1 Biomarkers and Clinical Care Lessons Learned from Case Studies: The Challenges and the Promise of Predictive Biomarkers Steven D. Averbuch, MD Vice President,

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Biomarkers and Clinical CareBiomarkers and Clinical Care

Lessons Learned from Case Studies:Lessons Learned from Case Studies:The Challenges and the Promise of The Challenges and the Promise of

Predictive BiomarkersPredictive Biomarkers

Steven D. Averbuch, MDSteven D. Averbuch, MDVice President, Oncology Transition Strategy & Development and Vice President, Oncology Transition Strategy & Development and

Head, PharmacodiagnosticsHead, Pharmacodiagnostics

Global Clinical ResearchGlobal Clinical Research

Bristol-Myers SquibbBristol-Myers Squibb

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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.

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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

Pla te 0000066592 Pro c e ss G ro up 0799006 Ma rke r WI7466-1 (#592)

Sta tus:GetGenos PassUser: vish Pass

Unkno wns: #Wells

Passed 84Failed 0

Averages X YXX 2.77 0.14XY 2.78 2.65YY 0.15 2.74

Co ntro ls: (Ma x)

X YNEG - PCR 0.12 0.07Syn 2.68 0.36

6659266592

0

0.5

1

1.5

2

2.5

3

3.5

0 0.5 1 1.5 2 2.5 3 3.5

Neg.

Unknown

Synthetic Temp

A/A

C/C

A/C

Treat

TEST

Don’t Treat?

* Specific blood, tissue or imaging marker that can be used to prospectively identify patients for efficacy, safety and/or dose

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PharmacodiagnosticsThe Hype Surrounding Personalized Medicine Needs to

be Balanced Against Many Challenges

Research & Development

Regulatory

Commercial / Economics

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PharmacodiagnosticsThe 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

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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 ID Lead discovery Pre-clin Ph IIa Ph IIb Ph III File Phase IV

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Only In Few Cases Have Subgroups Been Defined in Only In Few Cases Have Subgroups Been Defined in Advance With Formal AnalysisAdvance 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

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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

Value Good BetterSource: Pharma 2010: The Threshold of Innovation.

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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 drug’s safety and efficacy and for verification of the clinical utility of the biomarker in guiding the drug’s use including appropriate patient selection, and consequently enables labeling

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Only In Few Cases Have Subgroups Been Defined in Only In Few Cases Have Subgroups Been Defined in Advance With Formal AnalysisAdvance 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

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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 ID Lead discovery Pre-clin Ph IIa Ph IIb Ph III File Phase IV

Scientific K

nowledge Timed to

Enable Prospectiv

e & Paralle

l

Drug-D

iagnostic C

o-Development

is th

e

Exception – N

ot the R

ule

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PharmacodiagnosticsThe 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

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Classified by Risk:I Low RiskII Med Risk 510KIII High Risk PMA

• Analytical Validation• System Quality• Clinical Validation not

required

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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

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PharmacodiagnosticsThe 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

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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 LDT’s, homebrews– E) Diag, Inc. can only survive with Rx support so lack of

intrinsic value limits innovation

P. Collins, Qiagen

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Pharmacodiagnostic Case Studies

Clopidogrel

Lung Cancer

Abacavir

Cetuximab

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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;65:148Plavix Package Insert October 2007Herbert 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

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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 CaucasiansCYP2C19 *2/*2 ~3% of Caucasians

CYP2C19*1/*1 ~70% of Caucasians

12.1 %

Prim

ary

Eff

icac

y O

utco

me

(%)

Days since Randomization

P = 0.018.0 %

Mega et al, N Engl J Med 2009; 360:354-62

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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

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October, 2006Hulot et al identify CYP2C19 polymorphisms as major determinant of variability in platelet aggregation in healthy subjects; additional publications later confirm this finding

2006 2007 2008

May, 2008Trenk et al find CYP2C19 polymorphismis associated with adverse outcomes forpatients on clopidogrel followed for one year

2009

December, 2008Three additional outcome studies, including TRITON-TIMI 38, demonstrate a higher risk of CV events for CYP2C19 poor metabolizers on clopidogrel

May, 2009FDA revises clopidogrel label to include descriptiveInformation about individuals with geneticallyreduced 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

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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

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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

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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

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Results of PREDICT-I (Mallal et al, New Eng J Results of PREDICT-I (Mallal et al, New Eng J Med, 2008)Med, 2008)

0

1

2

3

4

5

6

7

8

9

Inci

den

ce (

%)

3.4%(27/803)

7.8%(66/847)

2.7%(23/842)

OR 0.40P < 0.0001

OR 0.03P < 0.0001

Control arm

Prospective HLA-B*5701 screening arm

Clinically SuspectedHSR

Immunologically ConfirmedHSR

0.0%(0/802)

(0.25, 0.62)

(0, 0.18)

Patch Test

PPV = 48%

NPV = 100%

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HLA-B*5701 association in two

independent groups

2002 2004 2006

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

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Introduction of HLA-B*5701

Testing

Pharmacodiagnostic Case Study: Abacavir HypersensitivityIncreased Value with Introduction of PDx – Giving the Right Drug to the Right Patient

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Companion Pharmacodiagnostics: individualized medicine in cancer

PROLIFERATIONKi-67

STK15Survivin

Cyclin B1MYBL2

ESTROGENERPR

Bcl2SCUBE2

INVASIONStromelysin 3Cathepsin L2

HER2GRB7HER2

BAG1GSTM1

REFERENCEBeta-actinGAPDHRPLPO

GUSTFRC

CD68

16 Cancer and 5 Reference Genes From 3 Studies

Category RS (0 -100)

Low risk RS <18

Int risk RS 18 - 30

High risk RS ≥ 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

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Companion Pharmacodiagnostics: individualized medicine in cancer

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Companion Pharmacodiagnostics: individualized medicine in cancer

"Here's my

sequence..."

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ErbituxErbitux®® (Cetuximab) FDA Approved (Cetuximab) FDA Approved IndicationsIndications

Clinical SettingClinical SettingTumor SelectionTumor Selection

CriteriaCriteria

Colorectal CancerColorectal Cancer

Erbitux with IrinotecanErbitux with Irinotecan

20042004

Patients refractory to irinotecan Patients refractory to irinotecan containing therapycontaining therapy

EGFR-expressingEGFR-expressing

Erbitux as Single agentErbitux as Single agent

20042004

Patients intolerant of irinotecan Patients intolerant of irinotecan containing therapycontaining therapy

EGFR-expressingEGFR-expressing

Erbitux as Single agentErbitux as Single agent

20072007

After failure of both irinotecan and After failure of both irinotecan and oxaliplatin containing therapyoxaliplatin containing therapy

EGFR-expressingEGFR-expressing

Head & Neck CancerHead & Neck Cancer

Erbitux with Radiation Erbitux with Radiation Therapy 2006Therapy 2006

Locally or regionally advancedLocally or regionally advancedSCCHNSCCHN

NoneNone

Erbitux as Single agentErbitux as Single agent20062006

Recurrent / metastatic SCCHN after Recurrent / metastatic SCCHN after failure of platinum based therapyfailure of platinum based therapy

NoneNone

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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 1st, 2nd, & 3rd line treatment for CRC

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Key K-Ras Events: April 2008 – July 2009

Apr May Jun Jul Aug Sep Oct Nov Dec Jan Feb Mar Apr May Jun Jul Aug

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

ASCOProvisional

Clinical opinion

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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

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Predictive Biomarkers:Predictive Biomarkers:Lessons LearnedLessons Learned

Subgroup analyses – either prospective or retrospective - have Subgroup analyses – either prospective or retrospective - have become routinebecome routine

– Often exploratory but may influence labeling/approvalOften exploratory but may influence labeling/approval

– Recent examples of analyses showing associations between biomarker Recent examples of analyses showing associations between biomarker and outcomes have rapidly influenced medical practiceand outcomes have rapidly influenced medical practice

Clinical utility of a diagnostic test and level of evidence may be Clinical utility of a diagnostic test and level of evidence may be elusive elusive

– Impact of false + or false – in the context of useImpact of false + or false – in the context of use

– How will individualized therapy (e.g., in cancer) be generalized to How will individualized therapy (e.g., in cancer) be generalized to populations for evidence based medicinepopulations for evidence based medicine

Diagnostic ConsiderationsDiagnostic Considerations

– Diagnostic company development – technical and commercialDiagnostic company development – technical and commercial

– Regulatory approval and oversightRegulatory approval and oversight

– Access to the testAccess to the test

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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

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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

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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