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Defined Health is pleased to present:

BioEurope Spring25h Annual Cancer Progress Conference BioEurope Spring March 10 – 12, 2014

Turin, Italywww.therapeuticinsight.com

25h Annual Cancer Progress ConferenceMarch 4 – 5, 2014

New York Citywww.cancerprogressbyDH.com

Defined Health will be participating in the following industry events:

Cancer Progress by Defined Health | March 4 - 5, 2014 | New York City | http://www.cancerprogressbyDH.com

Therapeutic Insight by Defined Health at BIO-Europe Spring® | March 10 - 12, 2014 | Turin, Italy | http://dfndhlth com/BES-2014

© Defined Health, 2014Defined Health Oncology Webinar, January 29, 2014

http://dfndhlth.com/BES-2014

A Pre-Cancer Progress 2014 High LevelA Pre Cancer Progress 2014 High Level Snapshot of Challenges & Opportunities in the Oncology Market.gy

Jeffrey M. Bockman, PhD

Vice President

Defined HealthDefined Health

Updated January 29, 2014

A High Level Snapshot of Challenges & Opportunities in the Oncology Market

• The cancer field has been undergoing some significant changes and challenges, especially in this age of premium-priced, targeted therapies: from molecular stratification of patients to the increasing pushback from payers and cancer centers themselves around the cost benefits of new therapies. To some degree, the use of molecularly targeted agents directed to specific patient populations can help overcome market access barriers by providing a stronger efficacy signal and hence meaningful clinical value. The potential downside to the "niche-ification" of cancer is that supporting a sustainable oncology franchise expansion could become more difficult. This talk will explore at a high level how novel targets and trial designs are enabling advances that can provide unique ways for oncology companies to grow their franchises by generating data for novel products with differentiated value propositions that garner the interest of all the key constituencies—patients, physicians, regulators and payers.


Disclaimer

The information in this report has been obtained from what are believed to be reliable sources d h b ifi d h ibl N h l h i f iand has been verified whenever possible. Nevertheless, we cannot guarantee the information

contained herein as to accuracy or completeness. All expressions of opinion are the responsibility of Cancer Progress, and though current as of the date of this report, are subject to change. The opinions and information set forth herein are expressed solely for the benefit of the addressee and only for the purpose(s) for which the report was produced. Without the prior written consent of Cancer Progress, this report may not be relied on in whole or in part for any other purpose or by any other person or entity, provided that this report may be disclosed where disclosure is required by law.This report may contain information provided by third parties such as Thomson Reuters, WoltersKluwer, EvaluatePharma, Datamonitor, Informa Healthcare, IMS Health and others with a proprietary interest in the data provided herein. Please note that you are not permitted to redistribute any such third party information without consent from the originator company.y p y g p y

Cancer Progress © 2014


Disclaimer (Cont.) - Discriminating Self From Non-Self


KUDOS TO ALLKUDOS TO ALL


FDA Approval: 2012

First Approval

Axitinib, Renal Cancer

Glucarpidase, Chemoprotection

Vismodegib, Basal Cell Cancer Pertuzumab, Breast Cancer

Carfilzomib, Multiple Myeloma

Cetuximab, mCRC

Enzalutamide, Prostate Cancer

Vincristineliposomal, ALL

Afilbercept, mCRC

Bosutinib, CML

Regorafenib, mCRC

Omacetaxinemepsuccinate, CML

Rituximab, NHLCabozantinib, MTC

Abirateroneacetate, Prostate Cancer

Ponatinib, CMLPazopanib, STS

Jan Feb Mar Apr May June July Aug Sep Oct Nov Dec

Imatinib, GIST Everolimus, Astrocytoma

Everolimus, Angiomyolipoma

Everolimus, Breast Cancer

Albumin-bound paclitaxel, NSCLC

Line Extension


FDA, http://www.fda.gov/drugs/informationondrugs/approveddrugs/ucm279174.htm

Line Extension

FDA Approval: 2013

Doxorubicin liposomal,

Dabrafenib, Malignant Melanoma

First ApprovalJan 10, 2014 - FDA granted accelerated approval to trametinib (Mekinist tablets, GlaxoSmithKline, LLC) and dabrafenib (Tafinlar capsules, GlaxoSmithKline, LLC) for use in combination in the treatment of patients with unresectable or metastatic melanoma with a BRAF V600E or V600K mutation as detected by an FDA-approved test

Bevacizumab, mCRC

Doxorubicin liposomal, Kaposi’s sarcoma/Ovarian cancer

Pomalidomide, MM

Trastuzumab emtansine, Breast Cancer

Afatinib, NSCLC

Erlotinib, NSCLC

Radium-223 chloride, Bone metastases

Trametinib, Malignant melanoma

Pertuzumab, Breast cancer

Crizotinib, NSCLC

Ibrutinib, MCL

Obinutuzumab, CLL

Jan Feb Mar Apr May June July Aug Sep Oct Nov Dec

Lenalidomide, MCLDenosumab, Bone metastases

Albumin-bound Paclitaxel, Pancreatic Cancer

Sorafenib, DTC

Line Extension


FDA, http://www.fda.gov/drugs/informationondrugs/approveddrugs/ucm279174.htm

Line Extension

THE INCREASINGLY CROWDED &THE INCREASINGLY CROWDED & DYNAMIC ONCOLOGY SPACE


And Cancer Still Dominates the Clinical Development Pipeline

Pipeline includes products in research P1-3 and pre-registration shown based on likely time to approval but are not adjusted to reflect likelihood of launch.


The Global Use of Medicines: Outlook Through 2016, IMS Institute for Healthcare Informatics, July 2012

Solid Tumors Still Dominate the Pipeline

80%

90%

100%Solid Liquid

50%

60%

70%

80%

erce

ntag

e

10%

20%

30%

40%Pe

Marketed 278 100Registered 21 8Pre-Reg 23 6

0%

10%

gPh 3 195 58Ph 2 912 201Ph 1/2 334 132Ph 1 895 261


Source: ADIS R&D Insight, Nov 2013

Top 10 Oncology Blockbusters

Top Ten Oncology Blockbusters are Expected to Grow 26% Over the Next Five Years

2018 Top 10 Cancer Drugs ($41 3B)2018 Top 10 Cancer Drugs ($41.3B)

Product Company Class Patent Expiry Revenue 2018 ($B)

Avastin Roche VEGF MAbs 2018 $7.6

R li id C l IMID 2026 $6 7Revlimid Celgene IMID 2026 $6.7

Rituxan Roche CD20 MAbs 2018 $6.3

Herceptin Roche HER2 MAbs 2019 $5.6

Perjeta Roche HER2 MAbs -- $3.0

Xtandi Astellas AR Inhibitor 2027 $2.9

Afinitor Novartis MTOR Inhibitor 2019 $2.8

Tasigna Novartis Abl/c-Kit Inhibitor 2023 $2.5

Sprycel BMS Abl/SRC/c-Kit Inhibitor 2020 $2.0

Alimta Eli Lilly Antimetabolites 2017 $1 9


Evaluate Pharma

Alimta Eli Lilly Antimetabolites 2017 $1.9

Oncology Remains Dominant: Blockbusters Built from Expanding Labels, Chronic/Repeat Use, & High Pricing (Increasingly in Unique Patient Subsets)Unique Patient Subsets)

Top 10 Oncology Drugs (WW) Top 10 Drugs (WW)


EvaluatePharma, Defined Health

Pipeline Activity Versus Epidemiology & Unmet Needs: Why a Spike for Leukemia But Not Pancreatic & Ovarian?p

300,000 New Cases

Deaths

200

250

Drugs in clinical development

Drugs in clinical development200,000

250,000Deaths

New Cases and Deaths Per Year

100

150

100,000

150,000

0

50

1 2 3 4 5 6 7 8 9 10 11

0

50,000


American Cancer Society, Leukemia & Lymphoma Society, Defined Health

But Then, the Improvements, While Important & Sometimes Dramatic, Have Been Mostly Incrementaly

Disability-adjusted life-years (DALYs)Total DALYs and the five cancers that contributed most to the total for each region

Lancet. 2012 Nov 24;380(9856):1840-5


Lancet. 2012 Nov 24;380(9856):1840 5

Oncology & the First-in-Class Barrier: Is This Changing?

• TKIs and mTORs, Anti-VEGF, Anti-CD20s, Anti-EGFR• On the other hand, Herceptin, Perjecta, Kadcyla are all from the same company!!

DiMasi and Grabowski, Economics of New Oncology Drug Development, J Clin Oncology Vol. 25, pp. 209-216, Jan 10, 2007


Shortening Timelines from Discovery to Market

N t M d 2011 M 17(3) 297 303


Nat Med. 2011 Mar;17(3):297-303

Fast-Followers, Especially Enabled by Biomarkers and Refractory Patients, Linked to MutationsDrug Company Phase Mechanism Indication & Phase Comment

Crizotinib Pfizer MRKTALK inhibitor, Proto oncogene protein c met inhibitor

NSCLC – MRKT US, PreReg EUNSCLC (combo therapy) - P1/2Solid tumors – P1

ALK-positive diseaseinhibitor Solid tumors P1

AF 802 Chugai P1/2 ALK inhibitor NSCLC – P1/2 JPN ALK-positive NSCLC

AP 26113 ARIAD P1ALK inhibitor, EGFR antagonist, ROS1-protein-inhibitor

NSCLC – P1 US/EUSolid tumors – P1 US/EU

Pts whose tumors exhibit ALK rearrangements

ASP 3026 Astellas P1 ALK inhibitorB cell lymphoma – P1 USSolid tumors – P1 US/JPN

Pts with advanced solid tumors

LDK 378 Novartis P1 ALK inhibitor Solid tumors – P1 US/EUPts with confirmed ALK positive tumors

X-396 Xcovery P1 ALK inhibitor Solid tumors – P1 US

ALK inhibitors Tesaro, Amgen PC ALK inhibitor Cancer, NSCLC – Preclinical

Anticancer mAbsMedImmune, Georgetown

PC ALK inhibitor Solid tumors – Preclinical

Cancer therapeutics Sanofi-Aventis PC ALK inhibitor Cancer – Preclinical

Kinase inhibitors Cephalon PC ALK inhibitor NHL, Solid tumors – Preclinical

Kinase inhibitors Nerviano PC ALK inhibitor Cancer – Preclinical

Therapeutic antibody Delenex PC ALK inhibitor

Cancer, Neurologic disorders, skin disorders –


fragmentsDelenex PC ALK inhibitor

Preclinical

18

The Many Lung Cancer Drugs That Reach the Market Will Have to Do a Lot of Slicing, Dicing and Vying

Sequist, Sci Transl Med 201


Genetic Engineering News Webinar, Jan 31, 2013: Personalized Cancer Treatment and Patient Stratification Using NGS and Other OMICs Data

19

Will the Ongoing Paradigm Shift of Targeted Therapies and Precision Medicine Get Us Beyond Incrementalism?

With the Caveat That Such Comparisons Are Necessarily Based on Median OS!


Clinical Cancer Res Vol 16, pp. 5951-5955, 2010

Oncology & Its Rates of Success & Failure


Nature Reviews Drug Discovery 12, 569 (2013) ; Nature Reviews Drug Discovery 5, 741-754 (September 2006)

Fun With Math - Attrition Rate Riddle: More Drugs Than Possible, But Less Than Necessary?y

Phase* Number of Cancer Drugs

Cancer Drugs Reaching Market –BioMedTracker**

Cancer Drugs Reaching Market -Nat Rev Drug Discov***

Number of Lung Cancer Drugs

Lung Cancer DrugsReaching Market**

PreReg/Reg 42 34 159 10 8

Phase III 145 64 50 22

Phase II 476 71 320 115 17

Phase I 771 69 456 35 3

Total 1434 238 935 210 50

Adis R&D Insight, WW* h / i d ** d k *** ( )


*Phase II/III categorized as Phase II; Phase I/II as Phase I

**BioMedTracker, BIO presentation, BIO 2011 ***Nature Reviews Drug Discovery 8, 15-16 (January 2009)

Oncology’s New Equation: Value Vs. Cost of Drugs…The Good & the Bad (…& in the Not Too Distant Future, Maybe the Ugly?)


BBC News, Jan 14, 2013; BioCentury, Feb 15, 2013

Rising Costs of Drugs: The Payer Pressure on Performance of Any Individual Drug Is Increasingg g

Graph provided courtesy of Dr. Peter Bach, Memorial


Sloan-Kettering Cancer Center N Engl J Med. 2009 Feb 5;360(6):626-33

Is There a Value Price Disconnect between Individual Drugs, Regimens and the Overall Cost of Management?g g

The cost of managing CRC has risen more exponentially (~ 500-fold), while the clinical benefits have risen meaningfully but more arithmetically (from

d h d f h )around 11 months to upwards of 30 months).


J Clin Oncol 25:180-186, 2007.

Even in the US, Cancer Is Losing Its Privileged Status

Sanofi Halves Price of Cancer Drug Zaltrap After Sloan-Kettering RejectionNovember 8, 2012 – The New York TimesIn an unusual move, a big drug company said on Thursday that it would effectively cut in half the price of a new cancer drug after a leading cancer center said it would not use th d b it t i Th d b S fi f th l d Z lt ld b i f i t t th f tt d i i ththe drug because it was too expensive. The move — announced by Sanofi for the colon cancer drug Zaltrap — could be a sign of resistance to the unfettered increase in the prices of cancer drugs, some of which cost more than $100,000 a year and increase survival by a few months at best. Zaltrap came to market in August at a price of about $11,000 a month. Soon after, Memorial Sloan-Kettering Cancer Center in New York decided not to use the drug, saying it was twice as expensive but no more effective than a similar medicine, Avastin from Genentech. Both drugs improved median survival by 1.4 months, doctors there said. Three doctors at Sloan-Kettering publicized the cancer center’s decision last month in an Op-Ed article in The New York Times. “Ignoring the cost of care is no longer tenable,” they wrote. ”Soaring spending has presented the medical community with a new obligation. When choosing treatments for patients, we have to consider the financial strains they may cause alongside the benefits they may deliver.”

In an unusual move, a big drug company said on Thursday that it would effectively cut in half the price of a new cancer drug after a

Sanofi executives argued that the price they had set was very similar to that of Avastin. “The intent was not to charge a premium,” Christopher A. Viehbacher, the chief executive of Sanofi, said in an interview last month. Sloan-Kettering, he said, was basing its price comparison on a dose of Avastin that was half the dose Sanofi used in its own comparison. On Thursday, Sanofi backed down. “We believe that Zaltrap is priced competitively as used in real-world situations,” it said in a statement. “However, we recognize that there was some market resistance to the perceived relative price of Zaltrap in the U.S. — especially in light of low awareness of Zaltrap in the U.S. market. As such, we are taking immediate action across the U.S. oncology community to reduce the net cost of Zaltrap.” The move was first reported on Thursday by The Cancer Letter, a newsletter about cancer issues. Sanofi said it would not change the official price for Zaltrap but would offer discounts of about 50 percent. Zaltrap, which is given intravenously, is not bought directly by

y p gleading cancer center said it would not use the drug because it was too expensive. The move — announced by Sanofi for the colon cancer drug Zaltrap — could be a sign of resistance to the

patients but is sold to doctors or hospitals, which administer it. The cost is then reimbursed by Medicare or private insurers. Patients could be liable for a co-payment. Dr. Leonard B. Saltz, chief of gastrointestinal oncology at Sloan-Kettering and one of the authors of the Op-Ed article, said Sanofi’s offer of discounts “doesn’t really address the problem from our perspective” because Medicare reimbursement and patient co-payments would still be based on the higher list price, at least for several more months. Also, he said, the discounts could give doctors and hospitals an incentive to use Zaltrap because they could profit from the difference between the discounted price they pay for the drug and the higher price at which they are reimbursed by insurers. Dr. Saltz said even at the lower price, he did not foresee Sloan-Kettering doctors using Zaltrap because it was no better than Avastin and might be more toxic. Dr. Saltz is now a consultant to Genentech and has been one to Sanofi. Zaltrap, developed by Sanofi and Regeneron Pharmaceuticals, a biotechnology company in Tarrytown, N.Y., was approved by the Food and Drug Administration in August for

unfettered increase in the prices of cancer drugs, some of which cost more than $100,000 a year and increase survival by a few months at best. S fi id it ld t h th ffi i l i f Z lt b tuse as a second-line treatment for colorectal cancer, meaning after an initial regimen had stopped working. Like Avastin, Zaltrap impedes the formation of blood vessels that

nourish cancer cells. Dr. Peter B. Bach, director of the Center for Health Policy and Outcomes at Sloan-Kettering and one of the authors of the Op-Ed piece, said the price of Zaltrap reflected a bigger problem — that over all there was little relation between drug prices and the value they provided. “Normal markets wouldn’t behave like this,” he said on Thursday. “You couldn’t introduce something twice as expensive and no better and still sell it.” Dr. Lee Newcomer, senior vice president for oncology at UnitedHealthcare, said it was the first time he could recall a company cutting the price of a cancer drug so much. “It was the first time physicians have stood up and said, “Enough is enough,’ ” he said. “And I think that was a watershed moment.”

Sanofi said it would not change the official price for Zaltrap but would offer discounts of about 50 percent.


http://www.nytimes.com/2012/11/09/business/sanofi-halves-price-of-drug-after-sloan-kettering-balks-at-paying-it.html?_r=0&pagewanted=print

26

Oncologists Revolt, Again…And Payers Are Paying Attention


Oncology Market: Business as Usual?

Pfizer-Drug Xalkori Approved for Lung Cancer, but at What Cost?August 30 2011New York City-based Pfizer Inc. gained FDA approval for their drug Xalkori, the first new medicine in several years for deadly, advanced lung cancer, according to new research. Xalkori is used to treat certain patients with late-stage -- advanced or metastatic -- lung cancer along with an abnormal anaplastic lymphoma kinase (ALK) gene, which causes cancer development and growth. The drug, which works by blocking certain proteins called kinases, including the protein produced by gene abnormality, is being approved with a companion diagnostic test from Abbott Molecular Oncology that helped determine if a patient has the gene.“The approval of Xalkori with a specific test allows the selection of patients who are more likely to respond to the drug,” said Richard Pazdur, M D director of the Office of Oncology Drug Products in the FDA’s Center for Drug Evaluation and Research “Targeted therapies such as XalkoriM.D., director of the Office of Oncology Drug Products in the FDA s Center for Drug Evaluation and Research. Targeted therapies such as Xalkoriare important options for treating patients with this disease and may ultimately result in fewer side effects.”The Wall Street Journal reports that, four years ago, Pfizer Inc. was on the verge of abandoning a cancer therapy until scientists discovered its effectiveness for, at the time, only a small group of people -- 6,000 patients a year in the U.S. The results may not achieve multi-billion-dollar sales, but whether that yields a product for tens of millions of patients or 10,000 patients, we're interested, Geno Germano, who runs Pfizer's specialty-care and cancer businesses, told WSJ. In two clinical trials involving about 255 patients, Xalkori delayed tumor progression for at least t th i li htl th h lf th ti t h h d ifi ti t ti th t d t d R hl t t f th

Pfizer plans to charge $115,200 a year per patient for Xalkori.

ten months in slightly more than half the patients who had a specific genetic mutation, the study noted. Roughly one to seven percent of those with larger-celled lung cancer have the ALK gene abnormality, according to the FDA. Patients with this form of lung cancer are typically non-smokers. Federal health regulators discussed the drug shortly after its U.S. approval based on it being reasonably likely to predict a clinical benefit to [lung cancer] patients, they said. Xalkori is approved for the roughly four percent of patients with non-small cell lung cancer who have the gene.In one study, the objective response rate was 50 percent with a median response duration of 42 weeks. In another, the objective response rate was 61 percent with a median response duration of 48 weeks with most patients tested had tumors shrink or disappear for months, without the nasty side effects of chemotherapy. FDA officials said the most common side effects reported in patients receiving Xalkori included vision disorders, nausea, diarrhea, vomiting, swelling, and constipation.Pfizer plans to charge $115,200 a year per patient for Xalkori.


http://www.ibtimes.com/pfizer-drug-xalkori-approved-lung-cancer-what-cost-306928

28

Even the Patient-Stratified Approach May Not Be A Sure Thing

German Cost Agency Spurns XalkoriFebruary 21, 2013

The well-armed German pricing gatekeepers have dismissed another Big Pharma drug. Pfizer's lung cancer treatment Xalkori got an initial thumbs-down from the Institute for Quality and Efficiency in Health Care (IQWiG).

Under recent healthcare reforms--and budget cuts--in Germany, IQWiG assesses new treatments in comparison with existing alternatives The agency's decisions determine whether new drugs can wear premium price tags If theIf the treatments aren't deemed superior to older drugs thenexisting alternatives. The agency s decisions determine whether new drugs can wear premium price tags. If the treatments aren't deemed superior to older drugs, then companies' pricing power is virtually nil. "No additional benefit" is the operative phrase when IQWiG is least impressed. And that's the designation the agency awarded Xalkori.

The Pfizer lung cancer drug is designed for patients with an abnormal ALK gene. That's about 5% of people diagnosed with non small cell lung cancer It was greeted with great fanfare in the U S when FDA approved it in 2011 as a highly

If the treatments aren t deemed superior to older drugs, then companies' pricing power is virtually nil.

"No additional benefit" is the operative phrase when IQWiGwith non-small cell lung cancer. It was greeted with great fanfare in the U.S. when FDA approved it in 2011 as a highly effective, targeted drug for patients whose disease is particularly difficult to treat. But it's highly expensive as well.

IQWiG took issue with Xalkori's side effects in comparison with other NSCLC chemotherapies. And it slapped a "no additional benefit" on the drug in comparison with best supportive care because Pfizer hadn't provided any data.

No additional benefit is the operative phrase when IQWiG[Institute for Quality and Efficiency in Health Care] is least impressed. And that's the designation the agency awarded Xalkori.

Pfizer, in turn, took issue with the assessments in a statement titled "IQWiG method distorts the benefits of personalized cancer medicine." The company says it believes Xalkori offers a "significant benefit" for appropriate patients. And it plans to argue its case before the agency deadline in early March.


http://www.fiercepharma.com/node/93063/print (modified)

29

The Times They Are a Changin’: Cancer Is No Longer Sacrosanct & For the Moment We Are Not Yet Under as Draconian a System as NICENICE

Source: In Vivo , May 2011, “What New Cancer Pathway Programs Mean for the Drug Industry”


The Times They Are a Changin’: Moving to Differentiate Based on Outcomes – Evidence-Based Medicine

New Competitive Arena Emerges for Pharmaceutical Companies in Healthcare’s Changing Payment Landscape, Finds PwC Health Research Institute StudyInstitute StudyNEW YORK, May 17, 2012Pharmaceutical companies that are first to meet healthcare’s new expectations pof value could have an advantage in the competition for market share and brand differentiation, according to a report published today by the Health Research p y yInstitute (HRI) at PwC US. Physicians, health insurers and patients now want to know how well a drug will work and affect total medical costs. Yet an HRI survey of health plan executives finds the information currently provided by the biopharmaceutical industry no longer suffices.


www.pwc.com/us/en/health-industries/publications/pharma-reimbursement-value.jhtml

g

31

Fending Off Clinical Pathways With Personalized Causal Pathways?y


Genetic Engineering News Webinar, Jan 31, 2013: Personalized Cancer Treatment and Patient Stratification Using NGS and Other OMICs Data; Thomson Reuters’ Metaminer

Niche-ification & PCP-ification: Dynamic Tension

Niche-ification PCP-ification

• Identifying the subsets• Matching the target, novel or not,

• Chasing established markets• Chasing established MOAs

and the patient• Therapeutic and companion

diagnostic pathsAdd i ifi b fi (i

• Chasing validated development paths

• Add-on to SOC regimens for i l b fi• Add-on or not, significant benefit (in

PFS if not OS)incremental benefit


WHAT STANDARD DO WE AIMWHAT STANDARD DO WE AIM FOR GOING FORWARD:

FOR REGULATORSFOR REGULATORS, PHYSICIANS, PATIENTS, PAYERS & PARTNERS?PAYERS & PARTNERS?

P f f R lProof of Relevance


The Challenge of Developing an Optimal Label for Any New Oncology Agent

Activity Efficacy=Activity EfficacyEfficacy Regulatory Approval

R l A l C i l T i

==

Regulatory Approval Commercial Traction or Access to Patients

=

Clinical & Market Success Require Evidenceof Differentiation AND Value

M difi d f d d t f St H ll S H ll LLC O l St t Ali i R&D d M k t


Modified from and used courtesy of Steve Heller, S Heller LLC - Oncology Strategy: Aligning R&D and Markets

The Evolution of Hurdles for the Industry Across All Therapeutic Areas Has Reached Oncology

RR → PFS → OS → HEOR

Overall Improved Outcomes

Overall Improved Outcomes

Pharmacoeconomicbenefit

Pharmacoeconomicbenefit

Utility in first line nonUtility in first line non Improved OverallImproved Overall

No prior therapyNo prior therapyOrphanOrphan

Extended survivalExtended survival

Utility in first line non-responders or as add-onUtility in first line non-responders or as add-on

Tolerability, Safety & QoLTolerability, Safety & QoL

Improved Overall Therapeutic ProfileImproved Overall Therapeutic Profile


Extended survivalExtended survival y Qy Q

Focus Is Shifting to Proof of Relevance: Clinically Meaningful Differentiation for Patients, Physicians, Regulators and Payers, y , g y

The Zen Zone of Balancing Commercial and Scientific/Clinical Risk


PoR Is Not So Easy for the 15th, 30th, or 70th Anti-VEGF Agent in Clinical Developmentp

Bruce Booth’s timely Forbes blog from last year’s ASCO: 8 targets are addressed by >20% of pipeline projects, each of which has more than 24 projects in clinical development.


Forbes, Pharma & Healthcare 6/07/2012 (using Thomson Pipeline)

http://www.forbes.com/sites/brucebooth/2012/06/07/cancer-drug-targets-the-march-of-the-lemmings/

38

PoR Built Into PoC: Biomarker Strategy + Strong Differentiation = Short Term Value Creation Past Consensus Analyst Forecasts

Recent Consensus Analyst Forecasts


Plexxikon press releases; EvaluatePharma, Zelboraf projections 2011 and May 2013

39

And Facilitating Follow-on Products & Fast-FollowersSimilar clinical and commercial developments have been seen with follow-ons to Gleevec(imatinib), with BMS’ dasatinib (Sprycel), Novartis’ own nilotinib (Tasigna), Pfizer’s bosutinib (Bosulif) and Ariad’s ponatinib.

FierceMarkets Webinar, June 12, 2012 – Getting the most PoC data in Phase I cancer studies – Jamie Freedman, MD, PhD, VP Cancer Research,


Phase I cancer studies Jamie Freedman, MD, PhD, VP Cancer Research, GSK

40

Trying to Differentiate in the Anti-EGFR Space: Novel, Synergistic Anti-EGFR Antibody Mixturey g y• Sym004 is a combination of two monoclonal antibodies

which target different non-overlapping eptiopes of EGFR• In murine tumor xenograft models, Sym004 demonstrated

efficacy superior to Erbitux and Vectibix – like these agents, Sym004 inhibits ligand binding and EGFR activation, and also induces immune-mediated killing of cancer cells

• However, Sym004 induces more rapid internalization and greater degradation of EGFRgreater degradation of EGFR

• It has been hypothesized that the increased rate of receptor internalization and degradation may account for the greater anti-tumor efficacy of Sym004 compared to conventional anti-EGFR antibodies

• Sym004 is believed to form larger antibody-receptor complexes at the cell surface than antibodies targeting single epitopes and these larger complexes apparently promote an increased rate of receptor internalization

• Agents which promote increased internalization and degradation of EGFR may provide superior anti-tumor activity compared to conventional anti-EGFR antibodies for the following reasons:

o More complete inhibition of ligand binding and EGFR activationo Increased EGFR degradation prevents ligand-independent signaling via interaction with other

receptors


ADIS R&D Insight, Cancer Res. 2010 Jan15;70(2);588-97; www.symphogen.com

o Less susceptible to resistance due to increased EGFR ligand production

41

$25M for Phase I/II Compound with Animal Model PoR

Merck KGaA grabs a cancer antibody hybrid in $625M Symphogen pactg y y y p g pSeptember 6, 2012 | By John CarrollDanish biotech Symphogen picked up a major league pharma partner today along with an injection of fresh cash. Merck KGaA snagged Symphogen's second program--an anti-EGFR "mixed" antibody now in Phase II--with a €20 million ($25 million) upfront payment and promises of up to €475 million ($600 million) more in development and commercial milestonesmillion) more in development and commercial milestones.Merck KGaA gets Sym004, which is engaged in a mid-stage efficacy study. Antibodies, of course, have now become a standard feature in the biotech landscape. But Symphogen is one of a number of developers working on a next-gen approach by concocting antibody "mixtures" that can attack disease along multiple fronts. Genentech teamed with Symphogen on polyclonal antibodies four years ago.Merck KGaA's treatment is a combo threat weaving two antibodies together which have the potential toMerck KGaA s treatment is a combo threat, weaving two antibodies together which have the potential to "block ligand binding, receptor activation and downstream signaling but are also thought to elicit removal of the EGFR receptors from the cancer cell surface by inducing EGFR internalization and degradation." And the pharma giant says that it sees the program as a natural extension of its Erbitux franchise.A Phase I/II study has begun to produce safety and biomarker data for patients with KRAS wild-type metastatic colorectal cancer. And a year ago Symphogen launched a mid-stage study of the treatment formetastatic colorectal cancer. And a year ago Symphogen launched a mid stage study of the treatment for head and neck cancer.


FierceBiotech

42

Ipilimumab and BMS’s PD-1 Program Open the Door for Biotechs Targeting Other Checkpoint Moleculesg g p

Anti-PD-1 MAb


Trends in Mol Med Vol 14: 550-559, Dec 2008, ; J Clin Oncol Vol. 29:4828-4836, Dec 2011; Nature 480, 480–489 (22 December 2011); EvauatePharma , May 2013

43

Related PoR Can Provide Halo Effect Over PoC!

MacroGenics pockets $20M in $450M deal with ServierDecember 1, 2011 | By Ryan McBride

Taking another step forward after the failure of a late-stage trial of its lead drug last year, MacroGenics has bagged a pharma deal to fuel development of an immune-stimulating antibody against cancer. Servier, France's second-largest drugmaker has ponied up $20 million upfront inFrance s second-largest drugmaker, has ponied up $20 million upfront in the deal that gives it an option to develop and commercialize the drug, dubbed MGA271, for the European market.

Rockville, MD-based MacroGenics is testing the antibody drug in a Phase I trial in patients with solid tumors. The drug is intended to target the B7-H3 immune receptor, which is overexpressed in a wide variety of malignancies such as non-small cell lung, prostate and colorectal cancers. The developer is using a companion diagnostic in the trial to screen patients for the B7-H3 receptor, the company said.

The pact with Servier gives the French drugmaker the option to license the antibody after Phase I testing, at which point payments tied to the deal would total $60 million for MacroGenics. MacroGenics could reap up to an additional $390 million in payments if other development and commercial goals are reached, and the deal enables the company to hold on to rights to the drug in North America, Japan, India and Korea,


hold on to rights to the drug in North America, Japan, India and Korea, according to a press release. Servier gets rights to the drug in Europe and the rest of the world.

Clin Cancer Res Published OnlineFirst May 21, 2012; 1–12

44

DEALS IN ONCOLOGY:DEALS IN ONCOLOGY:

THE HISTORICAL CONTEXT TO THETHE HISTORICAL CONTEXT TO THE COMING CHANGE


Defined Heath’s Analysis of Deals: Oncology Continues to Lead and Recover in 2012 from Hit of Prior Few Years


EvaluatePharma report - Therapy area licensing in 2012 – Rags and riches

Dealmaking in M&A in 2013 Continued Strength of Oncology


Thomson Reuters Recap Webinar: 2013 Year in Review, January 21, 2014

Dealmaking in Licensing in 2013 Continued Dominance of Oncologygy



Oncology Licensing 2008-2013: Oncology, Autoimmune Deals Break Away from the Packy



Cancer M&A Trends: 30% of Acquisitions are Early Stage Versus 15% for Non-Cancer

Percent Distribution of Lead Product Stages For Therapeutic Product Company M&As (2008 – 2012)

36% 22%Cancer(n = 81) Phase II Marketed / Approved

Cancer(n=81)

22% 53%Average,

All Therapeutic Areas M k t d / A dh

Average,All Therapeutic

Areas

0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100%

Areas(n = 419)

Marketed / ApprovedPhase II(n=419)

Lead Molecule Preclinical Phase I Phase II Phase III Registration Stage Marketed / Approved

Source: Deloitte Recap LLC

Early Stage Products Late Stage Products

Data Source: Deloitte Recap LLCInsight into Action | www.recap.comCopyright © 2013 Deloitte Development LLC. All rights reserved.


ppy g p g

SOME FINAL THOUGHTSSOME FINAL THOUGHTS


The Hope & the Challenge of Precision Medicine in the Face of the Harsh Realities of Tumor Heterogeneityg y


The Hope & the Challenge of Precision Medicine in the Face of the Harsh Realities of Tumor Heterogeneityg y

• Intratumor heterogeneity can lead tocan lead to underestimation of the tumor genomics landscape portrayed from single tumor-biopsysingle tumor biopsy samples and may present major challenges to personalized-medicine and biomarker development.

• Intratumor heterogeneity, associated with heterogeneous proteinheterogeneous protein function, may foster tumoradaptation and therapeutic failure through Darwinian

l J d V l 366(10) 883 892 h 8 2012


selection.

53

N Engl J Med Vol 366(10):883-892, March 8, 2012

Schema for Prioritizing Targets: A Multi-Pronged Approach of the Biological and Chemical Spaceg p

• “Selecting the best targets is a key challenge for drug Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Researchkey challenge for drug discovery, and achieving this effectively, efficiently and systematically is particularly important for prioritizing

Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research

candidates from the sizeable lists of potential therapeutic targets that are now emerging from large-scale multi-omicsinitiatives such as those ininitiatives, such as those in oncology. Here, we describe an objective, systematic, multifaceted computational assessment of biological and h l h bchemical space that can be

applied to any human gene set to prioritize targets for therapeutic exploration. “


Nat Rev Drug Discov. 2013 Jan;12(1):35-50

We Must Be Thinking Mechanistically, Holistically & Dynamically

Nature Reviews Cancer 6, 924-935 (December 2006)Cancer as an evolutionary and ecological processLauren M.F. Merlo, John W. Pepper, Brian J. Reid3 & Carlo C. Maley

Nature Reviews Cancer 11, 375-382 (May 2011)An analogy between the evolution of drug resistance in bacterial communities and malignant tissuesG ill L b t L i E té S l St OhGuillaume Lambert, Luis Estévez-Salmeron, Steve Oh, David Liao, Beverly M. Emerson Thea D. Tlsty & Robert H. Austin

© Defined Health, 2014Defined Health Oncology Webinar, January 29, 2014 © Defined Health, 201355

Hopefully We Will Look Back in Ten Years Time & Marvel at How Far We Have Come



http://pharmaphorum.com/articles/the-rapidly-changing-face-of-oncology

25th Annual Cancer Progress Conference“The Premier Cancer Conference for Industry Leaders”

Cancer Progress, now in its 25th year, is the only oncology conference that invites a discussion of scientific progress within thecontext of development, regulatory, clinical, commercial and investment perspectives in two days of interactive dialogue between key opinion leaders from academia, industry, government, payers and investors. Pivotal topics, frank discussions, vigorous debate, lively

audience participation and generous networking combine to make this a highly impactful conference.We invite you to join us in New York City on March 4-5th, 2014 for the 25th Annual Cancer Progress Conference.

For more information please go to www cancerprogressbydh comFor more information, please go to www.cancerprogressbydh.com

AGENDATuesday, March 4, 2014

8:15 - 8:45am Keynote Address Axel Hoos, MD, PhD, VP, Oncology Research and Development, GlaxoSmithKline

8:45 - 10:00am Taking Immunotherapy Seriously: New Targets and CombinationsModerator:•Axel Hoos, MD, PhD, VP, Oncology Research and Development, GlaxoSmithKline

Panelists:Panelists:•Jeff Bockman, PhD, VP, Defined Health•Ira Mellman, PhD, VP, Research Oncology, Genentech•Galit Rotman, PhD, Chief Scientist of Therapeutics, Compugen•Michel Sadelain, MD, PhD, Director, Center for Cell Engineering, Memorial Sloan-Kettering Cancer Center •Lauren V. Wood, MD, Senior Clinical Investigator, Vaccine Branch, National Cancer Institute

10:30 - 11:45am Brain Cancer - Tackling the Intractable: Novel Targets and ApproachesModerator: •Minesh P. Mehta, MD, Medical Director, Maryland Proton Treatment Center, University of Maryland

Panelists: •Lauren Abrey MD Oncology Development Site Head F Hoffmann La Roche Inc•Lauren Abrey, MD, Oncology Development Site Head, F. Hoffmann-La Roche Inc.•Thomas Davis, MD, CMO and SVP Clinical Development, Celldex Therapeutics•H. Ian Robins, MD, PhD, Faculty, University of Wisconsin School of Medicine and Public Health •Eric Rowinsky, MD, Chief Medical Officer, Head of Research & Development, Stemline Therapeutics

11:45 - 1:00pm Big Data and Cancer: Transforming Patient Care by Turning Data into DecisionsM dModerator:•Colin Hill, Chief Executive Officer, President & Chairman, GNS Healthcare

Panelists:•Alexis Borisy, Entrepreneur in Residence, Third Rock Ventures •Joel Dudley, PhD, Director of Biomedical Informatics and Assistant Professor of Genetics and Genomics Sciences, Icahn School of Medicine at Mount Sinai•Brian Leyland-Jones, MD, VP, Molecular and Experimental Medicine, Avera Health•Michael Kolodziej, MD, National Medical Director, Oncology Strategies, Aetna Ventures, LLC •Timothy J. Thompson, CEO, Intervention Insights

2:15 - 3:30pm Evidentiary Standards for Diagnostics: When does a Biomarker Become a Diagnostic for Cancer Treatment?for Cancer Treatment?Moderator: •Steven Averbuch, MD, VP, Translational Clinical Development & Pharmacodiagnostics, Bristol-Myers Squibb Company

Panelists:•Anna Barker, PhD, Director, Transformative Healthcare Networks, Arizona State University•Richard Brian Gaynor MD VP Product Development/Medical Affairs Eli Lilly and Company•Richard Brian Gaynor, MD, VP, Product Development/Medical Affairs, Eli Lilly and Company•Steven Gutman, MD, Strategic Advisor, Myraqa•Michael Kolodziej, MD, National Medical Director, Oncology Strategies, Aetna Ventures, LLC •Howard I. Scher, MD, Chief, Genitourinary Oncology Service, Memorial Sloan-Kettering Cancer Center •Kim Zerba, PhD, Group Director, Global Biometric Sciences, Bristol-Myers Squibb

00 O l & O d h i4:00 - 5:15pm Oncology R&D: ROI and the New ExpectationsModerator:•Steve Heller, Principal, OncStrat LLC

Panelists:•Walter Capone, President, The Multiple Myeloma Research Foundation•Jeanne Farrell, PhD, Business Development Director, Icahn School of Medicine at Mount Sinai•Debasish Roychowdhury, MD•Mark J. Simon, Advisor, Torreya Partners LLC

5:15 – 6:30pm New Treatment Options for Prostate CancerModerator: •Jeremy P. Goldberg, President, JPG Healthcare LLC

Panelists:•Richard Heyman, CEO, Seragon (ex-CEO Aragon) •Philip Kantoff, MD, Director, Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute•Peter Lebowitz, MD, PhD, Therapeutic Area Head, Janssen Research & DevelopmentPeter Lebowitz, MD, PhD, Therapeutic Area Head, Janssen Research & Development •Marianne Sadar, PhD, Distinguished Scientist, BC Cancer Agency. Professor of Pathology and Laboratory Medicine, University of British Columbia•William R. Sellers, MD, VP, Global Head, Oncology, Novartis Institute Biomedical Research

6:30-8:30pm Cancer Progress 2014 Reception

Wednesday, March 5, 2014

8:15 – 9:15 am Keynote Address - A Dialogue: Valuing Value in Oncology•Peter Bach, MD, Attending Physician, Memorial Sloan-Kettering Cancer Center •Professor David Haslam, CBE, FRCGP, FRCP, FFPH Chairman, NICE•Clifford A. Hudis, MD, Chief, Breast Cancer Medicine Service, Memorial Sloan-Kettering Cancer Center,

2013-2014 President, ASCO

9:15 – 10:30am Antibody-Drug Conjugates: Supercharging the Blockbuster Antibody ClassModerator: •Jeff Bockman, PhD, VP, Defined Health

Panelists:•Robert Cohen, MD, Calico Life Sciences•Jonathan Drachman, MD, SVP, Research and Translational Medicine, Seattle Genetics, , , ,•Hans-Peter Gerber, PhD, VP, BioConjugate Discovery & Development, Oncology Research, Pfizer•John Lambert, PhD, EVP, Research & Development & Chief Scientific Officer, ImmunoGen, Inc.

10:45 – 12:00pm Cancer Gene & Cell Therapy: Expanding Therapeutic Options With Living DrugsModerator: •Mike Rice, MS, MBA, Senior Consultant, Defined HealthMike Rice, MS, MBA, Senior Consultant, Defined Health

Panelists:•Estuardo Aguilar-Cordova, PhD, Chief Executive OfficerAdvantagene, Inc.•Robert Coffin, PhD, Founder, BioVex•Harry Gruber MD Chairman Tocagen Inc•Harry Gruber, MD, Chairman, Tocagen, Inc.•Angela Shen, MD, MBA, Global Clinical Program Head, CTL019, Oncology Clinical Development, Novartis Pharmaceuticals Corp

12:00 – 1:15pm Intrinsic and Acquired Resistance in Cancer: Getting Smarter About Combinations and SequencingModerator: •Neal Rosen, MD, PhD, Director, Center for Mechanism-Based Therapeutics, Memorial Sloan-Kettering Cancer Center

Panelists:•Jeffrey A. Engelman, MD, PhD, Director of Thoracic Oncology and Director of Molecular Therapeutics, Massachusetts General Hospital Cancer Center •Greg Plowman, MD, PhD, VP, Oncology Research Eli Lilly and Company•David Solit, MD, Director, Developmental Therapeutics, Memorial Sloan-Kettering Cancer Center

2:30 - 3:45pm Challenging Established Paradigms in Cancer Moderator: •Sol J. Barer, PhD, SJBarer Consulting LLC

Panelists:•Giulio Draetta, MD, PhD, Director, Institute for Applied Cancer Science, Professor, Genomic Medicine, MD Anderson Cancer Center•Tak Mak, PhD, University Professor, Ontario Cancer Institute, University of Toronto•Neal Rosen, MD, PhD, Director, Center for Mechanism-Based Therapeutics, Memorial Sloan-Kettering Cancer Center•William R. Sellers, MD, VP, Global Head, Oncology, Novartis Institute Biomedical Research

4:00- 5:15pm Translational Oncology: How to Better Transform Targets into Relevant Drugs for PatientsModerators: •Jeffrey M. Bockman, PhD, VP, Defined Health•Mike Rice, MS, MBA, Senior Consultant, Defined Health

Panelists:•Joseph Beechem, PhD, SVP, Research and Development, NanoString Technologies•Pamela Carroll, PhD, VP, Oncology, Innovation Center in Boston, Janssen Research & Development•Rajesh Chopra, PhD, Corporate VP, Translational and Early Drug Development, Celgene Corporation•Victoria Richon, PhD, VP and Head of Cancer Research, Discovery and Early Development, Sanofi•Spiro G. Rombotis, President & CEO, Cyclacel Pharmaceuticals, Inc.

5:15pm Closing Remarks

5:30pm Cancer Progress 2014 Conference Concludes

Defined Health is pleased to present:

BioEurope Spring25h Annual Cancer Progress Conference BioEurope Spring March 10 – 12, 2014

Turin, Italywww.therapeuticinsight.com

25h Annual Cancer Progress ConferenceMarch 4 – 5, 2014

New York Citywww.cancerprogressbyDH.com

Defined Health will also be participating in the following industry events:

Cancer Progress by Defined Health | March 4 5 2014 | New York City |Cancer Progress by Defined Health | March 4 - 5, 2014 | New York City | http://www.cancerprogressbyDH.com

Therapeutic Insight by Defined Health at BIO-Europe Spring® | March 10 - 12, 2014 | Turin, Italy |


http://dfndhlth.com/BES-2014

defined health is pleased to present · metastatic melanoma with a braf v600e or v600k mutation as...

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