Role of Pharmacogenomics in Drug Development – An Industry ...

Role of Pharmacogenomics inDrug Development – An IndustryPerspectiveColin SpraggsPharmacogeneticsGlaxoSmithKline

New Medicines Are Increasingly MoreExpensive To Develop1970’s1980’s1990’s$138m$318m$800m - Duration 15Yr• Need to reduce Pipeline Attrition– >70% of cost is allocated to failures–

Variation in medicine response to can beclassified by Pharmacogenetics• Pharmacogenetics (PGx) is the study of how drugresponse varies in individuals, due to differences intheir DNA• Variation includes differences in pharmacokinetics,efficacy, safety and/or tolerability• PGx does not change how a person will respond to amedicine• PGx is a tool that can be used to identify patients whowill have the desired response (efficacy & safety)

We want to describe individual risk better, now we can…2001 - Human genome known and bounded2004 - 10+ Million SNP markers mapped2005 - Human LD map (HapMap)

GSK Pharmacogenetic StrategyOngoing investigations for efficacy andsafety of compounds in phase I, II, III and IVclinical trials• DNA (and other samples) collected from subjectsenrolled in GSK clinical trials• Appropriate consents - globally• ‘Collect and hold’ strategy pending results• >55,000 PGx samples• Samples from >70 countries• 99% ethics committee approval rate

PG Opportunities in the ‘Pipeline’Target selectionPathway analysisResponderpopulationidentificationRisk ManagementPost MarketingSurveillanceEarly risk discharge(tolerability)TargetLeadCandidateFTIHPOCPhase 2Phase 3RegSubmissionLaunchand LCMPredictiveToxicologyExposurePK / dosingResponders:stratify / enrich

Efficacy PGx: Opportunities• Associate genetic variation with differences indrug efficacy response• Provide the means to classify patients asresponders or non-responders• Enable enrichment of subsequent studies withresponders• Enable dose adjustments by genotype• Enable progression in responder subset forotherwise ‘failed’ drugs• More focused, better defined studies

PGx reveals efficacy for rosiglitazone inAlzheimer’s Disease (AD)• PPARγ agonist approved for the treatment of Type 2 Diabetes• Rationale in AD– Decline in cerebral glucose utilisation linked to AD progression– PPARγ agonists may increase glucose brain entry and utilization– Positive cognitive effect in pilot study (n=30)• Phase II, 24 week placebo controlled, dose ranging study of rosiglitazoneefficacy in mild to moderate AD patients• DNA samples collected for PGx analysis of rosiglitazone response followingstratification of APOE4 carriage– APOE ε4 positive & APOE ε4 negative• Clinical study results published– Risner et al, Pharmacogenomics Journal, 2006; doi:1038/sj.tpj.6500369

APOE4 - a susceptibility gene variant forcommon forms of Alzheimer diseaseProportion of eachgenotype unaffected1.00.82/30.62/43/30.43/40.24/4060 65 70 75 80 85Age at onsetMean age ofonset ofAlzheimerdisease as afunction of theinheritance of thefive commonAPOE genotypes

Change from Baseline in ADAS-CogTotal Scores in the ITT PopulationMean Change in ADAS-Cog Score-2.5-2-1.5-1-0.500.511.5ClinicalimprovementClinical declineBaseline Week 8 Week 16 Week 24RSG 8mg RSG 4mg RSG 2mg PlaceboTreatment differences between rosiglitazone and placebo for ADAS-Cog total scores did not reach statisticalsignificance at Week 24 LOCF. Adapted from The Pharmacogenomics Journal 2006, online publication, 31January 2006; doi:10.1038/sj.tpj.6500369.

ADAS-Cog Score in APOE ε4-Negativevs. APOE ε4-Positive CohortsMean Change in ADAS-Cog Score-2.5-2-1.5-1-0.500.511.522.5Baseline Week 8 Week 16 Week 248mg E4+8mg E4-4mg E4+4mg E4-2mg E4+ Pbo E4+2mg E4- Pbo E4-• Analysis of interaction between APOE carriage status and ADAS Cog change frombaseline to Week 24 was significant (P

ADAS-Cog Score in APOE ε4-Negativevs. APOE ε4-Positive CohortsMean Change in ADAS-Cog Score-2.5-2-1.5-1-0.500.511.522.5Baseline Week 8 Week 16 Week 248mg E4+ 4mg E4+ 2mg E4+ Pbo E4+8mg E4- 4mg E4- 2mg E4- Pbo E4-• Analysis of interaction between APOE carriage status and ADAS Cog change from baseline to Week 24 wassignificant (P

Rosiglitazone in ADPhase III progression enabled by PGx hypothesis• Phase II Results– Results suggest AD patients without an APOE ε4 allele responded betterthan patients who carry either 1 or 2 APOE ε4 alleles– Results are exploratory and do not inform clinical practice, further studiesare required to confirm these findings– No conclusions can be drawn about clinical management of patients with AD• Prospective Phase III hypothesis– Patients without an APOE ε4 allele will show more improvement comparedto patients who carry an APOE ε4 allele– Phase III subjects will be randomised by APOE ε4 allele status(positive/negative)• Efficacy PGx– Associates genetic variation with differences in drug response– Provides the means to classify patients as responders or non-responders– Enables progression in responder subset for otherwise ‘failed’ drugs

Safety PGx: Opportunities• Associate genetic variation with drug inducedadverse events• Provide the means to classify patients’ risk ofdrug induced adverse events• Enable exclusion of ‘at risk’ patients fromsubsequent studies• Enable dose adjustment to reduce exposuredrivenAEs in ‘poor metaboliser’ patients• Potential markers require full evaluation ofperformance characteristics in broad studypopulation to ensure suitability for safetymanagement

Abacavir and Hypersensitivity (HSR)• Abacavir is a nucleoside reverse transcriptase inhibitor fortreatment of HIV infection• Active agent in Ziagen, Trizivir, and Epzicom/Kivexa• Approximately 5% of patients receiving abacavir develophypersensitivity reaction (HSR)– Vast majority of HSR cases are non-serious adverse events andresolve with permanent drug discontinuation– HSR toxicity burden includes excess clinic visits, provision ofalternate antiretroviral drug(s), hospitalizations and rare fataloutcomes• Clinical risk management is highly effective in reducingserious outcomes

Abacavir HSR and HLA B*5701Performance characteristics among ethnic groupsStudyGroupCasennp valueSensitivitySpecificityPPVNPVOR(95%CI)CNA30027Whites56744x10 -1457%99%69%98%97(12-751)CNA30032Whites1821678x10 -2348%96%37%97%21(10-48)CNA30032Hispanics51532x10 -422%100%100%95%30(2-531)CNA30032Blacks37410.278%98%12%96%4(0-36)Mallalet al18167

Abacavir HSR Prospective PGx study• A prospective study evaluate the utility ofHLA-B*5701 screening on Abacavir HSR rate• 6 weeks treatment with Abacavir containingantiviral regimens (2 x 900 patients)• Comparison of HSR rates between patients– Receiving current standard of care (all comers)versus– Prospective HLA-B*5701 screening and inclusion ofmarker negative patients (marker positive patientsexcluded)

No Samples, No Science• Clinical trial pharmacogenetics requires the prospectivecollection of samples and data• Samples should be collected even in situations where studyphenotype(s) are not yet identified• Requires appropriate informed consent• Reduces potential misrepresentation of the clinical trialpopulation and sample bias that may occur when samplesare collected retrospectively• DNA collection and storage enables pharmacogenetic studywhen new biological information emerges, even after studyhas completed• As illustrated ………

PPARγ agonist FarglitazarOedema AE PGx• PPARγ agonists are clinically effective treatments ofType 2 Diabetes• Most common side effects are fluid retention/oedema,can range from inconvenient to clinical concernrequiring discontinuation• Mechanism and optimal management not fullyunderstood

Farglitazar Clinical Studies• Farglitazar, PPARγ agonist in Phase III studies in Type2 diabetic patients• 647/1106 (59%) subjects provided informed consentand DNA samples for PGx analysis whilst participatingin clinical studies• 555/647 (86%) were categorised as White• White subjects were allocated to three groups basedon study treatment– Farglitazar monotherapy: 6 studies (n=337)– Farglitazar plus glyburide: 1 study (n=77)– Farglitazar plus insulin: 2 studies (n=141)

Farglitazar oedema AE PGxSCNN1B Genetic LocusP valueGeneLDPattern(r 2 )

Farglitazar oedema AE PGx• Based on data emerging after completion of clinicaltrials this study was conducted on stored DNAsamples• Several polymorphisms in SCNN1B were highlysignificantly associated with oedema adverse events inFarglitazar clinical trials• These findings strengthen the hypothesis implicatingrenal sodium handling in the development of PPARγinduced fluid retention and suggest opportunities formanagement (eg, amiloride)• “No samples, no science”

Ethical considerations• PGx is not ‘exceptional’• PGx information is treated the same as otherclinical data– DNA samples are collected following clinicaltrial informed consent– DNA samples for PGx are coded to protectpatient identity• Primary goal of PGx is to investigate geneticvariation relating to drug effects, not to predictlikelihood of developing a disease

PGx is happening now• Routine DNA collection in clinical trials• Retrospective analysis of efficacy and safety– Hypothesis generation• Prospective Efficacy PGx and Safety PGx– Hypothesis testing– Clinical study design• Applications will be case specific– Support internal decision making– Support Regulatory approval– May not result in a PGx test• High interest and engagement from Regulators andHealthcare policymakers