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Personalized Medicine & Pharmacogenomics (PMP) in drug R&D
from discovery to reposi/oning
ESPT 27 Sep 2013 Portugal
Iris Grossman, PhD Global Head, Personalized Medicine & Pharmacogenomics, Teva Pharmaceu?cal Industries
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Outline of presentation
§ The case for integrating personalized medicine (PM) approaches into drug R&D
§ Regulatory agencies – attitudes and key guidance documents
§ PM value added opportunities throughout the pipeline
§ Focus on PM and drug safety
§ Integration of PM into the R&D process – strategy and challenges
§ Examples: discovery and early development
§ Summary
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Integra6ng Personalized Medicine Strategies into Drug R&D
§ Stakeholders promote Personalized Medicine in drug R&D and in the clinic
§ Targeted therapeutics are being approved quickly and priced competitively
§ Technology is reliable § Scientific insights grow exponentially by the day
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The Regulatory perspective
http://www.fda.gov/drugs/scienceresearch/researchareas/pharmacogenetics/ucm083378.htm
Over 100 drugs
and are working together to establish a list of European Public Assessment Reports (EPAR)s that contain PGx information:
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6 Issam Zineh, PharmD, MPH, FCCP (May 2, 2012)
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Enhancing drug development – Cont.
§ Phase-appropriate risk mitigation § Early attrition – improved resource allocation § Strategic positioning and repurposing § Enhanced regulatory filings § Improved Benefit/Risk profiles § Leveraged reimbursement position § Enhanced trust in therapy § Increased adherence to medication § Overall improved outcomes for patients and
healthcare systems
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Biomarkers and adverse drug reactions (ADRs)
§ FDA: pharmacogenomic analyses employing samples collected from all study participants may support investigation of unexpected adverse events
§ Safety associated markers tend to have large effect sizes, detectable even in small datasets
§ DILI & skin rush are only a few ADRs with repeatedly demonstrated genomic associations in diverse therapeutic areas and with different drugs § Abacavir (Ziagen) potentially fatal hypersensitivity reaction (frequency 5% of prescribers) is tightly associated with a single genetic marker (HLA allele)
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Cornerstones of Successful Implementation of PM in R&D
§ Samples collected throughout drug development
§ Begin PM activities early
§ Study design and biomarker selection tailor fitted to each program, backed by sound scientific know-how and clear strategy
§ Collaboration across R&D functions paves the way to clinically useful data interpretation
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Building the Evidence Base
Hypothesis Generation BM sampling in clinical trials ID genomic/other marker associated w/ response differentiation (safety/efficacy)
Hypothesis/Marker Confirmation BM sampling in additional clinical trials Independent confirmation of BM association
Marker Validation Marker evaluation in clinical setting Co-development of reliable test to predict drug response for prescribing in patient subset
Relevance to prescribing
Many
Few BM – biomarker
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Challenges of the Drug R&D Pipeline
Clinical trials Post-marketing
#’s 10’s 100’s 1,000’s 10,000’s++ Clinical trials
I II III
Clinical study design challenges for PM: • Power • Endo-phenotypes • Timelines • Population Heterogeneity • Program sample sizes
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Genes are Insufficient: Valida6on is Essen6al
Poten?al Drug Targets
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ABri?on Rates 1990 2010
Current Reasons for Failure
Phase II 43% 66% • Insufficient efficacy (51%) • Safety concerns (19%) • Strategic issues (29%)
Phase III 20% 30% • Insufficient efficacy (66%) • Safety concerns (21%)
Industry ABri?on Rates
Source : pwc
Importance of Target Valida6on
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September 16, 2013: Cancer Research Technology (CRT) and Teva Pharmaceuticals Form R&D Alliance for Cancer DNA Damage Response Drugs
Example of PM Drug Discovery efforts in Teva
Cell cycle checkpoint activation
UV light Infection Replication
errors Alkylation
agents
Radio and chemotherapy
Cellular metabolism
Apoptosis DNA repair Double strand break repair
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“Desirable Phenotype” (resistance to pain or to obesity, excess iron, dense bone)
Most gene mutations cause loss of function
The Opposite Phenotype Approach guides R&D in Teva
“Gene blocker” can partially
reproduce “Desirable Phenotype”
Some gene mutations cause gain of function
Gene identified
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Edward Gibson ‘The Human Pincushion’ 1920
Extremely Rare Pain Phenotype: Congenital Indifference to Pain (CIP)
November 18, 2012
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CIP: Loss of Function Mutations in Nav1.7
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Continuum of Pain Phenotypes & Nav1.7 Genetic Variation in Humans
CIP - Congenital Indifference to Pain; PEPD - Paroxysmal extreme pain disorder; PE - Primary (idiopathic) Erythromelalgia/IEM
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Nav1.7: A Novel Strategy for Pain
§ Loss of function SCN9A mutations result in complete indifference to pain (CIP)
§ Gain of function SCN9A mutations result in opposite phenotype of erythromelalgia (EM)
§ Common functional SCN9A variant (R1150W) increases pain sensitivity in human pain states
§ Up-regulated in human pain states
New non-opioid mechanism
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Subject Pain Reduction on TV-45070* P 1001 10% NS 1002 21% 0.011 1003 33% 0.004 1004 88% 0.031
TV-45070 Oral Phase 2a IEM
* Compared to placebo
Mean pain reduction on TV-45070 of 38%
NS: not significant
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Preliminary results: R1150W Carriers are More Likely to Respond to Topical TV-45070
• 15-30% of the population carries the pain sensitivity allele
• This may allow selection of responders in subsequent trials
§ % TV-45070
§ % Placebo
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Summary
§ Personalized medicine approaches are integral to drug R&D in Teva
§ Utility in studying patterns of treatment response, safety, dose adjustment and identification of target populations
§ Opportunities span discovery through late development
§ Similar approaches provide novel opportunities for drug repositioning and repurposing
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Acknowledgments
§ Patients in Teva clinical trials § Michael Hayden, President of Global R&D & CSO § Clinical development teams at Teva § Xenon
Thank you! [email protected]
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