1. 1 Biomarkers and Clinical Care Lessons Learned from Case Studies: The Challenges and the Promise of Predictive Biomarkers Steven D. Averbuch, MD Vice President, Oncology Transition Strategy & Development and Head, Pharmacodiagnostics Global Clinical Research Bristol-Myers Squibb

2. 2 Disclosure I am an employee of Bristol-Myers Squibb Company and I own stock in Bristol-Myers Squibb and in other pharmaceutical companies ® ® Bristol-Myers Squibb manufactures and sells Plavix ® and Erbitux ® Any reference to information not contained within drug labeling is unintentional.

3. 3 Personalized Medicine A shift from conventional disease oriented approach to biologically defined personalized approach leads to improved performance of drugs Test for drug response* 60% benefit from therapy 86% benefit from therapy Try alternate therapy High response to therapy Low response to therapy A/A C/C A/C Treat TEST Dont Treat? * Specific blood, tissue or imaging marker that can be used to prospectively identify patients for efficacy, safety and/or dose

4. 4 Pharmacodiagnostics The Hype Surrounding Personalized Medicine Needs to be Balanced Against Many Challenges Research & Development Regulatory Commercial / Economics

5. 5 Pharmacodiagnostics The Hype Surrounding Personalized Medicine Needs to be Balanced Against Many Challenges Research & Development –Establishing molecular mechanism and biomarkers –Selecting and optimizing diagnostic platforms –Clinical specimen acquisition –Clinical validation –Potential decrease in therapeutic development productivity –Relevant biomarker science is often out of step with drug development timing

6. 6 Test Validation Patient Stratification Clinical Validation Clinical Utility Marketing Authorization --- Dx DEVELOPMENT--- Co-Development: Drug and PDx Ideal Paradigm --- MARKER DISCOVERY--- Identify Stratification Markers Assay Development Test Development Ph I Exploratory discovery Early discovery Full discovery Exploratory Development Full development, Regulatory Approval Commercial Prep Launch and LCM Target IDLead discoveryPre-clinPh IIaPh IIbPh IIIFilePhase IV

7. 7 Only In Few Cases Have Subgroups Been Defined in Advance With Formal Analysis Imatinib and Kit + GIST (prospective, preapproval) Dasatinib and PH + ALL (prospective, preapproval) Maraviroc and CCR5 + (tropic) HIV-1 (prospective, preapproval) Tetrabenazine and 2D6 dosing (prospective, preapproval) Trastuzumab and HER2+ Br Ca (prospective, preapproval) L. Lesko, FDA

8. 8 How Pharmacodiagnostics can Streamline Clinical Development and Increase Value 10-12 years 5-7 years Broad patient population Traditional clinical trials Responders only Pharmacogenomics-based trials Cost of Development >$1,000 Million <$500 Million Success Rate 5-10% 25-50% Patients Per NDA > 2,000 > 600 ValueGoodBetter Source: Pharma 2010: The Threshold of Innovation.

9. 9 Trial Design to Establish Clinical Utility: An Ideal Situation A definitive clinical study for a drug used in conjunction with a predictive biomarker allows for assessment of a drugs safety and efficacy and for verification of the clinical utility of the biomarker in guiding the drugs use including appropriate patient selection, and consequently enables labeling

10. 10 Only In Few Cases Have Subgroups Been Defined in Advance With Formal Analysis Imatinib and Kit + GIST (prospective, preapproval) Dasatinib and PH + ALL (prospective, preapproval) Maraviroc and CCR5 + (tropic) HIV-1 (prospective, preapproval) Tetrabenazine and 2D6 dosing (prospective, preapproval) Trastuzumab and HER2+ Br Ca (prospective, preapproval) Nilotinib and UGT hyperbilirubin (retrospective, preapproval) Abacavir and HLAB*5701 HAS (prospective, post-approval) Clopidegrel and 2C19 resistance (prospective, post-approval) Cetuximab / Panitumamab and KRAS (retrospective, post- approval) Carbamazepine and HLAB*1502 SJS (retrospective, post- approval) Warfarin and 2C9/VKORC1 dosing (retrospective, post- approval) L. Lesko, FDA

11. 11 Test Validation Patient Stratification Clinical Validation Clinical Utility Marketing Authorization --- Dx DEVELOPMENT--- Co-Development: Drug and PDx Ideal Paradigm --- MARKER DISCOVERY--- Identify Stratification Markers Assay Development Test Development Ph I Exploratory discovery Early discovery Full discovery Exploratory Development Full development, Regulatory Approval Commercial Prep Launch and LCM Target IDLead discoveryPre-clinPh IIaPh IIbPh IIIFilePhase IV Scientific Knowledge Timed to Enable Prospective & Parallel Drug-Diagnostic Co-Development is the Exception – Not the Rule

12. 12 Pharmacodiagnostics The Hype Surrounding Personalized Medicine Needs to be Balanced Against Many Challenges Research & Development –Establishing molecular mechanism and biomarkers –Selecting and optimizing diagnostic platforms –Clinical specimen acquisition –Clinical validation –Potential decrease in therapeutic development productivity –Relevant biomarker science is often out of step with drug development timing Regulatory –Integrated regulatory requirements (e.g., evidentiary standard) are not established and currently inconsistent –Regulatory and reimbursement standards within and across major markets (US, EU, and JP) are not harmonized

13. 13 Classified by Risk: I Low Risk II Med Risk 510K III High Risk PMA Analytical Validation System Quality Clinical Validation not required

14. 14 Regulatory Considerations for Drug/Diagnostic Development Integrated regulatory requirements (e.g., evidentiary standard) are not established and currently inconsistent Regulatory and reimbursement standards within and across major markets (US, EU, and JP) are not harmonized US: both drugs and diagnostics are regulated by FDA –drugs under CDER or CBER –IVDs under CDRH PMAs and 510Ks –LDTs under CMS (CLIA) EU: –centralized drug approval –devices are certified (CE mark) via conformity assessment

15. 15 Pharmacodiagnostics The Hype Surrounding Personalized Medicine Needs to be Balanced Against Many Challenges Research & Development –Establishing molecular mechanism and biomarkers –Selecting and optimizing diagnostic platforms –Clinical specimen acquisition –Clinical validation –Potential decrease in therapeutic development productivity –Relevant biomarker science is often out of step with drug development timing Regulatory –Integrated regulatory requirements (e.g., evidentiary standard) are not established and currently inconsistent –Regulatory and reimbursement standards within and across major markets (US, EU, and JP) are not harmonized Commercial / Economics –Incentives poorly aligned between stakeholders –Liability and IP issues –Market access for the diagnostic and for therapeutic Physician Education Laboratory Testing Infrastructure, Distribution and Reimbursement –Market share and pricing for the therapeutic –Diagnostic value and the diagnostic company return on investment

16. 16 Diagnostic Company (Diag, Inc.) Business Model Diag, Inc. sell diagnostic products, the pharmaceutical company sell drugs –Diag, Inc. provides the tools for patients, providers, payers, regulators and pharmaceutical company Constraints to viability of the diagnostic business: –A) need for clinical trial as stated by FDA –B) cost of clinical trial for clinical validation of a companion pharmacodiagnostic –C) relatively low price of reimbursement –D) no protection from LDTs, homebrews –E) Diag, Inc. can only survive with Rx support so lack of intrinsic value limits innovation P. Collins, Qiagen

17. 17 Pharmacodiagnostic Case Studies Clopidogrel Lung Cancer Abacavir Cetuximab

18. 18 Polymorphisms: Potential Factors Contributing to Variability of Response to Clopidogrel Clopidogrel has to be converted to an active metabolite (bioactivation) Bioactivation is achieved via P450 enzyme(s)-mediated metabolism CYP2C19, CYP3A4, CYP1A2 and CYP2B6 are involved in bioactivation, Other CYP enzymes are being studied Active metabolite generation may vary through: Drug-drug interaction (e.g. potentially Omeprazole) Polymorphism of CYP 450 enzymes Hirota T, et al. Clin Pharmacol Ther 1999;65:148 Plavix Package Insert October 2007 Herbert JM, et al. Semin Vasc Med 2003;2:113-21 UM (31%) Ultra-Metabolizers *1*17 *17/*17 EM (39%) Extensive Metabolizers *1/*1 IM (21 %) Intermediate Metabolizers *1/*2, *1/*3 PM (2.4 %) Poor Metabolizers *2/*2, *2/*3 and *3/*3 Unknown (6.8 %) *2/*17 2C19 Metabolizer phenotypes* * Frequencies observed in CHARISMA

19. 19 Mega Study CYP2C19*2 predicts worse outcome –1 or 2 copies of variant No data for other CYP2C19 alleles –Gain of function: *17 *1/*1 ~ 40% Caucasian *1/*17 or *17/*17 ~ 35% Caucasian *2/*17 ~ 5% Caucasian –Loss of function: *3, *4, *5 All rare in Caucasian *3: 6 % - Chinese *3/ 26% - Japanese CYP2C19*1/*2 ~27% of Caucasians CYP2C19 *2/*2 ~3% of Caucasians CYP2C19*1/*1 ~70% of Caucasians 12.1 % Primary Efficacy Outcome (%) Days since Randomization P = 0.01 8.0 % Mega et al, N Engl J Med 2009; 360:354-62

20. 20 Simon Study Registry analysis( n=2208) CYP2C19*2*2, not CYP2C19 *1*2 were at risk for a MACE Simon et al, N Engl J Med 2009; 360:363-75

21. 21 October, 2006 Hulot et al identify CYP2C19 polymorphisms as major determinant of variability in platelet aggregation in healthy subjects; additional publications later confirm this finding 200620072008 May, 2008 Trenk et al find CYP2C19 polymorphism is associated with adverse outcomes for patients on clopidogrel followed for one year 2009 December, 2008 Three additional outcome studies, including TRITON-TIMI 38, demonstrate a higher risk of CV events for CYP2C19 poor metabolizers on clopidogrel May, 2009 FDA revises clopidogrel label to include descriptive Information about individuals with genetically reduced CYP2C19 activity Emerging information established a role for CYP2C19 in clopidogrel response Oct, 2009 Press Release: Quest Diagnostics Brings Genetic Testing for Plavix(R) Response to Coronary Stent Patients at Scripps Health; First saliva-based cardiovascular disease test from Quest Diagnostics identifies gene variants implicated in potentially lethal reaction to popular anti-clotting drug 2010 October, 2009 Press Release: MEDCO announces the Genotype-Guided Comparison of Clopidogrel and Prasugrel Outcomes Study to enroll > 14,000 patients with ACS

22. 22 Does Variability of Platelet Response correlate to Variability of Clinical Outcomes? Adapted from: Serebruany V, et al. J Am Coll Cardiol 2005;45:246-51 To date, no definitive correlation has been established between the level of platelet response and clinical outcomes

23. 23 Outstanding Questions for Genomic Testing for Clopidogrel Therapy Quest Diagnostics Press Release (Oct, 2009) –Patients who test positive for the mutated alleles may receive alternative treatments based on a variety of factors. These treatments may include increased monitoring increased dosage of clopidogrel the use of alternative therapies

24. 24 Outstanding Questions for Genomic Testing for Clopidogrel Therapy Quest Diagnostics Press Release (Oct, 2009) –Patients who test positive for the mutated alleles may receive alternative treatments based on a variety of factors. These treatments may include increased monitoring increased dosage of clopidogrel the use of alternative therapies More Evidence-based Medicine Required Challenging Landscape with Multiple Stakeholders –Regulatory –Providers –Payors

25. 25 Results of PREDICT-I (Mallal et al, New Eng J Med, 2008) 0 1 2 3 4 5 6 7 8 9 Incidence (%) 3.4% (27/803) 7.8% (66/847) 2.7% (23/842) OR 0.40 P < 0.0001 OR 0.03 P < 0.0001 Control arm Prospective HLA-B*5701 screening arm Clinically Suspected HSR Immunologically Confirmed HSR 0.0% (0/802) (0.25, 0.62) (0, 0.18) Patch Test PPV = 48% NPV = 100%

26. 26 HLA-B*5701 association in two independent groups 200220042006 Discovery 2008 From Research to Clinical Practice: The Abacavir Paradigm* 2010 * Adapted from Phillips & Mallal, Personalized Med. 6:393, 2009 Clinical Evidence (High Level) Clinical Application (Depends on Lab Test) Clinical Adoption & Performance Evaluation Genetic & Cellular Studies PREDICT-1, SHAPE, & observational studies HIV Treatment Guidelines & Labeling Change PCR-based techniques Ongoing studies & QA

27. 27 Introduction of HLA-B*5701 Testing Pharmacodiagnostic Case Study: Abacavir Hypersensitivity Increased Value with Introduction of PDx – Giving the Right Drug to the Right Patient

28. 28 Companion Pharmacodiagnostics: individualized medicine in cancer PROLIFERATION Ki-67 STK15 Survivin Cyclin B1 MYBL2 ESTROGEN ER PR Bcl2 SCUBE2 INVASION Stromelysin 3 Cathepsin L2 HER2 GRB7 HER2 BAG1GSTM1 REFERENCE Beta-actin GAPDH RPLPO GUS TFRC CD68 16 Cancer and 5 Reference Genes From 3 Studies CategoryRS (0 -100) Low riskRS <18 Int riskRS 18 - 30 High riskRS 31 Paik et al. N Engl J Med. 2004;351:2817-2826. RS =+ 0.47 x HER2 Group Score - 0.34 x ER Group Score + 1.04 x Proliferation Group Score + 0.10 x Invasion Group Score + 0.05 x CD68 - 0.08 x GSTM1 - 0.07 x BAG1 Oncotype DX ® 21-Gene Recurrence Score (RS) Assay BATTLE I I-SPY 2 TailorRx BATTLE II BATTLE III

29. 29 Companion Pharmacodiagnostics: individualized medicine in cancer

30. 30 Companion Pharmacodiagnostics: individualized medicine in cancer

31. 31 Erbitux ® (Cetuximab) FDA Approved Indications Clinical Setting Tumor Selection Criteria Colorectal Cancer Erbitux with Irinotecan Erbitux with Irinotecan2004 Patients refractory to irinotecan containing therapy EGFR-expressing Erbitux as Single agent Erbitux as Single agent2004 Patients intolerant of irinotecan containing therapy EGFR-expressing Erbitux as Single agent Erbitux as Single agent2007 After failure of both irinotecan and oxaliplatin containing therapy EGFR-expressing Head & Neck Cancer Erbitux with Radiation Therapy 2006 Erbitux with Radiation Therapy 2006 Locally or regionally advanced SCCHN None Erbitux as Single agent 2006 Recurrent / metastatic SCCHN after failure of platinum based therapy None

32. 32 History of Companion Drug-Diagnostic Considerations for Cetuximab (2002 - 2007) Early clinical development assumed EGFR expression would be predictive of benefit –Specificity of cetuximab for its target –Precedent for other targeted mAbs (e.g. trastuzumab, rituxumab) Continuous and dedicated effort by academic and industry scientists to validate EGFR expression as a predictive marker and to further improve patient selection criteria for improved therapeutic index –Preclinical models and biomarker discovery –Exploratory prospective pharmacogenomic trial Insufficient scientific foundation for prospectively incorporating other predictive markers (e.g. K-ras) at the time that 4 large randomized clinical trials were initiated in 1 st, 2 nd, & 3 rd line treatment for CRC

33. 33 Key K-Ras Events: April 2008 – July 2009 AprMayJunJulAugSepOctNovDecJanFebMarAprMayJunJulAug VGDS to FDA ASCO & World GI K-Ras presentations NCI / CTEP Action Letter K-Ras in ERBITUX European label NCIC CO.17 K-Ras NEJM publication NCCN changes guidelines FDA ODAC Meeting Class Label Change in US 20092008 New class label for lack of benefit in K-ras mutants FDA PMA approved diagnostic required before labeling can describe benefit in K-Ras WT ASCO Provisional Clinical opinion

34. 34 KRAS Testing and Regulation EU Vectibix and Erbitux are indicated for KRAS WT CRC – Approval supported by retrospective data – EMEA required a CE marked test Not considered a high risk device by EU directive USA Vectibix and Erbitux label update in 2009 based on safety information – no treatment benefit for patients with KRAS mutations. Treatment not recommended for patients with KRAS mutations Since treatment decisions will be based on test results, a PMA approved kit is required before a efficacy claim on benefit for KRAS WT – Considered Class III high risk device – FDA approved KRAS test under development

35. 35 Predictive Biomarkers: Lessons Learned Subgroup analyses – either prospective or retrospective - have become routine Subgroup analyses – either prospective or retrospective - have become routine –Often exploratory but may influence labeling/approval –Recent examples of analyses showing associations between biomarker and outcomes have rapidly influenced medical practice Clinical utility of a diagnostic test and level of evidence may be elusive Clinical utility of a diagnostic test and level of evidence may be elusive –Impact of false + or false – in the context of use –How will individualized therapy (e.g., in cancer) be generalized to populations for evidence based medicine Diagnostic Considerations Diagnostic Considerations –Diagnostic company development – technical and commercial –Regulatory approval and oversight –Access to the test

36. 36 Companion Drug-Diagnostic Medicine in the Future Expand and Accelerate the dialogue among stakeholders –The macro-environment of companion drug-diagnostics –The micro-environment of product development and labeling Flexible process –Not a one size fits all approach –Weighing the evidence Plausibility and relevance of biological underpinning Replication of the observation Provide incentives for the enterprise: –Therapeutic and Diagnostic sponsors –Patients, Physicians (especially specimen acquisition) –Payors Reimbursement for the value of the test-drug combination

37. 37 Workshop on the Impact of Biomarkers on the Complexity of Drug Development FDA, MIT Workshop: Impact of Biomarkers on Drug Development 21, 22 October 2009 Contributing organizations –Adaptive Pharmacogenomics, LLC –Bristol-Myers Squibb –Eli Lilly and Company –FDA –Glaxo SmithKline –IMS Health –Merck –MIT –Roche –Van Andel Research Institute Functional specialties –Biomarker Development –Commercial Development –Economics –Finance & Planning –Regulatory –Statistics

38. 38 Conclusions Many challenges remain for predictive medicine to be realized in the future The experiences in these case studies discussed here are likely to be repeated, i.e., –post approval scientific discovery leading to clinical application An open dialogue and participation of a broad range of stakeholders is required to bring innovation to clinical and regulatory science to optimize patient selection for new and existing therapies