EMEA1definition:Pharmacogenomicsappliesgenomicinformationtodrugdesign,discoveryandclinicaldevelopment,reflectingthestateorresponsesatcellular,tissue,individualorpopulationlevels.Pharmacogenetics&Pharmacogenomics

PWGdefinition:Pharmacogenetics:thestudyofDNAsequencevariationasitrelatestodifferentialdrugresponse.Pharmacogenomics:thestudyofthegenomeanditsproducts(includingRNAandprotein)asitrelatestodrugdiscoveryanddevelopment.1-TheEuropeanAgencyfortheEvaluationofMedicinalProducts

LillyDefinitions:DiscoveryGeneticsutilizesgeneticinformationtoimprovetargetidentification/verificationandMOAtesting.Pharmacogenomicsutilizesgenebasedinformationtopredict,assessandevaluatedrugresponse.EMEA1definition:Pharmacogeno1ThePromiseofPharmacogenomics"Pharmacogenomicswillradicallychangethemannerinwhichwedevelopdrugs.""Soon,wewillbeabletogettherightdrugintotherightpatient.""Applyingpharmacogenomicstodrugdevelopmentwillcutcycletimesto1.5-2years.""Pharmacogenomicswillbeabletobringremoveddrugsbackonthemarket,bypredictingwhoissusceptibletoadverseevents."HowCloseAreWe?ThePromiseofPharmacogenomic2IntegratingEmergingTechnologyIntegratingEmergingTechnolog3Pharmacogenomics:

applicationsandkeyactivitiesThreebroadapplicationsDiscoveryTargetIdentificationMechanismofActionTargetDifferentiationBiomarkerIdentificationPre-clinicalToxicologyToxicogenomicsInvivoMechanismofActionBiomarkerIdentificationClinicalInvivoMechanismofActionBiomarkerDevelopment&ValidationTwokeyactivitiesIdentify&UnderstandTargetsDevelopHumanBiomarkersPharmacogenomics:application4GeneticsinDrugDevelopment

GeneticChangesasBiomarkersDiseaseSusceptibilityBiomarkersSingleDiseaseGenes(MendelianInheritance)GeneticAssociationsinComplexDiseasesGeneticChangesAssociatedwithTumorogenesisInheritedMutationsSpontaneousMutationsintheTumorMultipleTranscriptChangesLeadingtoReclassificationDrugActivityBiomarkersGeneticPolymorphismsPredictingDrugMetabolismDNAVariationsPredictingDrugResponseDNAVariationsPredictingAdverseEventsGeneticsinDrugDevelopment5GeneticindrugdevelopmentConditionswhenLillywouldchoosetoincludegeneticsindrugdevelopmentEarlyphasedevelopment(CandidateselectionthroughphaseII)AnimaltoxicityprofiletopredicthumantoxicityMechanismofactionEarlytarget/receptorinteractionandPK/PDeffectsPhaseIII/PhaseIVdevelopmentWhenmedicallynecessarySafetyissueWhentestcandifferentiatedrugBetterresponseprofileAdverseeventmanagementGeneticindrugdevelopmentCon6StratteraandCYP2D6MetabolismPrimarilymetabolizedbyCYP2D6PlasmaclearanceEM0.35L/hr/kg PM0.03L/hr/kgAUCPM:EM10folddifferenceT1/2EM5.2hours PM21.6hoursSafetyvsTolerabilityvsEfficacyIssuesInterplayhasimpactonlabelStratteraandCYP2D6Metabolis7EmpiricalBayesianEstimatesofClearanceforeachPatientinPopulationPKAnalysisWitcheretal.2001.PopulationPharmacokineticAnalysisofAtomoxetineinPediatricPatients.PopulationPharmacokineticsReport.LillyResearchLaboratories.EmpiricalBayesianEstimateso8CYP2D6Polymorphisms:AssessingSafetyInitialclinicalpharmacologystudiesaboveproposedmaximumdoseCYP2D6genotypeobtainedunderdouble-blindconditionsinclinicaltrialsCliniciansadjustdoseandassesssafety/tolerability/efficacywithoutknowledgeofmetabolicstatusCYP2D6Polymorphisms:Assessin9MeanDosebyVisitandMetabolicRates

N789/50770/50758/50743/47721/46695/44676/43644/41614/37590/37535/36MeanDosebyVisitandMetabolEMvsPMSummarySafety&TolerabilityAdverseeventdiscontinuations-allstudiesEM6% PM 9% CloselabelcomparisonStrattera3.5%Placebo1.5%Insomnia,IrritabilityEfficacyPMshaveastatisticallysignificantdecreaseinADHDRScomparedtoEMsEMvsPMSummarySafety&Toler11StratteraLabelCYP2D6statusmentioned7timesinlabelPharmacokineticssectionAdverseeventsDrug:druginteractionLaboratoryTestingPoormetabolizers(PMs)ofCYP2D6havea10foldhigherAUCanda5foldhigherpeakconcentrationtoagivendoseofStratteracomparedwithextensivemetabolizers(EMs).Approximately7%ofaCaucasianpopulationarePMs.LaboratorytestsareavailabletoidentifyCYP2D6PMs.ThebloodlevelsinPMsaresimilartothoseattainedbytakingstronginhibitorsofCYP2D6.ThehigherbloodlevelsinPMsleadtoahigherrateofsomeadverseeffectsofStrattera(seeadversereactions).StratteraLabelCYP2D6statusm12GeneticsinDrugLabellingHowtodefinePMstatus?EasyinsomeCYPP450s2C9-3alleles,*2and*3arebothclassifiedasPMs2C19-similarCYP2D6ismoreproblematic>40allelesdefined~10arecurrentlyclassifiedasgreatlydecreased,ornullAtleasttwoareclassifiedasdecreased,orintermediateDuplicationexists,leadingtoclassificationasultrametabolizersSignificantvariationsoffrequencyinethnicbackgroundsGeneticsinDrugLabellingHow13CYP2D6GenotypesbyEthnicityCaucasiansUM=1-2%EM=92-95%PM=5-7%AfricanAmericanUM=3-5%EM=92-95%PM=2-3%AsiansUM=??%EM=70-80%IM=20-30%PM=1%HispanicsUM=???EM=???PM=???CYP2D6GenotypesbyEthnicityC14CYP2D6GenotypevsPhenotypeSachseetal.AmJHumGenet60:2841997CYP2D6CYP2D6GenotypevsPhenotypeSa15CYP2D6Phenotypingvs.GenotypingPhenotypingAdvantagesPhenotypeisthedesireddesignation.Ethicalconsiderationsaresmall.Highsensitivity.VeryLowFalseNegatives.GenotypingAdvantagesRequiresnoextrasampling.Requiresnofollow-upvisit.Highsensitivityandspecificity.Analysisnotalteredbypatienttakingotherdrugs.CYP2D6Phenotypingvs.Genotyp16MethodologicalandOtherConsiderationsPrivacyandtheEthical,LegalandSocialImplicationsUtilityoftheinformation/biomarkerTranslationintoclinicalpracticeResistancetopharmacogenomicstratificationRegulatoryapprovalRealistictimelinesandexpectationsMethodologicalandOtherConsi17Ethical,LegalandSocialImplicationsConsistentguidelinesforthereviewandapprovalofinformedconsentproceduresandofpharmacogenomicprotocolsbyethicscommitteesSamplingproceduresselectedhaveimportantconsequencesforpatientprivacy,sampleaccessandcontrol,andultimatelygenediscovery,anddrugdevelopmentPWGandCPMPdefinitionsAccesstothegeneticinformation,andthemedicalandmedicaluseconsequencesofthirdparties.Ethical,LegalandSocialImpl18MethodologicalandOtherConsiderationsPrivacyandtheEthical,LegalandSocialImplicationsUtilityoftheinformation/biomarkerTranslationintoclinicalpracticeResistancetopharmacogenomicstratificationRegulatoryapprovalRealistictimelinesandexpectationsMethodologicalandOtherConsi19Utilityoftheinformation/biomarkerExamplesErbB-2over-expressionandresponsetoHerceptinALOX5promoterinasthmaCholesterylestertransferproteinandresponsetostatinsB2adrenergicgeneinasthmaRNAlevelsandresponseto5FUincoloncancerVariationVariationYYYYNNNNResponseYYNNBestGoodAveragePoorUtilityoftheinformation/bio20CYP2D6RecommendationsPMgenotypepredictsPMphenotypein99%ofcasesintwolargestudies(*3,4,5,6,&9,nointerferingdrugs).Toavoidconfusion,FDAshouldspecifythatbothphenotypingandgenotypingareacceptablemethodsofdeterminingPMstatus.Thisshouldincludearecommendationforwhatisminimalgenotyping.ThegenotypicdesignationsofUM,IMandEMhavedistinguishablephenotypes,butonlyinpopulationstudies.ClassificationofindividualpatientsasUM,IM,andEMisNOTindicatedbycurrentdata.GenotypingforCYP2D6mutantsiswarrantedonlywhenacompound'smarginofsafetyisexceededinPMs.CYP2D6RecommendationsPMgenot21TheBiotech/GenomicsRevolution:RightTargetRightDrugRightPatientsRightTimelineTheBiotech/Genomics22EMEA1definition:Pharmacogenomicsappliesgenomicinformationtodrugdesign,discoveryandclinicaldevelopment,reflectingthestateorresponsesatcellular,tissue,individualorpopulationlevels.Pharmacogenetics&Pharmacogenomics

PWGdefinition:Pharmacogenetics:thestudyofDNAsequencevariationasitrelatestodifferentialdrugresponse.Pharmacogenomics:thestudyofthegenomeanditsproducts(includingRNAandprotein)asitrelatestodrugdiscoveryanddevelopment.1-TheEuropeanAgencyfortheEvaluationofMedicinalProducts

LillyDefinitions:DiscoveryGeneticsutilizesgeneticinformationtoimprovetargetidentification/verificationandMOAtesting.Pharmacogenomicsutilizesgenebasedinformationtopredict,assessandevaluatedrugresponse.EMEA1definition:Pharmacogeno23ThePromiseofPharmacogenomics"Pharmacogenomicswillradicallychangethemannerinwhichwedevelopdrugs.""Soon,wewillbeabletogettherightdrugintotherightpatient.""Applyingpharmacogenomicstodrugdevelopmentwillcutcycletimesto1.5-2years.""Pharmacogenomicswillbeabletobringremoveddrugsbackonthemarket,bypredictingwhoissusceptibletoadverseevents."HowCloseAreWe?ThePromiseofPharmacogenomic24IntegratingEmergingTechnologyIntegratingEmergingTechnolog25Pharmacogenomics:

applicationsandkeyactivitiesThreebroadapplicationsDiscoveryTargetIdentificationMechanismofActionTargetDifferentiationBiomarkerIdentificationPre-clinicalToxicologyToxicogenomicsInvivoMechanismofActionBiomarkerIdentificationClinicalInvivoMechanismofActionBiomarkerDevelopment&ValidationTwokeyactivitiesIdentify&UnderstandTargetsDevelopHumanBiomarkersPharmacogenomics:application26GeneticsinDrugDevelopment

GeneticChangesasBiomarkersDiseaseSusceptibilityBiomarkersSingleDiseaseGenes(MendelianInheritance)GeneticAssociationsinComplexDiseasesGeneticChangesAssociatedwithTumorogenesisInheritedMutationsSpontaneousMutationsintheTumorMultipleTranscriptChangesLeadingtoReclassificationDrugActivityBiomarkersGeneticPolymorphismsPredictingDrugMetabolismDNAVariationsPredictingDrugResponseDNAVariationsPredictingAdverseEventsGeneticsinDrugDevelopment27GeneticindrugdevelopmentConditionswhenLillywouldchoosetoincludegeneticsindrugdevelopmentEarlyphasedevelopment(CandidateselectionthroughphaseII)AnimaltoxicityprofiletopredicthumantoxicityMechanismofactionEarlytarget/receptorinteractionandPK/PDeffectsPhaseIII/PhaseIVdevelopmentWhenmedicallynecessarySafetyissueWhentestcandifferentiatedrugBetterresponseprofileAdverseeventmanagementGeneticindrugdevelopmentCon28StratteraandCYP2D6MetabolismPrimarilymetabolizedbyCYP2D6PlasmaclearanceEM0.35L/hr/kg PM0.03L/hr/kgAUCPM:EM10folddifferenceT1/2EM5.2hours PM21.6hoursSafetyvsTolerabilityvsEfficacyIssuesInterplayhasimpactonlabelStratteraandCYP2D6Metabolis29EmpiricalBayesianEstimatesofClearanceforeachPatientinPopulationPKAnalysisWitcheretal.2001.PopulationPharmacokineticAnalysisofAtomoxetineinPediatricPatients.PopulationPharmacokineticsReport.LillyResearchLaboratories.EmpiricalBayesianEstimateso30CYP2D6Polymorphisms:AssessingSafetyInitialclinicalpharmacologystudiesaboveproposedmaximumdoseCYP2D6genotypeobtainedunderdouble-blindconditionsinclinicaltrialsCliniciansadjustdoseandassesssafety/tolerability/efficacywithoutknowledgeofmetabolicstatusCYP2D6Polymorphisms:Assessin31MeanDosebyVisitandMetabolicRates

N789/50770/50758/50743/47721/46695/44676/43644/41614/37590/37535/36MeanDosebyVisitandMetabolEMvsPMSummarySafety&TolerabilityAdverseeventdiscontinuations-allstudiesEM6% PM 9% CloselabelcomparisonStrattera3.5%Placebo1.5%Insomnia,IrritabilityEfficacyPMshaveastatisticallysignificantdecreaseinADHDRScomparedtoEMsEMvsPMSummarySafety&Toler33StratteraLabelCYP2D6statusmentioned7timesinlabelPharmacokineticssectionAdverseeventsDrug:druginteractionLaboratoryTestingPoormetabolizers(PMs)ofCYP2D6havea10foldhigherAUCanda5foldhigherpeakconcentrationtoagivendoseofStratteracomparedwithextensivemetabolizers(EMs).Approximately7%ofaCaucasianpopulationarePMs.LaboratorytestsareavailabletoidentifyCYP2D6PMs.ThebloodlevelsinPMsaresimilartothoseattainedbytakingstronginhibitorsofCYP2D6.ThehigherbloodlevelsinPMsleadtoahigherrateofsomeadverseeffectsofStrattera(seeadversereactions).StratteraLabelCYP2D6statusm34GeneticsinDrugLabellingHowtodefinePMstatus?EasyinsomeCYPP450s2C9-3alleles,*2and*3arebothclassifiedasPMs2C19-similarCYP2D6ismoreproblematic>40allelesdefined~10arecurrentlyclassifiedasgreatlydecreased,ornullAtleasttwoareclassifiedasdecreased,orintermediateDuplicationexists,leadingtoclassificationasultrametabolizersSignificantvariationsoffrequencyinethnicbackgroundsGeneticsinDrugLabellingHow35CYP2D6GenotypesbyEthnicityCaucasiansUM=1-2%EM=92-95%PM=5-7%AfricanAmericanUM=3-5%EM=92-95%PM=2-3%AsiansUM=??%EM=70-80%IM=20-30%PM=1%HispanicsUM=???EM=???PM=???CYP2D6GenotypesbyEthnicityC36CYP2D6GenotypevsPhenotypeSachseetal.AmJHumGenet60:2841997CYP2D6CYP2D6GenotypevsPhenotypeSa37CYP2D6Phenotypingvs.GenotypingPhenotypingAdvantagesPhenotypeisthedesireddesignation.Ethicalconsiderationsaresmall.Highsensitivity.VeryLowFalseNegatives.GenotypingAdvantagesRequiresnoextrasampling.Requiresnofollow-upvisit.Highsensitivityandspecificity.Analysisnotalteredbypatienttakingotherdrugs.CYP2D6Phenotypingvs.Genotyp38MethodologicalandOtherConsiderationsPrivacyandtheEthical,LegalandSocialImplicationsUtilityoftheinformation/biomarkerTranslationintoclinicalpracticeResistancetopharmacogenomicstratificationRegulatoryapprovalRealistictimelinesandexpectationsMethodologicalandOtherConsi39Ethical,LegalandSocialImplicationsConsistentguidelinesforthereviewandapprovalofinformedconsentproceduresandofpharmacogenomicprotocolsbyethicscommitteesSamplingproceduresselectedhaveimportantconsequencesforpatientprivacy,sampleaccessandcontrol,andultim