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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! iris.grossman@teva.co.il