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Collaborating with Merck in Drug Discovery

Rupert Vessey, MA, BM BCh, DPhil, FRCP.

Senior Vice-President, Early Development and Discovery Sciences

Merck Research Laboratories, Rahway, NJ

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The Research & Development ‘Process’

It takes ~10 -15 years and ~$BNs to develop one new medicine1-4

1Adams, CP, Brantner VV, Health Economics 2010, 19, 130-141 2Outlook 2010, Tufts Center for the Study of Drug Development 3DiMasi JA and Grabowski HG, Managerial and Decision Economics 2007, 28, 469–479 4DiMasi JA, Hansen RW, Grabowski HG, Journal of Health Economics 2003, 22, 151-185

FDA Review 1

5,000-10,000 Compounds

10-20 Compounds

2-4 Compounds

Drug Discovery

Clinical Trials and Product

Development

Post-Marketing

Preclinical

2

Year

s

Phase III n=1000-5000

Phase II n=100-500

Phase I n=20-100

6

1.5

5

Iterative and Not Strictly Linear Process

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What are the Scientific Challenges for Pharma R&D?

§  Knowledge explosion

§  Data integration

§  Disease phenotyping

§  Target/Patient selection

§  Product differentiation

Compound (Active Substance) POS**

Pre-clinical Phase I Phase II Phase

III Registration

70% 60% 34% 75% 100%

*Source: CMR 2005 Global Drug Discovery Performance Metrics Programme **Source: CMR 2007 Global R&D Performance Metrics Programme Industry Success Rates Report . Booth and Zemmel. Nature Reviews in Drug Discovery 3: 451.

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Reasons for Phase 2 Failures

§  Molecule related reasons (e.g. pharmacokinetics or toxicities) –  Pharma is generally quite good at solving these problems

§  Inadequate target validation –  Over reliance on non-predictive cell lines and animal models

§  No target engagement markers or ‘proof of biology’ models –  Failure to test mechanism at active dose

§  Failure to match target to patient subpopulation –  Reliance on ‘standard’ entry criteria leads to heterogeneous group not enriched for responders:

dilutes signal

§  Resistance to innovative trials designs –  Adaptive approaches can be used to enrich for responders

§  Insensitive outcome measures –  Failure to detect efficacy in small sample sizes

HOW CAN TRANSLATIONAL MEDICINE and ACADEMIC PARTNERSHIPS IMPACT THESE PROBLEMS AND IMPROVE

PROBABILITY OF SUCCESS?

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Successful Collaborations Require Complementary Skills and Capabilities

Drug Drug DiscoveryDiscovery

Early Early DevelopmentDevelopment

Late Late DevelopmentDevelopment

Target Target DiscoveryDiscovery

Increase drug target validation

Genetic studies to identify novel basis for human disease

Functional data to prioritize genetic hits

Novel translational systems to predict human outcome

Improve phase 2 success rates

Collaborate to identify biomarkers of drug effect

Improved patient phenotyping to select likely responders

Translate target validation to the clinic

Demonstrate Value for New Products

Enhanced efforts to identify responder populations

Access to major electronic health systems for ADR signal detection

Exploit Pharma core strengths

Utilize compound collections to provide validation tools

Focus on predictive models of compound toxicity

Utilize modeling an simulation to accelerate discovery

Emerging Collaboration Models

Open Source Innovation. Access to unrecognized innovation for future partnership

Tools4Targets. Provision of reagents to accelerate basic biomedical discoveries

Third Party Aggregators. Labs that develop and provide tools to translate academic discoveries

IP Sharing. Share objective and intellectual property (e.g initiate new drug discovery program)

Merck Research Labs – Early Development and Discovery Sciences

We …

§ Aim to be the premier scientific pharmaceutical research organization measured by delivery of novel medicines that have ‘unambiguous promotable advantages’ for patients

§ Are accountable for identification and validation of novel targets, discovery of drug candidates and generation of compelling clinical proof of concept

§ Want to capitalize on external opportunities and thus seek external partnerships that align with this mission; the Singapore community offers outstanding academic science and a collaborative environment

§ Look to combine our capabilities in drug discovery and early clinical development with the knowledge in the Singapore community to identify compelling new programs for our pipeline

§ Will develop Translational Medicines Research Center (TMRC) as the local catalyst for this vision

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Merck Early Development and Discovery Sciences Team

Mark Erion

Biology

Darryle Schoepp

Rupert Vessey EDDS

Daria Hazuda

Deborah Law

Pharma-cology

John Hunter

Discovery Chemistry

Chris Hill

Early Stage Development

Gary Herman

Genetics & Pharmaco-genomics

Robert Plenge

Immunology, IMR, Oncology

Infectious Diseases & Vaccines

Neuroscience Cardio-metabolics

Early Development and Discovery Sciences (EDDS) will deliver a pipeline of meaningful therapies by nurturing a culture of innovation

and collaboration between Clinical and Discovery sciences.

The Merck Translational Medicines Research Center

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Target Discovery Drug Discovery Early Clinical

Development

Pharmacology

Molecular Biomarkers & Diagnostics

Imaging

Early Stage Development Operations

Genetics & Pharmco-genomics

External Collaboration

Lead

Discovery Medicine

Combining Our Expertise

Singapore’s scientific

capabilities & expertise for

identification of novel drug targets,

biomarkers, and clinical populations

MRL’s expertise in molecule and

biologic discovery, pharmacology and

conduct of translational

medicine studies

Integrated projects that evolve from target

identification to translational drug

development programs

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Vision - Example

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Design and execute a genetic study to search

for human mutations that predispose to

diabetes in individuals of

Asian ancestry Sequencing; joint

data analysis

Functional studies to

understand mechanism of action of the

human mutations Small molecule

or biologic screen to identify

compounds that recapitulate the biology of the genetic finding

Tool compounds optimized at

AMRI or biologics at collaborator;

academic researchers

utilize to further investigate MOA

Clinical trials in diabetic patients

to provide additional

understanding of human

physiology.

§  Shared intellectual engagement –  Jointly conceive of questions and solutions

§  Align incentives –  Deliver on Merck’s pipeline and contribute to

Singapore’s success

§  Leverage substantial assets –  In-kind resources in addition to monetary funding

Summary

We should consider ourselves as one team!