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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
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1.5
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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.