 Leucopenia
Peak sales est at $25B
Infante JR Cassier PA Gerecitano JF Witteveen PO Chugh R Ribrag V Chakraborty A Matano A Dobson JR Crystal AS Parasuraman S Shapiro GI A Phase I Study of the Cyclin-Dependent Kinase 46 Inhibitor Ribociclib (LEE011) in Patients with Advanced Solid Tumors and Lymphomas Clin Cancer Res 2016 Dec 122(23)5696-5705 Epub 2016 Aug 19
Eli Lilly
Verzenioreg (abemaciclib)
CDK 46 Inhibitor
HR+HER2minusMBC
Heavily pretreatedRelapsed Met Cancer
16
12 (1 BC)
1 (312) 2 (212) 3+(7)
Abemaciclib 100 mg ranging up to 200 mg dose escalation
17 PR (included 1 BC)
17 Gr34 Neutropenia33 Gr34 Leucopenia
Peak sales est at $2B
Fujiwara Y Tamura K Kondo S Tanabe Y Iwasa S Shimomura A Kitano S Ogasawara K Turner PK Mori J Asou H Chan EM Yamamoto N Phase 1 study of abemaciclib an inhibitor of CDK 4 and 6 as a single agent for Japanese patients with advanced cancer Cancer Chemother Pharmacol 2016 Aug78(2)281-8 doi 101007s00280-016-3085-8 Epub 2016 Jun 16
41 Gr34 Neutropenia11 Gr34 Leucopenia11 Gr34 Febrileneutropenia2 Related mortalities
30 PRs in combination with Halaven
Bria-IMTTM
24 (safety)19 (efficacy)
Injection site reactions No related SAEs or SUSARs
Tumor vol darr ampor darr circul tumor cellsAll Comers 21(419) 26(519)One or More HLA matches 27(415) 33(515)Two or More HLA matches 50 (24) 75 (34)
Drug
Technology
Approved for
Market (US)
Ibrance (palbociclib)
CDK 46 Inhibitor
HR+HER2- MBC in combination with fluvestrant or aromatase inhibitor
$933M in 1Q2018 $3126M in 2017
Kisqali (ribociclib)
CDK 46 Inhibitor
2017 HR+HER2- MBC in combination with fluvestrant or aromatase inhibitor
Peak sales projected at $25B
Verzenio (abemaciclib)
CDK 46 Inhibitor
2017 HR+HER2- MBC in combination with fluvestrant or aromatase inhibitor
Peak sales projected at $2B
Lynparza (olaparib)
Poly (ADP-ribose) polymerase (PARP) inhibitor
2017 ovarian amp breast cancer
$997M in 2017
Halaven (eribulin mesylate)
Tubulin-based antimitotic
2H2017 3rd line MBC amp liposarcoma
$181M in 2017
balixafortide
CXCR4 antagonist
Fast track designation in 2018 for HER2- MBC who have failed 2 prior regimens
Immuno-oncology Deals
Recent deals of small biotechs with big pharma in immuno-oncology
35
Date PartnershipDevelopment stage at the time of the deal Deal size
07122018 Immatics-Genmab Preclinical Up to $28B
04042018 OSE Immunotherapeutics-Boehringer Ingelheim Preclinical Up to euro113B ($139B)
02092018 Pieris Pharmaceuticals-Seattle Genetics Preclinical Up to $123B
2142018 Nektar-BMS Ph III Up to $36B
01222018 Juno-Celgene Ph II $9B (Acquisition)
11142017 Loxo-Bayer Larotrectinib (Ph II) LOXO-195 (Ph III) Up to $155B
1032017 CytomX-Amgen Preclinical Up to $15B
03202017 CytomX--BMS Ph III Up to $36B
6282016 Xencor-Novartis Preclinical Up to $24B
Early Stage Clinical Studies (Comparison)
We compared the interim data of Ph IIIa study of Bria-IMTtrade in advanced breast cancer with thedata in the early stage clinical studies of recently approved breast cancer drugs and one fasttracked product candidate
Apples to apples comparison Early Stage Clinical Studies in oncology are typically done in patientswith no other therapeutic options Thus the patients have very advanced disease and response ratesare typically quite low
The patients in our Ph IIIa study have been heavily pre-treated (median 45 prior regimens)Some recent studies of relevance in breast cancer are noted in the following slides
36
Breast Cancer Market Opportunity
Drug Technology Approved for Market (US)Ibrance (palbociclib) CDK 46 Inhibitor HR+HER2- MBC in combination with
fluvestrant or aromatase inhibitor$933M in 1Q2018 $3126M in 2017
Kisqali (ribociclib) CDK 46 Inhibitor 2017 HR+HER2- MBC in combination with fluvestrant or aromatase inhibitor
Peak sales projected at $25B
Verzenio (abemaciclib) CDK 46 Inhibitor 2017 HR+HER2- MBC in combination with fluvestrant or aromatase inhibitor
balixafortide CXCR4 antagonist Fast track designation in 2018 for HER2- MBC who have failed 2 prior regimens
The market for breast cancer drugs is a multibillion dollar market with new drugs being approvedon an ongoing basis indicating the shortage of safe and effective treatments for this deadly disease
37
Competitors- Phase III Clinical Data Bria-IMTtrade shows superior safety and similar to superior efficacy data compared with those of the multi-billion dollar drugs when they were at a similar early stage of clinical development
Injection site reactions No related SAEs or SUSARs
Tumor vol darr ampor darr circul tumor cellsAll Comers 21(419) 26(519)One or More HLA matches 27(415) 33(515)Two or More HLA matches 50 (24) 75 (34)
Sheet1 (3)
Comp -Slides
Data
HLA (2)
HLA
Data (Ph1-2+4Pt)
Competitors (2018)-Slide
Competitors (2018)
In the Pipeline Protein Kinase C delta (PKCδ) Inhibitors
30 of all human malignancies display activating RAS mutations Another 60 showing over-activity of Ras-signaling pathways
Ras has been termed ldquoundruggablerdquo (no one has been able to make a Ras inhibitor drug)
BriaCellrsquos novel proprietary PKCδ inhibitors have shown activity against multiple RAS transformed tumors Lung cancer Melanoma Breast cancer Neuroendocrine cancer Pancreatic cancer Colorectal cancer
This target has an attractive safety profile based on in vivo studies and knock out mouse studies
PKCδ inhibitors should qualify for an accelerated clinical development plan and regulatory pathway
Could be in clinic within 24 months
Cost-Effective Additional Shot-on-Goal and additional partnership opportunities
Early-Stage Preclinical Program
39
Protein Kinase C delta (PKCδ) Inhibitors
Activated PKCδ inhibits RAS degradation which in turn stimulates tumor growth
Koo et al Oncotarget 621328 2016
30 of all human malignancies display activating RASmutations with another 60 showing over-activity of Ras-signaling pathways
BriaCellrsquos novel proprietary PKCδ inhibitors have shownactivity against multiple RAS transformed tumors
This target has an attractive safety profile based on in vivostudies and knock out mouse studies
PKCδ also has potential activity as an immunotherapeuticby blocking TGFβ signaling
PKCδ inhibitors are applicable to specific niche tumor typeswhich provide an accelerated clinical development plan
Structural aspects of first generation inhibitor rottlerin and staurosporine (pan-PKC activator) were combined to create second generation inhibitor KAM1
Third generation inhibitors such as BJE6-106 have improved potency and selectivity Fourth generation inhibitors under development to optimize drug-like characteristics PKCδ inhibitors lack endothelial cell cytotoxicity amp PKCδ deficient mice develop normally and are fertile Potentially no marked intrinsic toxicity by inhibiting PKCδ
Mukai H Saeki T Shimada K Naito Y Matsubara N Nakanishi T Obaishi H Namiki M Sasaki Y Phase 1 combination study of eribulin mesylate with trastuzumab for advanced or recurrent human epidermal growth factor receptor 2 positive breast cancer Invest New Drugs 2015 Feb33(1)119-27
AstraZeneca
Lynparza (Olaparib) + Cediranib
PARP inhibitor + inhibitor of VEGF receptor tyrosine kinases
HR+ HER2- MBC
BC amp OC
2013
28 (8 BC)
3 for BC
Olaparib (a poly (ADP-ribose) polymerase (PARP) inhibitor) amp Cediranib (Vascular endothelial growth factor receptor (VEGFR) 1 2 and 3 tyrosine kinase inhibitor)3 at dose level (DL) 0 (cediranib 20mg olaparib 100mg) 3 at DL1 (cediranib 20mg olaparib 200mg) 7 at DL2 (cediranib 30mg olaparib 200mg) 6 at DL3 (cediranib 30mg olaparib 400mg)
Liu JF Tolaney SM Birrer M Fleming GF Buss MK Dahlberg SE Lee H Whalen C Tyburski K Winer E Ivy P Matulonis UA A Phase 1 trial of the poly(ADP-ribose) polymerase inhibitor olaparib (AZD2281) in combination with the anti-angiogenic cediranib (AZD2171) in recurrent epithelial ovarian or triple-negative breast cancer Eur J Cancer 2013 Sep49(14)2972-8
Reyon Pharmaceutical
VM206RY
Heterologous prime-boost with a truncated HER2 sequence
HER2+ Stage IIIampIV BC
2015
9
2 chemo
Plasmid DNA (pHM-GM-CSF expressing truncated HER2 amp GM-CSF) amp adenoviral vector (Ad-HM containing modified HER2) (2 4 and 8 mgpatientvisit) of pHM-GM-CSF 3x IM weeks 0 2 and 4 Ad-HM 3 times 109 virus particles at week 6
11 PR
4 pts showed 7 minor AEs
Unclear
Kim SB Ahn JH Kim J Jung KH A phase 1 study of a heterologous prime-boost vaccination involving a truncated HER2 sequence in patients with HER2-expressing breast cancer Mol Ther Methods Clin Dev 2015 Sep 30215031 doi 101038mtm201531 eCollection 2015
Rodon J Peacuterez-Fidalgo A Krop IE Burris H Guerrero-Zotano A Britten CD Becerra C Schellens J Richards DA Schuler M Abu-Khalaf M Johnson FM Ranson M Edenfield J Silva AP Hackl W Quadt C Demanse D Duval V Baselga J Phase 11b dose escalation and expansion study of BEZ235 a dual PI3KmTOR inhibitor in patients with advanced solid tumors including patients with advanced breast cancer Cancer Chemother Pharmacol 2018 Jun 7 doi 101007s00280-018-3610-z [Epub ahead of print]
Celgene (Abraxane)
Gemcitabine + Abraxane (nab-paclitaxel)
Chemo + Chemo
OC BC NSCLC amp Panc cancer + Lung OC BC Kaposi sarcoma
MBC
2016
9
Adjuvant chemo (100)chemo post-adjuvant (33)
Gem (nucleoside metabolic inhibitor 1250 mgm2) on days 1 and 8 nab-Pac (microtubule inhibitor) starting dose of 180 mgm2 (cohort 1) 220 mgm2 (cohort 2) and 260 mgm2 (cohort 3) on day 1 of the 21-day cycle using a 3 + 3 design
0
MTD not reached29 Gr3 Neutropenia59 Gr1 Peripheralneuropathy
Yoshitomi S Taira N Doihara H Mizoo T Nogami T Iwamoto T Motoki T Shien T Ogasawara Y Matsuoka J Tsuji H Mitsuhashi T A phase 1 dose-finding and pharmacokinetic study of gemcitabine with nab-paclitaxel in patients with metastatic breast cancer Cancer Chemother Pharmacol 2016 Aug78(2)289-94
Eli Lilly
Erbituxreg (cetuximab) + Taxane
EGFR inhibitor antineoplastic agent + Chemo
Headamp Neck Colorectal Cancer
TNBC
2007-2010
18
1 chemo
Cetuximab (epidermal growth factor receptor (EGFR) antagonist ) an initial loading dose of cetuximab 400 mgm2 followed by a weekly dose of 250 mgm2Paclitaxel (microtubule inhibitor) 80 mgm2 or Docetaxel at an initial dose of 30 mgm2 was administered weekly
56 CR 22 PR
83 Dermatologic toxicity11 Grade3+
Nechushtan H Vainer G Stainberg H Salmon AY Hamburger T Peretz T A phase 12 of a combination of cetuximab and taxane for triple negative breast cancer patients Breast 2014 Aug23(4)435-8
Polyphor
Balixafortide (POL6326) + eribulin
CXCR4 antagonist + tubulin-based antimitotic
Heavily pretreated Relapsed MBC
2014-2016
56
3rd line 3 chemo
3+3 dose escalation The highest dose was established as eribulin 14 mgmsup2 on days 2 and 9 and balixafortide 55 mgkg on days 1minus3 and 8minus10 of the 21-day cycle
30 PR
41 Gr34 Neutropenia11 Gr34 Leucopenia11 Gr34 Febrileneutropenia2 Related mortalities
Apr 2018 Fast Track for HER2-MBC who have failed 2prior regimens
Pernas S Martin M Kaufman PA Gil-Martin M Gomez Pardo P Lopez-Tarruella S Manso L Ciruelos E Perez-Fidalgo JA Hernando C Ademuyiwa FO Weilbaecher K Mayer I Pluard TJ Martinez Garcia M Vahdat L Perez-Garcia J Wach A Barker D Fung S Romagnoli B Cortes J Balixafortide plus eribulin in HER2-negative metastatic breast cancer a phase 1 single-arm dose-escalation trial Lancet Oncol 2018 Jun19(6)812-824
11 PRndashbut only + letrozole (No Resp on monotherapy)
61 Gr34 Neutropenia39 Gr34 Leucopenia
$933M in 1Q2018 $31B in 2017
Tamura K Mukai H Naito Y Yonemori K Kodaira M Tanabe Y Yamamoto N Osera S Sasaki M Mori Y Hashigaki S Nagasawa T Umeyama Y Yoshino T Phase I study of palbociclib a cyclin-dependent kinase 46 inhibitor in Japanese patients Cancer Sci 2016 Jun107(6)755-63 doi 101111cas12932 Epub 2016 May 11
Pfizer
Ibrancereg (palbociclib)
CDK 46 Inhibitor
HR+ HER2- MBC
Heavily pretreated Relapsed Metastatic Cancer
2004-2008
41 (5 BC)
chemo naiumlve (17) 1-2 (51)3 (29) 3+ (2)
Palbociclib 25-150 mg dose ranging
0
20 Gr34 Neutropenia23 Gr34 Leucopenia
$933M in 1Q2018 $31B in 2017
Flaherty KT Lorusso PM Demichele A Abramson VG Courtney R Randolph SS Shaik MN Wilner KD ODwyer PJ Schwartz GK Phase I dose-escalation trial of the oral cyclin-dependent kinase 46 inhibitor PD 0332991 administered using a 21-day schedule in patients with advanced cancer Clin Cancer Res 2012 Jan 1518(2)568-76 doi 1011581078-0432CCR-11-0509 Epub 2011 Nov 16
Novartis
Kisqalireg (ribociclib)
CDK 46 Inhibitors
Premenopausal HR+ HER2- MBC
Heavily pretreated Relapsed Metastatic Cancer
2016
132 (20 BC)
0-1 (25) 2-3 (42) 4+ (32)
Ribociclib 50 mg ranging up to 1200 mg dose escalation
23 PRndashincluded 1 in BC (5 of BC pts)
27 Gr34 Neutropenia17 Gr34 Leucopenia
Peak sales projected at $25B
Infante JR Cassier PA Gerecitano JF Witteveen PO Chugh R Ribrag V Chakraborty A Matano A Dobson JR Crystal AS Parasuraman S Shapiro GI A Phase I Study of the Cyclin-Dependent Kinase 46 Inhibitor Ribociclib (LEE011) in Patients with Advanced Solid Tumors and Lymphomas Clin Cancer Res 2016 Dec 122(23)5696-5705 Epub 2016 Aug 19
Eli Lilly
Verzenioreg (abemaciclib)
CDK 46 Inhibitors
HR+HER2minusMBC
Heavily pretreated Relapsed Metastatic Cancer
2016
12 (1 BC)
1 (312) 2 (212) 3+ (7)
Abemaciclib 100 mg ranging up to 200 mg dose escalation
17 PR (included 1 in BC)
17 Gr34 Neutropenia33 Gr34 Leucopenia
Peak sales projected at $2B
Fujiwara Y Tamura K Kondo S Tanabe Y Iwasa S Shimomura A Kitano S Ogasawara K Turner PK Mori J Asou H Chan EM Yamamoto N Phase 1 study of abemaciclib an inhibitor of CDK 4 and 6 as a single agent for Japanese patients with advanced cancer Cancer Chemother Pharmacol 2016 Aug78(2)281-8 doi 101007s00280-016-3085-8 Epub 2016 Jun 16
Mukai H Saeki T Shimada K Naito Y Matsubara N Nakanishi T Obaishi H Namiki M Sasaki Y Phase 1 combination study of eribulin mesylate with trastuzumab for advanced or recurrent human epidermal growth factor receptor 2 positive breast cancer Invest New Drugs 2015 Feb33(1)119-27
AstraZeneca
Lynparza (Olaparib)+ Cediranib
PARP inhibitor+ inhibitor of VEGF RTK
HR+ HER2- MBC
BC amp OC
13
28 (8 BC)
3 for BC
Olaparib (a poly (ADP-ribose) polymerase (PARP) inhibitor) amp Cediranib (Vascular endothelial growth factor receptor (VEGFR) 1 2 and 3 tyrosine kinase inhibitor)3 at dose level (DL) 0 (cediranib 20mg olaparib 100mg) 3 at DL1 (cediranib 20mg olaparib 200mg) 7 at DL2 (cediranib 30mg olaparib 200mg) 6 at DL3 (cediranib 30mg olaparib 400mg)
Liu JF Tolaney SM Birrer M Fleming GF Buss MK Dahlberg SE Lee H Whalen C Tyburski K Winer E Ivy P Matulonis UA A Phase 1 trial of the poly(ADP-ribose) polymerase inhibitor olaparib (AZD2281) in combination with the anti-angiogenic cediranib (AZD2171) in recurrent epithelial ovarian or triple-negative breast cancer Eur J Cancer 2013 Sep49(14)2972-8
ReyonPharma
VM206RY
Heterologous prime-boost with a truncated HER2 sequence
HER2+ Stg IIIampIV BC
15
9
2 chemo
Plasmid DNA (pHM-GM-CSF expressing truncated HER2 amp GM-CSF) amp adenoviral vector (Ad-HM containing modified HER2) (2 4 and 8 mgpatientvisit) of pHM-GM-CSF 3x IM weeks 0 2 and 4 Ad-HM 3 times 109 virus particles at week 6
11 PR
4 pts 7 minor AEs
Unclear
Kim SB Ahn JH Kim J Jung KH A phase 1 study of a heterologous prime-boost vaccination involving a truncated HER2 sequence in patients with HER2-expressing breast cancer Mol Ther Methods Clin Dev 2015 Sep 30215031 doi 101038mtm201531 eCollection 2015
Rodon J Peacuterez-Fidalgo A Krop IE Burris H Guerrero-Zotano A Britten CD Becerra C Schellens J Richards DA Schuler M Abu-Khalaf M Johnson FM Ranson M Edenfield J Silva AP Hackl W Quadt C Demanse D Duval V Baselga J Phase 11b dose escalation and expansion study of BEZ235 a dual PI3KmTOR inhibitor in patients with advanced solid tumors including patients with advanced breast cancer Cancer Chemother Pharmacol 2018 Jun 7 doi 101007s00280-018-3610-z [Epub ahead of print]
Celgene(Abraxane)
Gemcitabine + Abraxane (nab-paclitaxel)
Chemo+ Chemo
OC BC NSCLC PC + LC OC BC KS
MBC
16
9
Adjuv chemo (100)chemo post-adjuv (33)
Gem (nucleoside metabolic inhibitor 1250 mgm2) on days 1 and 8 nab-Pac (microtubule inhibitor) starting dose of 180 mgm2 (cohort 1) 220 mgm2 (cohort 2) and 260 mgm2 (cohort 3) on day 1 of the 21-day cycle using a 3 + 3 design
0
MTD not reached29 Gr3 Neutropenia59 Gr1 Peripheralneuropathy
Yoshitomi S Taira N Doihara H Mizoo T Nogami T Iwamoto T Motoki T Shien T Ogasawara Y Matsuoka J Tsuji H Mitsuhashi T A phase 1 dose-finding and pharmacokinetic study of gemcitabine with nab-paclitaxel in patients with metastatic breast cancer Cancer Chemother Pharmacol 2016 Aug78(2)289-94
Eli Lilly
Erbituxreg (cetuximab) + Taxane
EGFR inhibitor antineoplastic agent + Chemo
Head amp NeckColorectal
TNBC
07-10
18
1 chemo
Cetuximab (epidermal growth factor receptor (EGFR) antagonist ) an initial loading dose of cetuximab 400 mgm2 followed by a weekly dose of 250 mgm2Paclitaxel (microtubule inhibitor) 80 mgm2 or Docetaxel at an initial dose of 30 mgm2 was administered weekly
56 CR 22 PR
83 Dermatologic toxicity11 Grade3+
Nechushtan H Vainer G Stainberg H Salmon AY Hamburger T Peretz T A phase 12 of a combination of cetuximab and taxane for triple negative breast cancer patients Breast 2014 Aug23(4)435-8
Polyphor
Balixafortide (POL6326) + eribulin
CXCR4 antagonist + tubulin-based antimitotic
Heavily pretreatedRelapsed MBC
14-16
56
3rd line 3 chemo
3+3 dose escalation The highest dose was established as eribulin 14 mgmsup2 on days 2 and 9 and balixafortide 55 mgkg on days 1minus3 and 8minus10 of the 21-day cycle
30 PR
41 Gr34 Neutropenia11 Gr34 Leucopenia11 Gr34 Febrileneutropenia2 Related mortalities
42018 Fast Track (HER2-MBC failed 2 prior regimens)
Pernas S Martin M Kaufman PA Gil-Martin M Gomez Pardo P Lopez-Tarruella S Manso L Ciruelos E Perez-Fidalgo JA Hernando C Ademuyiwa FO Weilbaecher K Mayer I Pluard TJ Martinez Garcia M Vahdat L Perez-Garcia J Wach A Barker D Fung S Romagnoli B Cortes J Balixafortide plus eribulin in HER2-negative metastatic breast cancer a phase 1 single-arm dose-escalation trial Lancet Oncol 2018 Jun19(6)812-824
1 PRndashbut only + letrozoleNo Resp on monotherapy
61 Gr34 Neutropenia39 Gr34 Leucopenia
$933M (1Q18)$31B (2017)
Tamura K Mukai H Naito Y Yonemori K Kodaira M Tanabe Y Yamamoto N Osera S Sasaki M Mori Y Hashigaki S Nagasawa T Umeyama Y Yoshino T Phase I study of palbociclib a cyclin-dependent kinase 46 inhibitor in Japanese patients Cancer Sci 2016 Jun107(6)755-63 doi 101111cas12932 Epub 2016 May 11
Pfizer
Ibrancereg (palbociclib)
CDK 46 Inhibitor
HR+ HER2- MBC
Heavily pretreatedRelapsed Met Cancer
04-08
41 (5 BC)
chemo naiumlve (17)1-2(51) 3(29) 3+(2)
Palbociclib 25-150 mg dose ranging
0
20 Gr34 Neutropenia23 Gr34 Leucopenia
$933M (1Q18)$31B (2017)
Flaherty KT Lorusso PM Demichele A Abramson VG Courtney R Randolph SS Shaik MN Wilner KD ODwyer PJ Schwartz GK Phase I dose-escalation trial of the oral cyclin-dependent kinase 46 inhibitor PD 0332991 administered using a 21-day schedule in patients with advanced cancer Clin Cancer Res 2012 Jan 1518(2)568-76 doi 1011581078-0432CCR-11-0509 Epub 2011 Nov 16
Novartis
Kisqalireg (ribociclib)
CDK 46 Inhibitor
Premenopausal HR+ HER2- MBC
Heavily pretreatedRelapsed Met Cancer
16
132 (20 BC)
0-1 (25) 2-3 (42)4+ (32)
Ribociclib 50 mg ranging up to 1200 mg dose escalation
23 PR-included 1 BC (5 of BC pts)
27 Gr34 Neutropenia17 Gr34 Leucopenia
Peak sales est at $25B
Infante JR Cassier PA Gerecitano JF Witteveen PO Chugh R Ribrag V Chakraborty A Matano A Dobson JR Crystal AS Parasuraman S Shapiro GI A Phase I Study of the Cyclin-Dependent Kinase 46 Inhibitor Ribociclib (LEE011) in Patients with Advanced Solid Tumors and Lymphomas Clin Cancer Res 2016 Dec 122(23)5696-5705 Epub 2016 Aug 19
Eli Lilly
Verzenioreg (abemaciclib)
CDK 46 Inhibitor
HR+HER2minusMBC
Heavily pretreatedRelapsed Met Cancer
16
12 (1 BC)
1 (312) 2 (212) 3+(7)
Abemaciclib 100 mg ranging up to 200 mg dose escalation
17 PR (included 1 BC)
17 Gr34 Neutropenia33 Gr34 Leucopenia
Peak sales est at $2B
Fujiwara Y Tamura K Kondo S Tanabe Y Iwasa S Shimomura A Kitano S Ogasawara K Turner PK Mori J Asou H Chan EM Yamamoto N Phase 1 study of abemaciclib an inhibitor of CDK 4 and 6 as a single agent for Japanese patients with advanced cancer Cancer Chemother Pharmacol 2016 Aug78(2)281-8 doi 101007s00280-016-3085-8 Epub 2016 Jun 16
41 Gr34 Neutropenia11 Gr34 Leucopenia11 Gr34 Febrileneutropenia2 Related mortalities
30 PRs in combination with Halaven
Bria-IMTTM
24 (safety)19 (efficacy)
Injection site reactions No related SAEs or SUSARs
Tumor vol darr ampor darr circul tumor cellsAll Comers 21(419) 26(519)One or More HLA matches 27(415) 33(515)Two or More HLA matches 50 (24) 75 (34)
Drug
Technology
Approved for
Market (US)
Ibrance (palbociclib)
CDK 46 Inhibitor
HR+HER2- MBC in combination with fluvestrant or aromatase inhibitor
$933M in 1Q2018 $3126M in 2017
Kisqali (ribociclib)
CDK 46 Inhibitor
2017 HR+HER2- MBC in combination with fluvestrant or aromatase inhibitor
Peak sales projected at $25B
Verzenio (abemaciclib)
CDK 46 Inhibitor
2017 HR+HER2- MBC in combination with fluvestrant or aromatase inhibitor
Peak sales projected at $2B
Lynparza (olaparib)
Poly (ADP-ribose) polymerase (PARP) inhibitor
2017 ovarian amp breast cancer
$997M in 2017
Halaven (eribulin mesylate)
Tubulin-based antimitotic
2H2017 3rd line MBC amp liposarcoma
$181M in 2017
balixafortide
CXCR4 antagonist
Fast track designation in 2018 for HER2- MBC who have failed 2 prior regimens
Early Stage Clinical Studies (Comparison)
We compared the interim data of Ph IIIa study of Bria-IMTtrade in advanced breast cancer with thedata in the early stage clinical studies of recently approved breast cancer drugs and one fasttracked product candidate
Apples to apples comparison Early Stage Clinical Studies in oncology are typically done in patientswith no other therapeutic options Thus the patients have very advanced disease and response ratesare typically quite low
The patients in our Ph IIIa study have been heavily pre-treated (median 45 prior regimens)Some recent studies of relevance in breast cancer are noted in the following slides
36
Breast Cancer Market Opportunity
Drug Technology Approved for Market (US)Ibrance (palbociclib) CDK 46 Inhibitor HR+HER2- MBC in combination with
fluvestrant or aromatase inhibitor$933M in 1Q2018 $3126M in 2017
Kisqali (ribociclib) CDK 46 Inhibitor 2017 HR+HER2- MBC in combination with fluvestrant or aromatase inhibitor
Peak sales projected at $25B
Verzenio (abemaciclib) CDK 46 Inhibitor 2017 HR+HER2- MBC in combination with fluvestrant or aromatase inhibitor
balixafortide CXCR4 antagonist Fast track designation in 2018 for HER2- MBC who have failed 2 prior regimens
The market for breast cancer drugs is a multibillion dollar market with new drugs being approvedon an ongoing basis indicating the shortage of safe and effective treatments for this deadly disease
37
Competitors- Phase III Clinical Data Bria-IMTtrade shows superior safety and similar to superior efficacy data compared with those of the multi-billion dollar drugs when they were at a similar early stage of clinical development
Injection site reactions No related SAEs or SUSARs
Tumor vol darr ampor darr circul tumor cellsAll Comers 21(419) 26(519)One or More HLA matches 27(415) 33(515)Two or More HLA matches 50 (24) 75 (34)
Sheet1 (3)
Comp -Slides
Data
HLA (2)
HLA
Data (Ph1-2+4Pt)
Competitors (2018)-Slide
Competitors (2018)
In the Pipeline Protein Kinase C delta (PKCδ) Inhibitors
30 of all human malignancies display activating RAS mutations Another 60 showing over-activity of Ras-signaling pathways
Ras has been termed ldquoundruggablerdquo (no one has been able to make a Ras inhibitor drug)
BriaCellrsquos novel proprietary PKCδ inhibitors have shown activity against multiple RAS transformed tumors Lung cancer Melanoma Breast cancer Neuroendocrine cancer Pancreatic cancer Colorectal cancer
This target has an attractive safety profile based on in vivo studies and knock out mouse studies
PKCδ inhibitors should qualify for an accelerated clinical development plan and regulatory pathway
Could be in clinic within 24 months
Cost-Effective Additional Shot-on-Goal and additional partnership opportunities
Early-Stage Preclinical Program
39
Protein Kinase C delta (PKCδ) Inhibitors
Activated PKCδ inhibits RAS degradation which in turn stimulates tumor growth
Koo et al Oncotarget 621328 2016
30 of all human malignancies display activating RASmutations with another 60 showing over-activity of Ras-signaling pathways
BriaCellrsquos novel proprietary PKCδ inhibitors have shownactivity against multiple RAS transformed tumors
This target has an attractive safety profile based on in vivostudies and knock out mouse studies
PKCδ also has potential activity as an immunotherapeuticby blocking TGFβ signaling
PKCδ inhibitors are applicable to specific niche tumor typeswhich provide an accelerated clinical development plan
Structural aspects of first generation inhibitor rottlerin and staurosporine (pan-PKC activator) were combined to create second generation inhibitor KAM1
Third generation inhibitors such as BJE6-106 have improved potency and selectivity Fourth generation inhibitors under development to optimize drug-like characteristics PKCδ inhibitors lack endothelial cell cytotoxicity amp PKCδ deficient mice develop normally and are fertile Potentially no marked intrinsic toxicity by inhibiting PKCδ
Mukai H Saeki T Shimada K Naito Y Matsubara N Nakanishi T Obaishi H Namiki M Sasaki Y Phase 1 combination study of eribulin mesylate with trastuzumab for advanced or recurrent human epidermal growth factor receptor 2 positive breast cancer Invest New Drugs 2015 Feb33(1)119-27
AstraZeneca
Lynparza (Olaparib) + Cediranib
PARP inhibitor + inhibitor of VEGF receptor tyrosine kinases
HR+ HER2- MBC
BC amp OC
2013
28 (8 BC)
3 for BC
Olaparib (a poly (ADP-ribose) polymerase (PARP) inhibitor) amp Cediranib (Vascular endothelial growth factor receptor (VEGFR) 1 2 and 3 tyrosine kinase inhibitor)3 at dose level (DL) 0 (cediranib 20mg olaparib 100mg) 3 at DL1 (cediranib 20mg olaparib 200mg) 7 at DL2 (cediranib 30mg olaparib 200mg) 6 at DL3 (cediranib 30mg olaparib 400mg)
Liu JF Tolaney SM Birrer M Fleming GF Buss MK Dahlberg SE Lee H Whalen C Tyburski K Winer E Ivy P Matulonis UA A Phase 1 trial of the poly(ADP-ribose) polymerase inhibitor olaparib (AZD2281) in combination with the anti-angiogenic cediranib (AZD2171) in recurrent epithelial ovarian or triple-negative breast cancer Eur J Cancer 2013 Sep49(14)2972-8
Reyon Pharmaceutical
VM206RY
Heterologous prime-boost with a truncated HER2 sequence
HER2+ Stage IIIampIV BC
2015
9
2 chemo
Plasmid DNA (pHM-GM-CSF expressing truncated HER2 amp GM-CSF) amp adenoviral vector (Ad-HM containing modified HER2) (2 4 and 8 mgpatientvisit) of pHM-GM-CSF 3x IM weeks 0 2 and 4 Ad-HM 3 times 109 virus particles at week 6
11 PR
4 pts showed 7 minor AEs
Unclear
Kim SB Ahn JH Kim J Jung KH A phase 1 study of a heterologous prime-boost vaccination involving a truncated HER2 sequence in patients with HER2-expressing breast cancer Mol Ther Methods Clin Dev 2015 Sep 30215031 doi 101038mtm201531 eCollection 2015
Rodon J Peacuterez-Fidalgo A Krop IE Burris H Guerrero-Zotano A Britten CD Becerra C Schellens J Richards DA Schuler M Abu-Khalaf M Johnson FM Ranson M Edenfield J Silva AP Hackl W Quadt C Demanse D Duval V Baselga J Phase 11b dose escalation and expansion study of BEZ235 a dual PI3KmTOR inhibitor in patients with advanced solid tumors including patients with advanced breast cancer Cancer Chemother Pharmacol 2018 Jun 7 doi 101007s00280-018-3610-z [Epub ahead of print]
Celgene (Abraxane)
Gemcitabine + Abraxane (nab-paclitaxel)
Chemo + Chemo
OC BC NSCLC amp Panc cancer + Lung OC BC Kaposi sarcoma
MBC
2016
9
Adjuvant chemo (100)chemo post-adjuvant (33)
Gem (nucleoside metabolic inhibitor 1250 mgm2) on days 1 and 8 nab-Pac (microtubule inhibitor) starting dose of 180 mgm2 (cohort 1) 220 mgm2 (cohort 2) and 260 mgm2 (cohort 3) on day 1 of the 21-day cycle using a 3 + 3 design
0
MTD not reached29 Gr3 Neutropenia59 Gr1 Peripheralneuropathy
Yoshitomi S Taira N Doihara H Mizoo T Nogami T Iwamoto T Motoki T Shien T Ogasawara Y Matsuoka J Tsuji H Mitsuhashi T A phase 1 dose-finding and pharmacokinetic study of gemcitabine with nab-paclitaxel in patients with metastatic breast cancer Cancer Chemother Pharmacol 2016 Aug78(2)289-94
Eli Lilly
Erbituxreg (cetuximab) + Taxane
EGFR inhibitor antineoplastic agent + Chemo
Headamp Neck Colorectal Cancer
TNBC
2007-2010
18
1 chemo
Cetuximab (epidermal growth factor receptor (EGFR) antagonist ) an initial loading dose of cetuximab 400 mgm2 followed by a weekly dose of 250 mgm2Paclitaxel (microtubule inhibitor) 80 mgm2 or Docetaxel at an initial dose of 30 mgm2 was administered weekly
56 CR 22 PR
83 Dermatologic toxicity11 Grade3+
Nechushtan H Vainer G Stainberg H Salmon AY Hamburger T Peretz T A phase 12 of a combination of cetuximab and taxane for triple negative breast cancer patients Breast 2014 Aug23(4)435-8
Polyphor
Balixafortide (POL6326) + eribulin
CXCR4 antagonist + tubulin-based antimitotic
Heavily pretreated Relapsed MBC
2014-2016
56
3rd line 3 chemo
3+3 dose escalation The highest dose was established as eribulin 14 mgmsup2 on days 2 and 9 and balixafortide 55 mgkg on days 1minus3 and 8minus10 of the 21-day cycle
30 PR
41 Gr34 Neutropenia11 Gr34 Leucopenia11 Gr34 Febrileneutropenia2 Related mortalities
Apr 2018 Fast Track for HER2-MBC who have failed 2prior regimens
Pernas S Martin M Kaufman PA Gil-Martin M Gomez Pardo P Lopez-Tarruella S Manso L Ciruelos E Perez-Fidalgo JA Hernando C Ademuyiwa FO Weilbaecher K Mayer I Pluard TJ Martinez Garcia M Vahdat L Perez-Garcia J Wach A Barker D Fung S Romagnoli B Cortes J Balixafortide plus eribulin in HER2-negative metastatic breast cancer a phase 1 single-arm dose-escalation trial Lancet Oncol 2018 Jun19(6)812-824
11 PRndashbut only + letrozole (No Resp on monotherapy)
61 Gr34 Neutropenia39 Gr34 Leucopenia
$933M in 1Q2018 $31B in 2017
Tamura K Mukai H Naito Y Yonemori K Kodaira M Tanabe Y Yamamoto N Osera S Sasaki M Mori Y Hashigaki S Nagasawa T Umeyama Y Yoshino T Phase I study of palbociclib a cyclin-dependent kinase 46 inhibitor in Japanese patients Cancer Sci 2016 Jun107(6)755-63 doi 101111cas12932 Epub 2016 May 11
Pfizer
Ibrancereg (palbociclib)
CDK 46 Inhibitor
HR+ HER2- MBC
Heavily pretreated Relapsed Metastatic Cancer
2004-2008
41 (5 BC)
chemo naiumlve (17) 1-2 (51)3 (29) 3+ (2)
Palbociclib 25-150 mg dose ranging
0
20 Gr34 Neutropenia23 Gr34 Leucopenia
$933M in 1Q2018 $31B in 2017
Flaherty KT Lorusso PM Demichele A Abramson VG Courtney R Randolph SS Shaik MN Wilner KD ODwyer PJ Schwartz GK Phase I dose-escalation trial of the oral cyclin-dependent kinase 46 inhibitor PD 0332991 administered using a 21-day schedule in patients with advanced cancer Clin Cancer Res 2012 Jan 1518(2)568-76 doi 1011581078-0432CCR-11-0509 Epub 2011 Nov 16
Novartis
Kisqalireg (ribociclib)
CDK 46 Inhibitors
Premenopausal HR+ HER2- MBC
Heavily pretreated Relapsed Metastatic Cancer
2016
132 (20 BC)
0-1 (25) 2-3 (42) 4+ (32)
Ribociclib 50 mg ranging up to 1200 mg dose escalation
23 PRndashincluded 1 in BC (5 of BC pts)
27 Gr34 Neutropenia17 Gr34 Leucopenia
Peak sales projected at $25B
Infante JR Cassier PA Gerecitano JF Witteveen PO Chugh R Ribrag V Chakraborty A Matano A Dobson JR Crystal AS Parasuraman S Shapiro GI A Phase I Study of the Cyclin-Dependent Kinase 46 Inhibitor Ribociclib (LEE011) in Patients with Advanced Solid Tumors and Lymphomas Clin Cancer Res 2016 Dec 122(23)5696-5705 Epub 2016 Aug 19
Eli Lilly
Verzenioreg (abemaciclib)
CDK 46 Inhibitors
HR+HER2minusMBC
Heavily pretreated Relapsed Metastatic Cancer
2016
12 (1 BC)
1 (312) 2 (212) 3+ (7)
Abemaciclib 100 mg ranging up to 200 mg dose escalation
17 PR (included 1 in BC)
17 Gr34 Neutropenia33 Gr34 Leucopenia
Peak sales projected at $2B
Fujiwara Y Tamura K Kondo S Tanabe Y Iwasa S Shimomura A Kitano S Ogasawara K Turner PK Mori J Asou H Chan EM Yamamoto N Phase 1 study of abemaciclib an inhibitor of CDK 4 and 6 as a single agent for Japanese patients with advanced cancer Cancer Chemother Pharmacol 2016 Aug78(2)281-8 doi 101007s00280-016-3085-8 Epub 2016 Jun 16
Mukai H Saeki T Shimada K Naito Y Matsubara N Nakanishi T Obaishi H Namiki M Sasaki Y Phase 1 combination study of eribulin mesylate with trastuzumab for advanced or recurrent human epidermal growth factor receptor 2 positive breast cancer Invest New Drugs 2015 Feb33(1)119-27
AstraZeneca
Lynparza (Olaparib)+ Cediranib
PARP inhibitor+ inhibitor of VEGF RTK
HR+ HER2- MBC
BC amp OC
13
28 (8 BC)
3 for BC
Olaparib (a poly (ADP-ribose) polymerase (PARP) inhibitor) amp Cediranib (Vascular endothelial growth factor receptor (VEGFR) 1 2 and 3 tyrosine kinase inhibitor)3 at dose level (DL) 0 (cediranib 20mg olaparib 100mg) 3 at DL1 (cediranib 20mg olaparib 200mg) 7 at DL2 (cediranib 30mg olaparib 200mg) 6 at DL3 (cediranib 30mg olaparib 400mg)
Liu JF Tolaney SM Birrer M Fleming GF Buss MK Dahlberg SE Lee H Whalen C Tyburski K Winer E Ivy P Matulonis UA A Phase 1 trial of the poly(ADP-ribose) polymerase inhibitor olaparib (AZD2281) in combination with the anti-angiogenic cediranib (AZD2171) in recurrent epithelial ovarian or triple-negative breast cancer Eur J Cancer 2013 Sep49(14)2972-8
ReyonPharma
VM206RY
Heterologous prime-boost with a truncated HER2 sequence
HER2+ Stg IIIampIV BC
15
9
2 chemo
Plasmid DNA (pHM-GM-CSF expressing truncated HER2 amp GM-CSF) amp adenoviral vector (Ad-HM containing modified HER2) (2 4 and 8 mgpatientvisit) of pHM-GM-CSF 3x IM weeks 0 2 and 4 Ad-HM 3 times 109 virus particles at week 6
11 PR
4 pts 7 minor AEs
Unclear
Kim SB Ahn JH Kim J Jung KH A phase 1 study of a heterologous prime-boost vaccination involving a truncated HER2 sequence in patients with HER2-expressing breast cancer Mol Ther Methods Clin Dev 2015 Sep 30215031 doi 101038mtm201531 eCollection 2015
Rodon J Peacuterez-Fidalgo A Krop IE Burris H Guerrero-Zotano A Britten CD Becerra C Schellens J Richards DA Schuler M Abu-Khalaf M Johnson FM Ranson M Edenfield J Silva AP Hackl W Quadt C Demanse D Duval V Baselga J Phase 11b dose escalation and expansion study of BEZ235 a dual PI3KmTOR inhibitor in patients with advanced solid tumors including patients with advanced breast cancer Cancer Chemother Pharmacol 2018 Jun 7 doi 101007s00280-018-3610-z [Epub ahead of print]
Celgene(Abraxane)
Gemcitabine + Abraxane (nab-paclitaxel)
Chemo+ Chemo
OC BC NSCLC PC + LC OC BC KS
MBC
16
9
Adjuv chemo (100)chemo post-adjuv (33)
Gem (nucleoside metabolic inhibitor 1250 mgm2) on days 1 and 8 nab-Pac (microtubule inhibitor) starting dose of 180 mgm2 (cohort 1) 220 mgm2 (cohort 2) and 260 mgm2 (cohort 3) on day 1 of the 21-day cycle using a 3 + 3 design
0
MTD not reached29 Gr3 Neutropenia59 Gr1 Peripheralneuropathy
Yoshitomi S Taira N Doihara H Mizoo T Nogami T Iwamoto T Motoki T Shien T Ogasawara Y Matsuoka J Tsuji H Mitsuhashi T A phase 1 dose-finding and pharmacokinetic study of gemcitabine with nab-paclitaxel in patients with metastatic breast cancer Cancer Chemother Pharmacol 2016 Aug78(2)289-94
Eli Lilly
Erbituxreg (cetuximab) + Taxane
EGFR inhibitor antineoplastic agent + Chemo
Head amp NeckColorectal
TNBC
07-10
18
1 chemo
Cetuximab (epidermal growth factor receptor (EGFR) antagonist ) an initial loading dose of cetuximab 400 mgm2 followed by a weekly dose of 250 mgm2Paclitaxel (microtubule inhibitor) 80 mgm2 or Docetaxel at an initial dose of 30 mgm2 was administered weekly
56 CR 22 PR
83 Dermatologic toxicity11 Grade3+
Nechushtan H Vainer G Stainberg H Salmon AY Hamburger T Peretz T A phase 12 of a combination of cetuximab and taxane for triple negative breast cancer patients Breast 2014 Aug23(4)435-8
Polyphor
Balixafortide (POL6326) + eribulin
CXCR4 antagonist + tubulin-based antimitotic
Heavily pretreatedRelapsed MBC
14-16
56
3rd line 3 chemo
3+3 dose escalation The highest dose was established as eribulin 14 mgmsup2 on days 2 and 9 and balixafortide 55 mgkg on days 1minus3 and 8minus10 of the 21-day cycle
30 PR
41 Gr34 Neutropenia11 Gr34 Leucopenia11 Gr34 Febrileneutropenia2 Related mortalities
42018 Fast Track (HER2-MBC failed 2 prior regimens)
Pernas S Martin M Kaufman PA Gil-Martin M Gomez Pardo P Lopez-Tarruella S Manso L Ciruelos E Perez-Fidalgo JA Hernando C Ademuyiwa FO Weilbaecher K Mayer I Pluard TJ Martinez Garcia M Vahdat L Perez-Garcia J Wach A Barker D Fung S Romagnoli B Cortes J Balixafortide plus eribulin in HER2-negative metastatic breast cancer a phase 1 single-arm dose-escalation trial Lancet Oncol 2018 Jun19(6)812-824
1 PRndashbut only + letrozoleNo Resp on monotherapy
61 Gr34 Neutropenia39 Gr34 Leucopenia
$933M (1Q18)$31B (2017)
Tamura K Mukai H Naito Y Yonemori K Kodaira M Tanabe Y Yamamoto N Osera S Sasaki M Mori Y Hashigaki S Nagasawa T Umeyama Y Yoshino T Phase I study of palbociclib a cyclin-dependent kinase 46 inhibitor in Japanese patients Cancer Sci 2016 Jun107(6)755-63 doi 101111cas12932 Epub 2016 May 11
Pfizer
Ibrancereg (palbociclib)
CDK 46 Inhibitor
HR+ HER2- MBC
Heavily pretreatedRelapsed Met Cancer
04-08
41 (5 BC)
chemo naiumlve (17)1-2(51) 3(29) 3+(2)
Palbociclib 25-150 mg dose ranging
0
20 Gr34 Neutropenia23 Gr34 Leucopenia
$933M (1Q18)$31B (2017)
Flaherty KT Lorusso PM Demichele A Abramson VG Courtney R Randolph SS Shaik MN Wilner KD ODwyer PJ Schwartz GK Phase I dose-escalation trial of the oral cyclin-dependent kinase 46 inhibitor PD 0332991 administered using a 21-day schedule in patients with advanced cancer Clin Cancer Res 2012 Jan 1518(2)568-76 doi 1011581078-0432CCR-11-0509 Epub 2011 Nov 16
Novartis
Kisqalireg (ribociclib)
CDK 46 Inhibitor
Premenopausal HR+ HER2- MBC
Heavily pretreatedRelapsed Met Cancer
16
132 (20 BC)
0-1 (25) 2-3 (42)4+ (32)
Ribociclib 50 mg ranging up to 1200 mg dose escalation
23 PR-included 1 BC (5 of BC pts)
27 Gr34 Neutropenia17 Gr34 Leucopenia
Peak sales est at $25B
Infante JR Cassier PA Gerecitano JF Witteveen PO Chugh R Ribrag V Chakraborty A Matano A Dobson JR Crystal AS Parasuraman S Shapiro GI A Phase I Study of the Cyclin-Dependent Kinase 46 Inhibitor Ribociclib (LEE011) in Patients with Advanced Solid Tumors and Lymphomas Clin Cancer Res 2016 Dec 122(23)5696-5705 Epub 2016 Aug 19
Eli Lilly
Verzenioreg (abemaciclib)
CDK 46 Inhibitor
HR+HER2minusMBC
Heavily pretreatedRelapsed Met Cancer
16
12 (1 BC)
1 (312) 2 (212) 3+(7)
Abemaciclib 100 mg ranging up to 200 mg dose escalation
17 PR (included 1 BC)
17 Gr34 Neutropenia33 Gr34 Leucopenia
Peak sales est at $2B
Fujiwara Y Tamura K Kondo S Tanabe Y Iwasa S Shimomura A Kitano S Ogasawara K Turner PK Mori J Asou H Chan EM Yamamoto N Phase 1 study of abemaciclib an inhibitor of CDK 4 and 6 as a single agent for Japanese patients with advanced cancer Cancer Chemother Pharmacol 2016 Aug78(2)281-8 doi 101007s00280-016-3085-8 Epub 2016 Jun 16
balixafortide CXCR4 antagonist Fast track designation in 2018 for HER2- MBC who have failed 2 prior regimens
The market for breast cancer drugs is a multibillion dollar market with new drugs being approvedon an ongoing basis indicating the shortage of safe and effective treatments for this deadly disease
37
Competitors- Phase III Clinical Data Bria-IMTtrade shows superior safety and similar to superior efficacy data compared with those of the multi-billion dollar drugs when they were at a similar early stage of clinical development
Injection site reactions No related SAEs or SUSARs
Tumor vol darr ampor darr circul tumor cellsAll Comers 21(419) 26(519)One or More HLA matches 27(415) 33(515)Two or More HLA matches 50 (24) 75 (34)
Sheet1 (3)
Comp -Slides
Data
HLA (2)
HLA
Data (Ph1-2+4Pt)
Competitors (2018)-Slide
Competitors (2018)
In the Pipeline Protein Kinase C delta (PKCδ) Inhibitors
30 of all human malignancies display activating RAS mutations Another 60 showing over-activity of Ras-signaling pathways
Ras has been termed ldquoundruggablerdquo (no one has been able to make a Ras inhibitor drug)
BriaCellrsquos novel proprietary PKCδ inhibitors have shown activity against multiple RAS transformed tumors Lung cancer Melanoma Breast cancer Neuroendocrine cancer Pancreatic cancer Colorectal cancer
This target has an attractive safety profile based on in vivo studies and knock out mouse studies
PKCδ inhibitors should qualify for an accelerated clinical development plan and regulatory pathway
Could be in clinic within 24 months
Cost-Effective Additional Shot-on-Goal and additional partnership opportunities
Early-Stage Preclinical Program
39
Protein Kinase C delta (PKCδ) Inhibitors
Activated PKCδ inhibits RAS degradation which in turn stimulates tumor growth
Koo et al Oncotarget 621328 2016
30 of all human malignancies display activating RASmutations with another 60 showing over-activity of Ras-signaling pathways
BriaCellrsquos novel proprietary PKCδ inhibitors have shownactivity against multiple RAS transformed tumors
This target has an attractive safety profile based on in vivostudies and knock out mouse studies
PKCδ also has potential activity as an immunotherapeuticby blocking TGFβ signaling
PKCδ inhibitors are applicable to specific niche tumor typeswhich provide an accelerated clinical development plan
Structural aspects of first generation inhibitor rottlerin and staurosporine (pan-PKC activator) were combined to create second generation inhibitor KAM1
Third generation inhibitors such as BJE6-106 have improved potency and selectivity Fourth generation inhibitors under development to optimize drug-like characteristics PKCδ inhibitors lack endothelial cell cytotoxicity amp PKCδ deficient mice develop normally and are fertile Potentially no marked intrinsic toxicity by inhibiting PKCδ
Mukai H Saeki T Shimada K Naito Y Matsubara N Nakanishi T Obaishi H Namiki M Sasaki Y Phase 1 combination study of eribulin mesylate with trastuzumab for advanced or recurrent human epidermal growth factor receptor 2 positive breast cancer Invest New Drugs 2015 Feb33(1)119-27
AstraZeneca
Lynparza (Olaparib) + Cediranib
PARP inhibitor + inhibitor of VEGF receptor tyrosine kinases
HR+ HER2- MBC
BC amp OC
2013
28 (8 BC)
3 for BC
Olaparib (a poly (ADP-ribose) polymerase (PARP) inhibitor) amp Cediranib (Vascular endothelial growth factor receptor (VEGFR) 1 2 and 3 tyrosine kinase inhibitor)3 at dose level (DL) 0 (cediranib 20mg olaparib 100mg) 3 at DL1 (cediranib 20mg olaparib 200mg) 7 at DL2 (cediranib 30mg olaparib 200mg) 6 at DL3 (cediranib 30mg olaparib 400mg)
Liu JF Tolaney SM Birrer M Fleming GF Buss MK Dahlberg SE Lee H Whalen C Tyburski K Winer E Ivy P Matulonis UA A Phase 1 trial of the poly(ADP-ribose) polymerase inhibitor olaparib (AZD2281) in combination with the anti-angiogenic cediranib (AZD2171) in recurrent epithelial ovarian or triple-negative breast cancer Eur J Cancer 2013 Sep49(14)2972-8
Reyon Pharmaceutical
VM206RY
Heterologous prime-boost with a truncated HER2 sequence
HER2+ Stage IIIampIV BC
2015
9
2 chemo
Plasmid DNA (pHM-GM-CSF expressing truncated HER2 amp GM-CSF) amp adenoviral vector (Ad-HM containing modified HER2) (2 4 and 8 mgpatientvisit) of pHM-GM-CSF 3x IM weeks 0 2 and 4 Ad-HM 3 times 109 virus particles at week 6
11 PR
4 pts showed 7 minor AEs
Unclear
Kim SB Ahn JH Kim J Jung KH A phase 1 study of a heterologous prime-boost vaccination involving a truncated HER2 sequence in patients with HER2-expressing breast cancer Mol Ther Methods Clin Dev 2015 Sep 30215031 doi 101038mtm201531 eCollection 2015
Rodon J Peacuterez-Fidalgo A Krop IE Burris H Guerrero-Zotano A Britten CD Becerra C Schellens J Richards DA Schuler M Abu-Khalaf M Johnson FM Ranson M Edenfield J Silva AP Hackl W Quadt C Demanse D Duval V Baselga J Phase 11b dose escalation and expansion study of BEZ235 a dual PI3KmTOR inhibitor in patients with advanced solid tumors including patients with advanced breast cancer Cancer Chemother Pharmacol 2018 Jun 7 doi 101007s00280-018-3610-z [Epub ahead of print]
Celgene (Abraxane)
Gemcitabine + Abraxane (nab-paclitaxel)
Chemo + Chemo
OC BC NSCLC amp Panc cancer + Lung OC BC Kaposi sarcoma
MBC
2016
9
Adjuvant chemo (100)chemo post-adjuvant (33)
Gem (nucleoside metabolic inhibitor 1250 mgm2) on days 1 and 8 nab-Pac (microtubule inhibitor) starting dose of 180 mgm2 (cohort 1) 220 mgm2 (cohort 2) and 260 mgm2 (cohort 3) on day 1 of the 21-day cycle using a 3 + 3 design
0
MTD not reached29 Gr3 Neutropenia59 Gr1 Peripheralneuropathy
Yoshitomi S Taira N Doihara H Mizoo T Nogami T Iwamoto T Motoki T Shien T Ogasawara Y Matsuoka J Tsuji H Mitsuhashi T A phase 1 dose-finding and pharmacokinetic study of gemcitabine with nab-paclitaxel in patients with metastatic breast cancer Cancer Chemother Pharmacol 2016 Aug78(2)289-94
Eli Lilly
Erbituxreg (cetuximab) + Taxane
EGFR inhibitor antineoplastic agent + Chemo
Headamp Neck Colorectal Cancer
TNBC
2007-2010
18
1 chemo
Cetuximab (epidermal growth factor receptor (EGFR) antagonist ) an initial loading dose of cetuximab 400 mgm2 followed by a weekly dose of 250 mgm2Paclitaxel (microtubule inhibitor) 80 mgm2 or Docetaxel at an initial dose of 30 mgm2 was administered weekly
56 CR 22 PR
83 Dermatologic toxicity11 Grade3+
Nechushtan H Vainer G Stainberg H Salmon AY Hamburger T Peretz T A phase 12 of a combination of cetuximab and taxane for triple negative breast cancer patients Breast 2014 Aug23(4)435-8
Polyphor
Balixafortide (POL6326) + eribulin
CXCR4 antagonist + tubulin-based antimitotic
Heavily pretreated Relapsed MBC
2014-2016
56
3rd line 3 chemo
3+3 dose escalation The highest dose was established as eribulin 14 mgmsup2 on days 2 and 9 and balixafortide 55 mgkg on days 1minus3 and 8minus10 of the 21-day cycle
30 PR
41 Gr34 Neutropenia11 Gr34 Leucopenia11 Gr34 Febrileneutropenia2 Related mortalities
Apr 2018 Fast Track for HER2-MBC who have failed 2prior regimens
Pernas S Martin M Kaufman PA Gil-Martin M Gomez Pardo P Lopez-Tarruella S Manso L Ciruelos E Perez-Fidalgo JA Hernando C Ademuyiwa FO Weilbaecher K Mayer I Pluard TJ Martinez Garcia M Vahdat L Perez-Garcia J Wach A Barker D Fung S Romagnoli B Cortes J Balixafortide plus eribulin in HER2-negative metastatic breast cancer a phase 1 single-arm dose-escalation trial Lancet Oncol 2018 Jun19(6)812-824
11 PRndashbut only + letrozole (No Resp on monotherapy)
61 Gr34 Neutropenia39 Gr34 Leucopenia
$933M in 1Q2018 $31B in 2017
Tamura K Mukai H Naito Y Yonemori K Kodaira M Tanabe Y Yamamoto N Osera S Sasaki M Mori Y Hashigaki S Nagasawa T Umeyama Y Yoshino T Phase I study of palbociclib a cyclin-dependent kinase 46 inhibitor in Japanese patients Cancer Sci 2016 Jun107(6)755-63 doi 101111cas12932 Epub 2016 May 11
Pfizer
Ibrancereg (palbociclib)
CDK 46 Inhibitor
HR+ HER2- MBC
Heavily pretreated Relapsed Metastatic Cancer
2004-2008
41 (5 BC)
chemo naiumlve (17) 1-2 (51)3 (29) 3+ (2)
Palbociclib 25-150 mg dose ranging
0
20 Gr34 Neutropenia23 Gr34 Leucopenia
$933M in 1Q2018 $31B in 2017
Flaherty KT Lorusso PM Demichele A Abramson VG Courtney R Randolph SS Shaik MN Wilner KD ODwyer PJ Schwartz GK Phase I dose-escalation trial of the oral cyclin-dependent kinase 46 inhibitor PD 0332991 administered using a 21-day schedule in patients with advanced cancer Clin Cancer Res 2012 Jan 1518(2)568-76 doi 1011581078-0432CCR-11-0509 Epub 2011 Nov 16
Novartis
Kisqalireg (ribociclib)
CDK 46 Inhibitors
Premenopausal HR+ HER2- MBC
Heavily pretreated Relapsed Metastatic Cancer
2016
132 (20 BC)
0-1 (25) 2-3 (42) 4+ (32)
Ribociclib 50 mg ranging up to 1200 mg dose escalation
23 PRndashincluded 1 in BC (5 of BC pts)
27 Gr34 Neutropenia17 Gr34 Leucopenia
Peak sales projected at $25B
Infante JR Cassier PA Gerecitano JF Witteveen PO Chugh R Ribrag V Chakraborty A Matano A Dobson JR Crystal AS Parasuraman S Shapiro GI A Phase I Study of the Cyclin-Dependent Kinase 46 Inhibitor Ribociclib (LEE011) in Patients with Advanced Solid Tumors and Lymphomas Clin Cancer Res 2016 Dec 122(23)5696-5705 Epub 2016 Aug 19
Eli Lilly
Verzenioreg (abemaciclib)
CDK 46 Inhibitors
HR+HER2minusMBC
Heavily pretreated Relapsed Metastatic Cancer
2016
12 (1 BC)
1 (312) 2 (212) 3+ (7)
Abemaciclib 100 mg ranging up to 200 mg dose escalation
17 PR (included 1 in BC)
17 Gr34 Neutropenia33 Gr34 Leucopenia
Peak sales projected at $2B
Fujiwara Y Tamura K Kondo S Tanabe Y Iwasa S Shimomura A Kitano S Ogasawara K Turner PK Mori J Asou H Chan EM Yamamoto N Phase 1 study of abemaciclib an inhibitor of CDK 4 and 6 as a single agent for Japanese patients with advanced cancer Cancer Chemother Pharmacol 2016 Aug78(2)281-8 doi 101007s00280-016-3085-8 Epub 2016 Jun 16
Mukai H Saeki T Shimada K Naito Y Matsubara N Nakanishi T Obaishi H Namiki M Sasaki Y Phase 1 combination study of eribulin mesylate with trastuzumab for advanced or recurrent human epidermal growth factor receptor 2 positive breast cancer Invest New Drugs 2015 Feb33(1)119-27
AstraZeneca
Lynparza (Olaparib)+ Cediranib
PARP inhibitor+ inhibitor of VEGF RTK
HR+ HER2- MBC
BC amp OC
13
28 (8 BC)
3 for BC
Olaparib (a poly (ADP-ribose) polymerase (PARP) inhibitor) amp Cediranib (Vascular endothelial growth factor receptor (VEGFR) 1 2 and 3 tyrosine kinase inhibitor)3 at dose level (DL) 0 (cediranib 20mg olaparib 100mg) 3 at DL1 (cediranib 20mg olaparib 200mg) 7 at DL2 (cediranib 30mg olaparib 200mg) 6 at DL3 (cediranib 30mg olaparib 400mg)
Liu JF Tolaney SM Birrer M Fleming GF Buss MK Dahlberg SE Lee H Whalen C Tyburski K Winer E Ivy P Matulonis UA A Phase 1 trial of the poly(ADP-ribose) polymerase inhibitor olaparib (AZD2281) in combination with the anti-angiogenic cediranib (AZD2171) in recurrent epithelial ovarian or triple-negative breast cancer Eur J Cancer 2013 Sep49(14)2972-8
ReyonPharma
VM206RY
Heterologous prime-boost with a truncated HER2 sequence
HER2+ Stg IIIampIV BC
15
9
2 chemo
Plasmid DNA (pHM-GM-CSF expressing truncated HER2 amp GM-CSF) amp adenoviral vector (Ad-HM containing modified HER2) (2 4 and 8 mgpatientvisit) of pHM-GM-CSF 3x IM weeks 0 2 and 4 Ad-HM 3 times 109 virus particles at week 6
11 PR
4 pts 7 minor AEs
Unclear
Kim SB Ahn JH Kim J Jung KH A phase 1 study of a heterologous prime-boost vaccination involving a truncated HER2 sequence in patients with HER2-expressing breast cancer Mol Ther Methods Clin Dev 2015 Sep 30215031 doi 101038mtm201531 eCollection 2015
Rodon J Peacuterez-Fidalgo A Krop IE Burris H Guerrero-Zotano A Britten CD Becerra C Schellens J Richards DA Schuler M Abu-Khalaf M Johnson FM Ranson M Edenfield J Silva AP Hackl W Quadt C Demanse D Duval V Baselga J Phase 11b dose escalation and expansion study of BEZ235 a dual PI3KmTOR inhibitor in patients with advanced solid tumors including patients with advanced breast cancer Cancer Chemother Pharmacol 2018 Jun 7 doi 101007s00280-018-3610-z [Epub ahead of print]
Celgene(Abraxane)
Gemcitabine + Abraxane (nab-paclitaxel)
Chemo+ Chemo
OC BC NSCLC PC + LC OC BC KS
MBC
16
9
Adjuv chemo (100)chemo post-adjuv (33)
Gem (nucleoside metabolic inhibitor 1250 mgm2) on days 1 and 8 nab-Pac (microtubule inhibitor) starting dose of 180 mgm2 (cohort 1) 220 mgm2 (cohort 2) and 260 mgm2 (cohort 3) on day 1 of the 21-day cycle using a 3 + 3 design
0
MTD not reached29 Gr3 Neutropenia59 Gr1 Peripheralneuropathy
Yoshitomi S Taira N Doihara H Mizoo T Nogami T Iwamoto T Motoki T Shien T Ogasawara Y Matsuoka J Tsuji H Mitsuhashi T A phase 1 dose-finding and pharmacokinetic study of gemcitabine with nab-paclitaxel in patients with metastatic breast cancer Cancer Chemother Pharmacol 2016 Aug78(2)289-94
Eli Lilly
Erbituxreg (cetuximab) + Taxane
EGFR inhibitor antineoplastic agent + Chemo
Head amp NeckColorectal
TNBC
07-10
18
1 chemo
Cetuximab (epidermal growth factor receptor (EGFR) antagonist ) an initial loading dose of cetuximab 400 mgm2 followed by a weekly dose of 250 mgm2Paclitaxel (microtubule inhibitor) 80 mgm2 or Docetaxel at an initial dose of 30 mgm2 was administered weekly
56 CR 22 PR
83 Dermatologic toxicity11 Grade3+
Nechushtan H Vainer G Stainberg H Salmon AY Hamburger T Peretz T A phase 12 of a combination of cetuximab and taxane for triple negative breast cancer patients Breast 2014 Aug23(4)435-8
Polyphor
Balixafortide (POL6326) + eribulin
CXCR4 antagonist + tubulin-based antimitotic
Heavily pretreatedRelapsed MBC
14-16
56
3rd line 3 chemo
3+3 dose escalation The highest dose was established as eribulin 14 mgmsup2 on days 2 and 9 and balixafortide 55 mgkg on days 1minus3 and 8minus10 of the 21-day cycle
30 PR
41 Gr34 Neutropenia11 Gr34 Leucopenia11 Gr34 Febrileneutropenia2 Related mortalities
42018 Fast Track (HER2-MBC failed 2 prior regimens)
Pernas S Martin M Kaufman PA Gil-Martin M Gomez Pardo P Lopez-Tarruella S Manso L Ciruelos E Perez-Fidalgo JA Hernando C Ademuyiwa FO Weilbaecher K Mayer I Pluard TJ Martinez Garcia M Vahdat L Perez-Garcia J Wach A Barker D Fung S Romagnoli B Cortes J Balixafortide plus eribulin in HER2-negative metastatic breast cancer a phase 1 single-arm dose-escalation trial Lancet Oncol 2018 Jun19(6)812-824
1 PRndashbut only + letrozoleNo Resp on monotherapy
61 Gr34 Neutropenia39 Gr34 Leucopenia
$933M (1Q18)$31B (2017)
Tamura K Mukai H Naito Y Yonemori K Kodaira M Tanabe Y Yamamoto N Osera S Sasaki M Mori Y Hashigaki S Nagasawa T Umeyama Y Yoshino T Phase I study of palbociclib a cyclin-dependent kinase 46 inhibitor in Japanese patients Cancer Sci 2016 Jun107(6)755-63 doi 101111cas12932 Epub 2016 May 11
Pfizer
Ibrancereg (palbociclib)
CDK 46 Inhibitor
HR+ HER2- MBC
Heavily pretreatedRelapsed Met Cancer
04-08
41 (5 BC)
chemo naiumlve (17)1-2(51) 3(29) 3+(2)
Palbociclib 25-150 mg dose ranging
0
20 Gr34 Neutropenia23 Gr34 Leucopenia
$933M (1Q18)$31B (2017)
Flaherty KT Lorusso PM Demichele A Abramson VG Courtney R Randolph SS Shaik MN Wilner KD ODwyer PJ Schwartz GK Phase I dose-escalation trial of the oral cyclin-dependent kinase 46 inhibitor PD 0332991 administered using a 21-day schedule in patients with advanced cancer Clin Cancer Res 2012 Jan 1518(2)568-76 doi 1011581078-0432CCR-11-0509 Epub 2011 Nov 16
Novartis
Kisqalireg (ribociclib)
CDK 46 Inhibitor
Premenopausal HR+ HER2- MBC
Heavily pretreatedRelapsed Met Cancer
16
132 (20 BC)
0-1 (25) 2-3 (42)4+ (32)
Ribociclib 50 mg ranging up to 1200 mg dose escalation
23 PR-included 1 BC (5 of BC pts)
27 Gr34 Neutropenia17 Gr34 Leucopenia
Peak sales est at $25B
Infante JR Cassier PA Gerecitano JF Witteveen PO Chugh R Ribrag V Chakraborty A Matano A Dobson JR Crystal AS Parasuraman S Shapiro GI A Phase I Study of the Cyclin-Dependent Kinase 46 Inhibitor Ribociclib (LEE011) in Patients with Advanced Solid Tumors and Lymphomas Clin Cancer Res 2016 Dec 122(23)5696-5705 Epub 2016 Aug 19
Eli Lilly
Verzenioreg (abemaciclib)
CDK 46 Inhibitor
HR+HER2minusMBC
Heavily pretreatedRelapsed Met Cancer
16
12 (1 BC)
1 (312) 2 (212) 3+(7)
Abemaciclib 100 mg ranging up to 200 mg dose escalation
17 PR (included 1 BC)
17 Gr34 Neutropenia33 Gr34 Leucopenia
Peak sales est at $2B
Fujiwara Y Tamura K Kondo S Tanabe Y Iwasa S Shimomura A Kitano S Ogasawara K Turner PK Mori J Asou H Chan EM Yamamoto N Phase 1 study of abemaciclib an inhibitor of CDK 4 and 6 as a single agent for Japanese patients with advanced cancer Cancer Chemother Pharmacol 2016 Aug78(2)281-8 doi 101007s00280-016-3085-8 Epub 2016 Jun 16
41 Gr34 Neutropenia11 Gr34 Leucopenia11 Gr34 Febrileneutropenia2 Related mortalities
30 PRs in combination with Halaven
Bria-IMTTM
24 (safety)19 (efficacy)
Injection site reactions No related SAEs or SUSARs
Tumor vol darr ampor darr circul tumor cellsAll Comers 21(419) 26(519)One or More HLA matches 27(415) 33(515)Two or More HLA matches 50 (24) 75 (34)
Drug
Technology
Approved for
Market (US)
Ibrance (palbociclib)
CDK 46 Inhibitor
HR+HER2- MBC in combination with fluvestrant or aromatase inhibitor
$933M in 1Q2018 $3126M in 2017
Kisqali (ribociclib)
CDK 46 Inhibitor
2017 HR+HER2- MBC in combination with fluvestrant or aromatase inhibitor
Peak sales projected at $25B
Verzenio (abemaciclib)
CDK 46 Inhibitor
2017 HR+HER2- MBC in combination with fluvestrant or aromatase inhibitor
Peak sales projected at $2B
Lynparza (olaparib)
Poly (ADP-ribose) polymerase (PARP) inhibitor
2017 ovarian amp breast cancer
$997M in 2017
Halaven (eribulin mesylate)
Tubulin-based antimitotic
2H2017 3rd line MBC amp liposarcoma
$181M in 2017
balixafortide
CXCR4 antagonist
Fast track designation in 2018 for HER2- MBC who have failed 2 prior regimens
Competitors- Phase III Clinical Data Bria-IMTtrade shows superior safety and similar to superior efficacy data compared with those of the multi-billion dollar drugs when they were at a similar early stage of clinical development
Injection site reactions No related SAEs or SUSARs
Tumor vol darr ampor darr circul tumor cellsAll Comers 21(419) 26(519)One or More HLA matches 27(415) 33(515)Two or More HLA matches 50 (24) 75 (34)
Sheet1 (3)
Comp -Slides
Data
HLA (2)
HLA
Data (Ph1-2+4Pt)
Competitors (2018)-Slide
Competitors (2018)
In the Pipeline Protein Kinase C delta (PKCδ) Inhibitors
30 of all human malignancies display activating RAS mutations Another 60 showing over-activity of Ras-signaling pathways
Ras has been termed ldquoundruggablerdquo (no one has been able to make a Ras inhibitor drug)
BriaCellrsquos novel proprietary PKCδ inhibitors have shown activity against multiple RAS transformed tumors Lung cancer Melanoma Breast cancer Neuroendocrine cancer Pancreatic cancer Colorectal cancer
This target has an attractive safety profile based on in vivo studies and knock out mouse studies
PKCδ inhibitors should qualify for an accelerated clinical development plan and regulatory pathway
Could be in clinic within 24 months
Cost-Effective Additional Shot-on-Goal and additional partnership opportunities
Early-Stage Preclinical Program
39
Protein Kinase C delta (PKCδ) Inhibitors
Activated PKCδ inhibits RAS degradation which in turn stimulates tumor growth
Koo et al Oncotarget 621328 2016
30 of all human malignancies display activating RASmutations with another 60 showing over-activity of Ras-signaling pathways
BriaCellrsquos novel proprietary PKCδ inhibitors have shownactivity against multiple RAS transformed tumors
This target has an attractive safety profile based on in vivostudies and knock out mouse studies
PKCδ also has potential activity as an immunotherapeuticby blocking TGFβ signaling
PKCδ inhibitors are applicable to specific niche tumor typeswhich provide an accelerated clinical development plan
Structural aspects of first generation inhibitor rottlerin and staurosporine (pan-PKC activator) were combined to create second generation inhibitor KAM1
Third generation inhibitors such as BJE6-106 have improved potency and selectivity Fourth generation inhibitors under development to optimize drug-like characteristics PKCδ inhibitors lack endothelial cell cytotoxicity amp PKCδ deficient mice develop normally and are fertile Potentially no marked intrinsic toxicity by inhibiting PKCδ
Mukai H Saeki T Shimada K Naito Y Matsubara N Nakanishi T Obaishi H Namiki M Sasaki Y Phase 1 combination study of eribulin mesylate with trastuzumab for advanced or recurrent human epidermal growth factor receptor 2 positive breast cancer Invest New Drugs 2015 Feb33(1)119-27
AstraZeneca
Lynparza (Olaparib) + Cediranib
PARP inhibitor + inhibitor of VEGF receptor tyrosine kinases
HR+ HER2- MBC
BC amp OC
2013
28 (8 BC)
3 for BC
Olaparib (a poly (ADP-ribose) polymerase (PARP) inhibitor) amp Cediranib (Vascular endothelial growth factor receptor (VEGFR) 1 2 and 3 tyrosine kinase inhibitor)3 at dose level (DL) 0 (cediranib 20mg olaparib 100mg) 3 at DL1 (cediranib 20mg olaparib 200mg) 7 at DL2 (cediranib 30mg olaparib 200mg) 6 at DL3 (cediranib 30mg olaparib 400mg)
Liu JF Tolaney SM Birrer M Fleming GF Buss MK Dahlberg SE Lee H Whalen C Tyburski K Winer E Ivy P Matulonis UA A Phase 1 trial of the poly(ADP-ribose) polymerase inhibitor olaparib (AZD2281) in combination with the anti-angiogenic cediranib (AZD2171) in recurrent epithelial ovarian or triple-negative breast cancer Eur J Cancer 2013 Sep49(14)2972-8
Reyon Pharmaceutical
VM206RY
Heterologous prime-boost with a truncated HER2 sequence
HER2+ Stage IIIampIV BC
2015
9
2 chemo
Plasmid DNA (pHM-GM-CSF expressing truncated HER2 amp GM-CSF) amp adenoviral vector (Ad-HM containing modified HER2) (2 4 and 8 mgpatientvisit) of pHM-GM-CSF 3x IM weeks 0 2 and 4 Ad-HM 3 times 109 virus particles at week 6
11 PR
4 pts showed 7 minor AEs
Unclear
Kim SB Ahn JH Kim J Jung KH A phase 1 study of a heterologous prime-boost vaccination involving a truncated HER2 sequence in patients with HER2-expressing breast cancer Mol Ther Methods Clin Dev 2015 Sep 30215031 doi 101038mtm201531 eCollection 2015
Rodon J Peacuterez-Fidalgo A Krop IE Burris H Guerrero-Zotano A Britten CD Becerra C Schellens J Richards DA Schuler M Abu-Khalaf M Johnson FM Ranson M Edenfield J Silva AP Hackl W Quadt C Demanse D Duval V Baselga J Phase 11b dose escalation and expansion study of BEZ235 a dual PI3KmTOR inhibitor in patients with advanced solid tumors including patients with advanced breast cancer Cancer Chemother Pharmacol 2018 Jun 7 doi 101007s00280-018-3610-z [Epub ahead of print]
Celgene (Abraxane)
Gemcitabine + Abraxane (nab-paclitaxel)
Chemo + Chemo
OC BC NSCLC amp Panc cancer + Lung OC BC Kaposi sarcoma
MBC
2016
9
Adjuvant chemo (100)chemo post-adjuvant (33)
Gem (nucleoside metabolic inhibitor 1250 mgm2) on days 1 and 8 nab-Pac (microtubule inhibitor) starting dose of 180 mgm2 (cohort 1) 220 mgm2 (cohort 2) and 260 mgm2 (cohort 3) on day 1 of the 21-day cycle using a 3 + 3 design
0
MTD not reached29 Gr3 Neutropenia59 Gr1 Peripheralneuropathy
Yoshitomi S Taira N Doihara H Mizoo T Nogami T Iwamoto T Motoki T Shien T Ogasawara Y Matsuoka J Tsuji H Mitsuhashi T A phase 1 dose-finding and pharmacokinetic study of gemcitabine with nab-paclitaxel in patients with metastatic breast cancer Cancer Chemother Pharmacol 2016 Aug78(2)289-94
Eli Lilly
Erbituxreg (cetuximab) + Taxane
EGFR inhibitor antineoplastic agent + Chemo
Headamp Neck Colorectal Cancer
TNBC
2007-2010
18
1 chemo
Cetuximab (epidermal growth factor receptor (EGFR) antagonist ) an initial loading dose of cetuximab 400 mgm2 followed by a weekly dose of 250 mgm2Paclitaxel (microtubule inhibitor) 80 mgm2 or Docetaxel at an initial dose of 30 mgm2 was administered weekly
56 CR 22 PR
83 Dermatologic toxicity11 Grade3+
Nechushtan H Vainer G Stainberg H Salmon AY Hamburger T Peretz T A phase 12 of a combination of cetuximab and taxane for triple negative breast cancer patients Breast 2014 Aug23(4)435-8
Polyphor
Balixafortide (POL6326) + eribulin
CXCR4 antagonist + tubulin-based antimitotic
Heavily pretreated Relapsed MBC
2014-2016
56
3rd line 3 chemo
3+3 dose escalation The highest dose was established as eribulin 14 mgmsup2 on days 2 and 9 and balixafortide 55 mgkg on days 1minus3 and 8minus10 of the 21-day cycle
30 PR
41 Gr34 Neutropenia11 Gr34 Leucopenia11 Gr34 Febrileneutropenia2 Related mortalities
Apr 2018 Fast Track for HER2-MBC who have failed 2prior regimens
Pernas S Martin M Kaufman PA Gil-Martin M Gomez Pardo P Lopez-Tarruella S Manso L Ciruelos E Perez-Fidalgo JA Hernando C Ademuyiwa FO Weilbaecher K Mayer I Pluard TJ Martinez Garcia M Vahdat L Perez-Garcia J Wach A Barker D Fung S Romagnoli B Cortes J Balixafortide plus eribulin in HER2-negative metastatic breast cancer a phase 1 single-arm dose-escalation trial Lancet Oncol 2018 Jun19(6)812-824
11 PRndashbut only + letrozole (No Resp on monotherapy)
61 Gr34 Neutropenia39 Gr34 Leucopenia
$933M in 1Q2018 $31B in 2017
Tamura K Mukai H Naito Y Yonemori K Kodaira M Tanabe Y Yamamoto N Osera S Sasaki M Mori Y Hashigaki S Nagasawa T Umeyama Y Yoshino T Phase I study of palbociclib a cyclin-dependent kinase 46 inhibitor in Japanese patients Cancer Sci 2016 Jun107(6)755-63 doi 101111cas12932 Epub 2016 May 11
Pfizer
Ibrancereg (palbociclib)
CDK 46 Inhibitor
HR+ HER2- MBC
Heavily pretreated Relapsed Metastatic Cancer
2004-2008
41 (5 BC)
chemo naiumlve (17) 1-2 (51)3 (29) 3+ (2)
Palbociclib 25-150 mg dose ranging
0
20 Gr34 Neutropenia23 Gr34 Leucopenia
$933M in 1Q2018 $31B in 2017
Flaherty KT Lorusso PM Demichele A Abramson VG Courtney R Randolph SS Shaik MN Wilner KD ODwyer PJ Schwartz GK Phase I dose-escalation trial of the oral cyclin-dependent kinase 46 inhibitor PD 0332991 administered using a 21-day schedule in patients with advanced cancer Clin Cancer Res 2012 Jan 1518(2)568-76 doi 1011581078-0432CCR-11-0509 Epub 2011 Nov 16
Novartis
Kisqalireg (ribociclib)
CDK 46 Inhibitors
Premenopausal HR+ HER2- MBC
Heavily pretreated Relapsed Metastatic Cancer
2016
132 (20 BC)
0-1 (25) 2-3 (42) 4+ (32)
Ribociclib 50 mg ranging up to 1200 mg dose escalation
23 PRndashincluded 1 in BC (5 of BC pts)
27 Gr34 Neutropenia17 Gr34 Leucopenia
Peak sales projected at $25B
Infante JR Cassier PA Gerecitano JF Witteveen PO Chugh R Ribrag V Chakraborty A Matano A Dobson JR Crystal AS Parasuraman S Shapiro GI A Phase I Study of the Cyclin-Dependent Kinase 46 Inhibitor Ribociclib (LEE011) in Patients with Advanced Solid Tumors and Lymphomas Clin Cancer Res 2016 Dec 122(23)5696-5705 Epub 2016 Aug 19
Eli Lilly
Verzenioreg (abemaciclib)
CDK 46 Inhibitors
HR+HER2minusMBC
Heavily pretreated Relapsed Metastatic Cancer
2016
12 (1 BC)
1 (312) 2 (212) 3+ (7)
Abemaciclib 100 mg ranging up to 200 mg dose escalation
17 PR (included 1 in BC)
17 Gr34 Neutropenia33 Gr34 Leucopenia
Peak sales projected at $2B
Fujiwara Y Tamura K Kondo S Tanabe Y Iwasa S Shimomura A Kitano S Ogasawara K Turner PK Mori J Asou H Chan EM Yamamoto N Phase 1 study of abemaciclib an inhibitor of CDK 4 and 6 as a single agent for Japanese patients with advanced cancer Cancer Chemother Pharmacol 2016 Aug78(2)281-8 doi 101007s00280-016-3085-8 Epub 2016 Jun 16
Mukai H Saeki T Shimada K Naito Y Matsubara N Nakanishi T Obaishi H Namiki M Sasaki Y Phase 1 combination study of eribulin mesylate with trastuzumab for advanced or recurrent human epidermal growth factor receptor 2 positive breast cancer Invest New Drugs 2015 Feb33(1)119-27
AstraZeneca
Lynparza (Olaparib)+ Cediranib
PARP inhibitor+ inhibitor of VEGF RTK
HR+ HER2- MBC
BC amp OC
13
28 (8 BC)
3 for BC
Olaparib (a poly (ADP-ribose) polymerase (PARP) inhibitor) amp Cediranib (Vascular endothelial growth factor receptor (VEGFR) 1 2 and 3 tyrosine kinase inhibitor)3 at dose level (DL) 0 (cediranib 20mg olaparib 100mg) 3 at DL1 (cediranib 20mg olaparib 200mg) 7 at DL2 (cediranib 30mg olaparib 200mg) 6 at DL3 (cediranib 30mg olaparib 400mg)
Liu JF Tolaney SM Birrer M Fleming GF Buss MK Dahlberg SE Lee H Whalen C Tyburski K Winer E Ivy P Matulonis UA A Phase 1 trial of the poly(ADP-ribose) polymerase inhibitor olaparib (AZD2281) in combination with the anti-angiogenic cediranib (AZD2171) in recurrent epithelial ovarian or triple-negative breast cancer Eur J Cancer 2013 Sep49(14)2972-8
ReyonPharma
VM206RY
Heterologous prime-boost with a truncated HER2 sequence
HER2+ Stg IIIampIV BC
15
9
2 chemo
Plasmid DNA (pHM-GM-CSF expressing truncated HER2 amp GM-CSF) amp adenoviral vector (Ad-HM containing modified HER2) (2 4 and 8 mgpatientvisit) of pHM-GM-CSF 3x IM weeks 0 2 and 4 Ad-HM 3 times 109 virus particles at week 6
11 PR
4 pts 7 minor AEs
Unclear
Kim SB Ahn JH Kim J Jung KH A phase 1 study of a heterologous prime-boost vaccination involving a truncated HER2 sequence in patients with HER2-expressing breast cancer Mol Ther Methods Clin Dev 2015 Sep 30215031 doi 101038mtm201531 eCollection 2015
Rodon J Peacuterez-Fidalgo A Krop IE Burris H Guerrero-Zotano A Britten CD Becerra C Schellens J Richards DA Schuler M Abu-Khalaf M Johnson FM Ranson M Edenfield J Silva AP Hackl W Quadt C Demanse D Duval V Baselga J Phase 11b dose escalation and expansion study of BEZ235 a dual PI3KmTOR inhibitor in patients with advanced solid tumors including patients with advanced breast cancer Cancer Chemother Pharmacol 2018 Jun 7 doi 101007s00280-018-3610-z [Epub ahead of print]
Celgene(Abraxane)
Gemcitabine + Abraxane (nab-paclitaxel)
Chemo+ Chemo
OC BC NSCLC PC + LC OC BC KS
MBC
16
9
Adjuv chemo (100)chemo post-adjuv (33)
Gem (nucleoside metabolic inhibitor 1250 mgm2) on days 1 and 8 nab-Pac (microtubule inhibitor) starting dose of 180 mgm2 (cohort 1) 220 mgm2 (cohort 2) and 260 mgm2 (cohort 3) on day 1 of the 21-day cycle using a 3 + 3 design
0
MTD not reached29 Gr3 Neutropenia59 Gr1 Peripheralneuropathy
Yoshitomi S Taira N Doihara H Mizoo T Nogami T Iwamoto T Motoki T Shien T Ogasawara Y Matsuoka J Tsuji H Mitsuhashi T A phase 1 dose-finding and pharmacokinetic study of gemcitabine with nab-paclitaxel in patients with metastatic breast cancer Cancer Chemother Pharmacol 2016 Aug78(2)289-94
Eli Lilly
Erbituxreg (cetuximab) + Taxane
EGFR inhibitor antineoplastic agent + Chemo
Head amp NeckColorectal
TNBC
07-10
18
1 chemo
Cetuximab (epidermal growth factor receptor (EGFR) antagonist ) an initial loading dose of cetuximab 400 mgm2 followed by a weekly dose of 250 mgm2Paclitaxel (microtubule inhibitor) 80 mgm2 or Docetaxel at an initial dose of 30 mgm2 was administered weekly
56 CR 22 PR
83 Dermatologic toxicity11 Grade3+
Nechushtan H Vainer G Stainberg H Salmon AY Hamburger T Peretz T A phase 12 of a combination of cetuximab and taxane for triple negative breast cancer patients Breast 2014 Aug23(4)435-8
Polyphor
Balixafortide (POL6326) + eribulin
CXCR4 antagonist + tubulin-based antimitotic
Heavily pretreatedRelapsed MBC
14-16
56
3rd line 3 chemo
3+3 dose escalation The highest dose was established as eribulin 14 mgmsup2 on days 2 and 9 and balixafortide 55 mgkg on days 1minus3 and 8minus10 of the 21-day cycle
30 PR
41 Gr34 Neutropenia11 Gr34 Leucopenia11 Gr34 Febrileneutropenia2 Related mortalities
42018 Fast Track (HER2-MBC failed 2 prior regimens)
Pernas S Martin M Kaufman PA Gil-Martin M Gomez Pardo P Lopez-Tarruella S Manso L Ciruelos E Perez-Fidalgo JA Hernando C Ademuyiwa FO Weilbaecher K Mayer I Pluard TJ Martinez Garcia M Vahdat L Perez-Garcia J Wach A Barker D Fung S Romagnoli B Cortes J Balixafortide plus eribulin in HER2-negative metastatic breast cancer a phase 1 single-arm dose-escalation trial Lancet Oncol 2018 Jun19(6)812-824
1 PRndashbut only + letrozoleNo Resp on monotherapy
61 Gr34 Neutropenia39 Gr34 Leucopenia
$933M (1Q18)$31B (2017)
Tamura K Mukai H Naito Y Yonemori K Kodaira M Tanabe Y Yamamoto N Osera S Sasaki M Mori Y Hashigaki S Nagasawa T Umeyama Y Yoshino T Phase I study of palbociclib a cyclin-dependent kinase 46 inhibitor in Japanese patients Cancer Sci 2016 Jun107(6)755-63 doi 101111cas12932 Epub 2016 May 11
Pfizer
Ibrancereg (palbociclib)
CDK 46 Inhibitor
HR+ HER2- MBC
Heavily pretreatedRelapsed Met Cancer
04-08
41 (5 BC)
chemo naiumlve (17)1-2(51) 3(29) 3+(2)
Palbociclib 25-150 mg dose ranging
0
20 Gr34 Neutropenia23 Gr34 Leucopenia
$933M (1Q18)$31B (2017)
Flaherty KT Lorusso PM Demichele A Abramson VG Courtney R Randolph SS Shaik MN Wilner KD ODwyer PJ Schwartz GK Phase I dose-escalation trial of the oral cyclin-dependent kinase 46 inhibitor PD 0332991 administered using a 21-day schedule in patients with advanced cancer Clin Cancer Res 2012 Jan 1518(2)568-76 doi 1011581078-0432CCR-11-0509 Epub 2011 Nov 16
Novartis
Kisqalireg (ribociclib)
CDK 46 Inhibitor
Premenopausal HR+ HER2- MBC
Heavily pretreatedRelapsed Met Cancer
16
132 (20 BC)
0-1 (25) 2-3 (42)4+ (32)
Ribociclib 50 mg ranging up to 1200 mg dose escalation
23 PR-included 1 BC (5 of BC pts)
27 Gr34 Neutropenia17 Gr34 Leucopenia
Peak sales est at $25B
Infante JR Cassier PA Gerecitano JF Witteveen PO Chugh R Ribrag V Chakraborty A Matano A Dobson JR Crystal AS Parasuraman S Shapiro GI A Phase I Study of the Cyclin-Dependent Kinase 46 Inhibitor Ribociclib (LEE011) in Patients with Advanced Solid Tumors and Lymphomas Clin Cancer Res 2016 Dec 122(23)5696-5705 Epub 2016 Aug 19
Eli Lilly
Verzenioreg (abemaciclib)
CDK 46 Inhibitor
HR+HER2minusMBC
Heavily pretreatedRelapsed Met Cancer
16
12 (1 BC)
1 (312) 2 (212) 3+(7)
Abemaciclib 100 mg ranging up to 200 mg dose escalation
17 PR (included 1 BC)
17 Gr34 Neutropenia33 Gr34 Leucopenia
Peak sales est at $2B
Fujiwara Y Tamura K Kondo S Tanabe Y Iwasa S Shimomura A Kitano S Ogasawara K Turner PK Mori J Asou H Chan EM Yamamoto N Phase 1 study of abemaciclib an inhibitor of CDK 4 and 6 as a single agent for Japanese patients with advanced cancer Cancer Chemother Pharmacol 2016 Aug78(2)281-8 doi 101007s00280-016-3085-8 Epub 2016 Jun 16
41 Gr34 Neutropenia11 Gr34 Leucopenia11 Gr34 Febrileneutropenia2 Related mortalities
30 PRs in combination with Halaven
Bria-IMTTM
24 (safety)19 (efficacy)
Injection site reactions No related SAEs or SUSARs
Tumor vol darr ampor darr circul tumor cellsAll Comers 21(419) 26(519)One or More HLA matches 27(415) 33(515)Two or More HLA matches 50 (24) 75 (34)
Drug
Technology
Approved for
Market (US)
Ibrance (palbociclib)
CDK 46 Inhibitor
HR+HER2- MBC in combination with fluvestrant or aromatase inhibitor
$933M in 1Q2018 $3126M in 2017
Kisqali (ribociclib)
CDK 46 Inhibitor
2017 HR+HER2- MBC in combination with fluvestrant or aromatase inhibitor
Peak sales projected at $25B
Verzenio (abemaciclib)
CDK 46 Inhibitor
2017 HR+HER2- MBC in combination with fluvestrant or aromatase inhibitor
Peak sales projected at $2B
Lynparza (olaparib)
Poly (ADP-ribose) polymerase (PARP) inhibitor
2017 ovarian amp breast cancer
$997M in 2017
Halaven (eribulin mesylate)
Tubulin-based antimitotic
2H2017 3rd line MBC amp liposarcoma
$181M in 2017
balixafortide
CXCR4 antagonist
Fast track designation in 2018 for HER2- MBC who have failed 2 prior regimens
In the Pipeline Protein Kinase C delta (PKCδ) Inhibitors
30 of all human malignancies display activating RAS mutations Another 60 showing over-activity of Ras-signaling pathways
Ras has been termed ldquoundruggablerdquo (no one has been able to make a Ras inhibitor drug)
BriaCellrsquos novel proprietary PKCδ inhibitors have shown activity against multiple RAS transformed tumors Lung cancer Melanoma Breast cancer Neuroendocrine cancer Pancreatic cancer Colorectal cancer
This target has an attractive safety profile based on in vivo studies and knock out mouse studies
PKCδ inhibitors should qualify for an accelerated clinical development plan and regulatory pathway
Could be in clinic within 24 months
Cost-Effective Additional Shot-on-Goal and additional partnership opportunities
Early-Stage Preclinical Program
39
Protein Kinase C delta (PKCδ) Inhibitors
Activated PKCδ inhibits RAS degradation which in turn stimulates tumor growth
Koo et al Oncotarget 621328 2016
30 of all human malignancies display activating RASmutations with another 60 showing over-activity of Ras-signaling pathways
BriaCellrsquos novel proprietary PKCδ inhibitors have shownactivity against multiple RAS transformed tumors
This target has an attractive safety profile based on in vivostudies and knock out mouse studies
PKCδ also has potential activity as an immunotherapeuticby blocking TGFβ signaling
PKCδ inhibitors are applicable to specific niche tumor typeswhich provide an accelerated clinical development plan
Structural aspects of first generation inhibitor rottlerin and staurosporine (pan-PKC activator) were combined to create second generation inhibitor KAM1
Third generation inhibitors such as BJE6-106 have improved potency and selectivity Fourth generation inhibitors under development to optimize drug-like characteristics PKCδ inhibitors lack endothelial cell cytotoxicity amp PKCδ deficient mice develop normally and are fertile Potentially no marked intrinsic toxicity by inhibiting PKCδ
Structural aspects of first generation inhibitor rottlerin and staurosporine (pan-PKC activator) were combined to create second generation inhibitor KAM1
Third generation inhibitors such as BJE6-106 have improved potency and selectivity Fourth generation inhibitors under development to optimize drug-like characteristics PKCδ inhibitors lack endothelial cell cytotoxicity amp PKCδ deficient mice develop normally and are fertile Potentially no marked intrinsic toxicity by inhibiting PKCδ
In the Pipeline Protein Kinase C delta (PKCδ) Inhibitors
Protein Kinase C delta (PKCδ) Inhibitors
Protein Kinase C delta (PKCδ) Inhibitors
PKCδ Inhibitors Block Growth in Various Cancers
Structural aspects of first generation inhibitor rottlerin and staurosporine (pan-PKC activator) were combined to create second generation inhibitor KAM1
Third generation inhibitors such as BJE6-106 have improved potency and selectivity Fourth generation inhibitors under development to optimize drug-like characteristics PKCδ inhibitors lack endothelial cell cytotoxicity amp PKCδ deficient mice develop normally and are fertile Potentially no marked intrinsic toxicity by inhibiting PKCδ
