new first-in-kind oral chemotherapeutic targets...

New First-in-Kind Oral Chemotherapeutic Targets Hematologic and Solid Tumor Cancers

Pacylex Pharmaceuticals 1

Overview• Recently discovered mechanism of cancer proliferation

exposes new therapeutic target• Pacylex is developing a rationally designed, first-in-kind, oral,

small molecule target inhibitor with high activity in vitro and in vivo• Lead drug PCLX-001 is water soluble and 93% orally

bioavailable

• The biomarker is lost in 19 cancer cell lines at prevalence ranging from 5-82% and at a much higher prevalence in tumor cells taken from patients• a predictive diagnostic test that identifies cancer patients

with key biomarker also in development

• POC in: DLBCL & AML• Proof-of-efficacy in 4 of 4 hematological cancer mouse

xenografts including one PDX

TeamCEO Michael J. Weickert PhDCSO Luc G. Berthiaume PhDCMO John Mackey, MD, FRCPCCOO Ryan Heit, MSc, MBA

Founded: 2012Non-dilutive capital to date ->$7,200,000 CADFounder capital - $590,000 CAD

Project status: Pre-INDCompleted: Animal efficacy, PK/PD, Biomarker monoclonal antibodyNext steps: pre-IND tox studies, Regulatory filings, Phase I/IIa study

Approximately $3 million in funding required to get to first Phase I clinical trials, $20+ million to finish initial Phase II

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Cancer survival still has a long way to go


Age-Standardised Ten-Year

Net Survival, Selected

Cancers, Adults (Aged 15-99),

England and Wales, 2010-

2011Overview

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Key finding: NMT2 low in poorer prognosis tumours


IM9

BL2

Ram

os

DOHH2

WSU-D

LCL2

0

5000

10000

15000

********* *** ***N

MT

2 m

RN

A c

op

ies/m

g R

NA

Kaplan-Meier plot of progression-free survival 470 DLBCL* patients with high (red) versus low (blue) NMT2 expression

***, P < 0.0001

Diffuse large B-cell lymphoma (DLBCL)

7X 300X

BL DLBCL

Number of NMT2 mRNA copies in various lymphocytic cell lines compared to an immortalized “normal” B cell line (IM9)

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Exit*Diffuse large B-cell lymphoma (DLBCL)

Myristoylation modifies proteins by adding a 14C-fatty acid myristate at their N-terminus- All human cells have two NMTs (NMT1 / NMT2):

• NMT1 and NMT2 are crucial for cell signaling and survival- Over 200 proteins are myristoylated in cells - Abrogation of myristoylation also abrogates proper targeting and function

Co- or post-translational myristoylation Mediates membrane binding

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NMT2 function: Myristoylation enzyme regulating cell homeostasis


TCF/LEF

β-catenin

β-catenin

Frizzled LRP5/6

Dvl

β-catenin

P

P

P

β-TrCP

APC CK1

GSK3

Axin

P

P

P

P

Nkd1CDK1cMycMmp-7…

Nkd1

cMyc CDK1

Mmp-7

Mmp-7

Wnt

Nkd1

Nkd1

NMT2

Wnt On

NMT2 (+) cells

β-catenin

P

P

NMT2 myristoylates Nkd1

Nkd1 localizes to membrane

Nkd1 inhibits Wnt signaling through Dvl and β-catenin

Wnt signaling controlled = Cell homeostasis maintained


Nkd1 is an obligate and universal Wnt-induced negative feedback regulator of the Wnt signaling pathway

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Key finding: NMT2 acts as a tumor suppressor and myristoylates Nkd1 which then can inhibit Wnt signaling


Epigenetic silencing NMT2

No myristoylation of Nkd1

Nkd1 localizes to cytosol not membrane

Wnt signaling up-regulated

Cell proliferation and metastasis

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Proposed Mechanism

Key finding: Loss of NMT2 through epigenetic silencing increases Wnt signaling output

N-myristoyltransferase (NMT) activity is essential for cell viabilityNMT2 deficient cancer cells should be more vulnerable to NMT inhibition

Our strategy: NMT2 silencing makes cancer cells vulnerable

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Normal cell Cancer cell

No treatment

NMT inhibitorTherapy

Normal cell survives NMT2 deficient cancer cell dies


Completely inhibiting

myristoylationselectively induces

apoptosis

PCLX-001 selectively kills cancer cells deficient in NMT2 by disabling myristoylation at a drug concentration to which normal cells are insensitive which initiates apoptosis

PCLX-001 (µM)

Cell viability Apoptosis*

NMT2 Normal Cells NMT2 Deficient Cells

Lead NMT inhibitor PCLX-001:Selectively kills cancer cells deficient in NMT2

Normal cell linesCancer cell lines

*indicated by cleaved PARP-1 and caspase-3

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Exit PCLX-001 has a large therapeutic windowPacylex Pharmaceuticals

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Breath of efficacy (BOE) study* of activity against various cancer cell lines including solid tumor lines: breast, non small cell lung cancer (NSCLC), small cell lung cancer (SCLC)

(*BOE study independently performed by large pharmaceutical company)

Efficacy

Breast AML NSCLC SCLC DLB

CL

Man

tle

Cel

l

PCLX-001 effect on 131 cell lines screened; 94% of cell lines tested are sensitive to PCLX-001(Cell Titer Blue Assay)

PCLX-001 Breadth of Efficacy Study*: Day 6

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PCLX-001 works against multiple cancers in vitro

Pacylex Pharmaceuticals

PCLX-001 dose-response curves for murine subcutaneous xenografts derived

from cell line BL2

PCLX-001 causes complete tumor regression in B cell lymphoma xenografts

0 5 10 150

500

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Vehicle

20mg/kg/day

50mg/kg/day

60mg/kg/day

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Day of study

BL

2 t

um

or

vo

lum

e (

mm

3)

Vehic

le

20m

g/kg/d

ay

50m

g/kg/d

ay

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g/kg/d

ay0

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NM

T s

pecif

ic a

cti

vit

y (

fmo

l/m

in/m

g p

rote

in)

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Total NMT specific activity in BL2 tumor samples


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PCLX-001 dose-response curves for murine xenograft derived from patient

DLBCL3

PCLX-001 causes complete regression of drug resistant* xenograft tumors from DLBCL Patient

Identification of NMT2-deficiency


0 5 10 15 200

500

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1500

2000

20mg/kg/day

50mg/kg/day******

***

Day of study

DL

BC

L3 t

um

or

vo

lum

e (

mm

3)

Vehicle

Diffuse large B-cell lymphoma (DLBCL)

(NMT2+control)

***(P<0.001)

*DLBCL cancer refractory to multiple lines of chemotherapy including CHOP, RICE, and DHAP

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xenograft

Initial Orphan Disease Candidates

North American market AML BL & DLBCLIncidence 20,000 65,000

Average treatment cost $100,000 $30,000

5 year relapse rate ~80% ~60%

Palliative costs per patient $500,000 $500,000

Primary treatment costs ~$2 B ~$3 B

Secondary and Palliative treatment costs ~$8 B ~$20 B


May also be eligible for Fast Track Designation

✓ Animal POC complete

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Tumor type% Cell lines NMT2 null

Burkitt’s lymphoma 82%Diffuse large B-cell Lymphoma 70%Acute myeloid leukaemia 41%Myeloma 36%Ovarian clear-cell carcinoma 29%Transitional cell carcinoma (ureter and bladder cancer) 21%Chronic myelogenous leukaemia 20%Chronic lymphocytic leukaemia 20%Small-cell lung carcinoma 13%Breast carcinoma 12%Colorectal adenocarcinoma 12%Pancreatic adenocarcinoma 9%Ovarian carcinoma 9%Non-small-cell lung carcinoma 8%Osteosarcoma 8%Melanoma 7%Gastric adenocarcinoma 5%Endometrial adenocarcinoma 5%Esophageal squamous carcinoma 5%

IHC based NMT2 Diagnostic test using proprietary monoclonal anti-NMT antibodies is in later phase of development and available if needed.

Frequency of NMT2 deficiency in tumors is higher than that seen in cancer cell lines.

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Frequency of NMT2 Deficiency is ≥ 5% in Cell Lines Originating from 19 Different Cancer Types

Clinical strategy: 3 Phase I/II Studies Planned

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Phase I/IIA oral monotherapy safety and dose escalationPopulation: Pre-treated advanced cancers, esp. DLBC LymphomaDesign: Standard 3+3 dose escalation

Phase IB/IIA oral monotherapy basket trialPopulation: Pre-treated advanced cancers, incl. DLBC Lymphoma, AML, myeloma, small cell lung and colon cancerDesign: RP2D in NMT2lo / sensitive histologies

Phase IB/IIA dose escalation combination basket trialPopulation: Pre-treated advanced cancers, combinations with gemcitabine, doxorubicin or carboplatinDesign: 3+3 PCLX escalation starting 50% RP2D standard dose partners with preclinical synergy


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Phase I/II Part 1

Phase I/II

Part 2

Phase I/II

Part 3Phase III

NDA Prep

FDA Review

IND

3-mo tox

Orphan drug designation

Fast Track designation

NDA submission

NDA approval

EOP2 meeting

Pre-NDA meeting

**Clinical costs do not include CMC/manufacturing, regulatory costs or operating costs

Clinical costs**

$3M $12M $60M


Clinical Development Overview: – Timeline and Clinical Costs

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Year 1 Year 2 Year 3

Based on development and registration of Tagrisso for NSCLC

Additional Advisors:Mark Vickers, LLC: IP CounselJacques Roberge: Chemistry and Manufacturing ControlsJohn Simon: Regulatory Planning

Experienced Team and Knowledgeable Advisors

Luc Berthiaume, PhD – CSO World leader in protein fatty acylation; Founder of Eusera and Pacylex; global distribution experience; 3 patents; commercialized antibody design and production

John Mackey, MD, FRCP – CMO Director of clinical trials at the CCI; Director of TRIO (International clinical trial organization, 200 people); founder of 3 companies including Pacylex; Extensive links to pharma

Ryan Heit, MSc, MBA – COO Technology and business development expert; 20+ companies assisted in early-stage commercialization; founder/co-founder of 4 companies; leads deal screening for VA Angels

Jason Ding – Licensing and TransactionsExpert and experience in Mergers & acquisitions, biotechnology & pharmaceutical partnering, licensing & alliances, corporate finance, valuations & accounting & audits

David Jenish – Drug Development30+ years experience in research and process development for therapeutics

Vanessa Grant - Counsel Counsel with expertise in mergers and acquisitions, corporate governance, and private equity and venture capital Recognized as Chambers Canada: 2017: Life Sciences

Team Advisors

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Michael Weickert, PhD – CEO CEO Sonescence and SEA Medical Systems, CBO, Corium, Stratagent Life Sciences, Therashock, VP Development Auspex, Senior Program Executive, Nektar, Ligand, NCI/NIH


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Established IP with Growing Portfolio

18Pacylex Pharmaceuticals

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• N-myristoyl transferase inhibitors - WO 2010026365 A1 (in-license)• Issued: EP 2323987 A1 and US 9,156,811 B2

• Filing date 2009/08/29

• Issued: US 9828346 B2 • Filing date 2015/08/31

• Synthetic lethality and the treatment of cancer - WO 2013013302 A1 (inventor)• USPTO application 14/234,312, PCT/CA2012/000696• National filing phase, AU & NZ, BR, CN, IL, JP, KR, MX,

RU, SG, ZA, EP, US, and CA• Filing date 2012/07/23

• Synthetic lethality and the treatment of cancer -WO2014067002 (inventor) A1• PCT/CA2013/050821


• Epigenetic silencing of NMT2 – WO2017/011907 (inventor)• PCT/CA2016/050846


Most Likely Exit Through M & A

• Four of top ten pharmaceutical firms already engaged in discussions• Scientific diligence successful at replicating and confirming Pacylex results


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Oncology is THE hot spot

BioPharma Dealmakers, Jun 09, 2017

https://biopharmadealmakers.nature.com/users/9880-biopharma-dealmakers

Investor Summary

• First-in-class, oral, small molecule chemotherapeutic• New mechanism – publication underway• Potentially effective against many cancer types

• Companion diagnostic in development if needed• Pharmaceutical interest and validation – hottest M&A space• Ready for pre-IND tox• First-in-man in ~1 year• Initial investment $1.5M note with matching $1.5M non-

dilutive funds available• Follow with $25M Series A later this year


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Thank you

Contact InfoMichael Weickert, [email protected]

Ryan Heit, MSc, [email protected]


mailto:[email protected]

mailto:[email protected]

new first-in-kind oral chemotherapeutic targets...

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