礼来公司在FDA的演讲择思达与课件.pptx

1、EMEA1 definition:Pharmacogenomics applies genomic information to drug design,discovery and clinical development,reflecting the state or responses at cellular,tissue,individual or population levels.Pharmacogenetics&Pharmacogenomics PWG definition:Pharmacogenetics:the study of DNA sequence variation a

2、s it relates to differential drug response.Pharmacogenomics:the study of the genome and its products(including RNA and protein)as it relates to drug discovery and development.1-The European Agency for the Evaluation of Medicinal Products Lilly Definitions:Discovery Genetics utilizes genetic informat

3、ion to improve target identification/verification and MOA testing.Pharmacogenomics utilizes gene based information to predict,assess and evaluate drug response.The Promise of Pharmacogenomics Pharmacogenomics will radically change the manner in which we develop drugs.Soon,we will be able to get the

4、right drug into the right patient.Applying pharmacogenomics to drug development will cut cycle times to 1.5-2 years.Pharmacogenomics will be able to bring removed drugs back on the market,by predicting who is susceptible to adverse events.How Close Are We?Integrating Emerging TechnologyPharmacogenom

5、ics:applications and key activitiesThree broad applicationsDiscoveryTarget IdentificationMechanism of ActionTarget DifferentiationBiomarker IdentificationPre-clinical ToxicologyToxicogenomicsIn vivo Mechanism of ActionBiomarker IdentificationClinical In vivo Mechanism of ActionBiomarker Development&

6、ValidationTwo key activitiesIdentify&Understand TargetsDevelop Human BiomarkersGenetics in Drug Development Genetic Changes as Biomarkers Disease Susceptibility Biomarkers Single Disease Genes(Mendelian Inheritance)Genetic Associations in Complex Diseases Genetic Changes Associated with Tumorogenesi

7、s Inherited Mutations Spontaneous Mutations in the Tumor Multiple Transcript Changes Leading to Reclassification Drug Activity Biomarkers Genetic Polymorphisms Predicting Drug Metabolism DNA Variations Predicting Drug Response DNA Variations Predicting Adverse EventsGenetic in drug developmentCondit

8、ions when Lilly would choose to include genetics in drug development Early phase development(Candidate selection through phase II)Animal toxicity profile to predict human toxicity Mechanism of action Early target/receptor interaction and PK/PD effects Phase III/Phase IV development When medically ne

9、cessary Safety issue When test can differentiate drug Better response profile Adverse event managementStrattera and CYP2D6 Metabolism Primarily metabolized by CYP2D6 Plasma clearance EM 0.35 L/hr/kgPM 0.03 L/hr/kg AUC PM:EM 10 fold difference T1/2 EM 5.2 hoursPM 21.6 hours Safety vs Tolerability vs

10、Efficacy Issues Interplay has impact on labelEmpirical Bayesian Estimates of Clearance for each Patient in Population PK AnalysisPost-hoc CL Distributions using Final ModelLn(CL/F)012345Number of Patients020406080PMEMUMWitcher et al.2001.Population Pharmacokinetic Analysis of Atomoxetine inPediatric

11、 Patients.Population Pharmacokinetics Report.Lilly Research Laboratories.Initial clinical pharmacology studies above proposed maximum dose CYP2D6 genotype obtained under double-blind conditions in clinical trials Clinicians adjust dose and assess safety/tolerability/efficacy without knowledge of met

12、abolic status00.20.40.60.811.21.41.61.821234567891011Weeks of TherapyMean Dose(mg/kg/day)EMPM N 789/50 770/50 758/50 743/47 721/46 695/44 676/43 644/41 614/37 590/37 535/36EM vs PM Summary Safety&Tolerability Adverse event discontinuations-all studies EM 6%PM9%Close label comparison Strattera 3.5%Pl

13、acebo 1.5%Insomnia,Irritability Efficacy PMs have a statistically significant decrease in ADHDRS compared to EMsStrattera Label CYP2D6 status mentioned 7 times in label Pharmacokinetics section Adverse events Drug:drug interaction Laboratory TestingPoor metabolizers(PMs)of CYP2D6 have a 10 fold high

14、er AUC and a 5 fold higher peak concentration to a given dose of Strattera compared with extensive metabolizers(EMs).Approximately 7%of a Caucasian population are PMs.Laboratory tests are available to identify CYP2D6 PMs.The blood levels in PMs are similar to those attained by taking strong inhibito

15、rs of CYP2D6.The higher blood levels in PMs lead to a higher rate of some adverse effects of Strattera(see adverse reactions).Genetics in Drug Labelling How to define PM status?Easy in some CYP P450s 2C9-3 alleles,*2 and*3 are both classified as PMs 2C19-similar CYP2D6 is more problematic 40 alleles

16、 defined 10 are currently classified as greatly decreased,or null At least two are classified as decreased,or intermediate Duplication exists,leading to classification as ultrametabolizers Significant variations of frequency in ethnic backgroundsCYP2D6 Genotypes by Ethnicity Caucasians UM=1-2%EM=92-

17、95%PM=5-7%African American UM=3-5%EM=92-95%PM=2-3%Asians UM=?%EM=70-80%IM =20-30%PM=1%Hispanics UM=?EM=?PM=?CYP2D6 Genotype vs PhenotypeSachse et al.Am J Hum Genet 60:284 1997CYP2D6CYP2D6 Phenotyping vs.Genotyping Phenotyping Advantages Phenotype is the desired designation.Ethical considerations are

18、 small.High sensitivity.Very Low False Negatives.Genotyping Advantages Requires no extra sampling.Requires no follow-up visit.High sensitivity and specificity.Analysis not altered by patient taking other drugs.Methodological and Other Considerations Privacy and the Ethical,Legal and Social Implicati

19、ons Utility of the information/biomarker Translation into clinical practice Resistance to pharmacogenomic stratification Regulatory approval Realistic timelines and expectationsEthical,Legal and Social ImplicationsConsistent guidelines for the review and approval of informed consent procedures and o

20、f pharmacogenomic protocols by ethics committeesSampling procedures selected have important consequences for patient privacy,sample access and control,and ultimately gene discovery,and drug development PWG and CPMP definitionsAccess to the genetic information,and the medical and medical use conseque

21、nces of third parties.Methodological and Other Considerations Privacy and the Ethical,Legal and Social Implications Utility of the information/biomarker Translation into clinical practice Resistance to pharmacogenomic stratification Regulatory approval Realistic timelines and expectationsUtility of

22、the information/biomarker Examples ErbB-2 over-expression and response to Herceptin ALOX5 promoter in asthma Cholesteryl ester transfer protein and response to statins B2 adrenergic gene in asthma RNA levels and response to 5FU in colon cancerVariationVariationYYYYNNNNResponseYYNNBestGoodAveragePoor

23、CYP2D6 Recommendations PM genotype predicts PM phenotype in 99%of cases in two large studies(*3,4,5,6,&9,no interfering drugs).To avoid confusion,FDA should specify that both phenotyping and genotyping are acceptable methods of determining PM status.This should include a recommendation for what is m

24、inimal genotyping.The genotypic designations of UM,IM and EM have distinguishable phenotypes,but only in population studies.Classification of individual patients as UM,IM,and EM is NOT indicated by current data.Genotyping for CYP2D6 mutants is warranted only when a compounds margin of safety is exceeded in PMs.The Biotech/GenomicsRevolution:Right TargetRight DrugRight PatientsRight Timeline