12/8/2011. David A Flockhart MD, PhD

Transcription

1 David A Flockhart MD, PhD 1 1

2 Outline Pharmacogenomics and rationale for the use of pharmacogenomics in the clinic Basic principals for the value of pharmacogenomics The unmet disease burden and the opportunity. Pharmacogenomic opportunities and their clinical utility in cancer, cardiovascular disease and psychiatry Avoiding pitfalls and optimizing clinician uptake 2

3 Outline Pharmacogenomics and rationale for the use of pharmacogenomics in the clinic Basic principals for the value of pharmacogenomics The unmet disease burden and the opportunity. Pharmacogenomic opportunities in cancer, cardiovascular disease and psychiatry Avoiding pitfalls and optimizing clinician uptake 3

4 The Genetic Evolution One Gene, One SNP One Gene, Multiple Variants Multiple Genes, Multiple Variants Pathways, Multiple Variants All Variants in the Genome 4

5 SNP Variability in The Human Genome December billion base pairs ~22,000 genes 1.7% of the genome codes for protein 3.3% of the genome is as conserved as the 1.7% that codes for protein On average 1 SNP/1.2kb million SNPs that occur at > 1% frequency ~450,000 SNPs in Multiply Conserved Regions Copy number variations exist in 5-7.5% of the germline genome Most tumor DNA sequence is identical to that of the host 4-5% of the genome is in areas with high copy number variation 5

6 Genome Wide Association as a Tool for Personalized Medicine: Effect Sizes are generally low Fletcher RL, Flockhart DA,

7 Pharmacogenomic Genome-Wide Association Studies Warfarin : CYP2C9 Clopidogrel: CYP2C19 Simvastatin: SLC101 Exemestane and Anastrozole: Tamoxifen : 7

8 Drugs and Their Available Pharmacogenetic Tests (As of September, most are monogenic tests) Abacavir HLA *B5701 Alcoho l ADH and ALDH Interferon α Il28B Clopidogrel CYP2C19 Venlafaxine CYP2D6 Codeine and hydrocodone CYP2D6 Tamoxifen CYP2D6 Methadone CYP2B6 Vincristine CYP3A5 Tacrolimus CYP3A5 Cyclophosphamide CYP2B6 Metformin OATP3 Imatinib BCR-ABL 5-Fluorouracil DPYD-TYMS Clozapine 2 SNPs in HLA-DQB1 Irinotecan UGT1A1 Azathioprine and Mercaptopurine TPMT Warfarin CYP2C9 and VKCoR Carbamazepine HLA-B* 1502 QT-prolonging Drugs Familion Adapted from Flockhart DA et al. Clin Pharmacol Ther Jul;86(1):

9 Many are Available But Which Tests Are Valuable? Analytical Validity Laboratory Integrity Clinical Validity Accurate biomarker prediction Clinical Utility Would it change what you do? i.e. change a drug or dose 9

10 Clinical Value of a Pharmacogenetic Test 12/8/2011 Principal Factors that Influence the Clinical Value of Any Pharmacogenomic Test Is there large variance in treatment outcomes? Are alternative therapies available? What s the current predictive value? A number of cancer therapies Antidepressants Azathioprine/TPMT β-blockers Current Clinical Ability to Predict Response 10

11 Clinical Value of a Pharmacogenetic Test 12/8/2011 Principles for Valuable Pharmacogenetic Tests 1. Large variance in treatment outcomes 2. Alternative therapies are available 3. Current predictive ability is low 4. Significant clinical consequences 5. Economically viable A number of cancer therapies Antidepressants Azathioprine/TPMT β-blockers Current Clinical Ability to Predict Response 11

12 Frequency 12/8/2011 Determining Whether Variability is Present: The Simple Polymorphic Distribution Activity (Phenotype) Antimode 12

13 The Value of Normit Distribution Plots: Population Distribution of CYP2C19 phenotype Flockhart et al: Clin Pharmacol Ther 1995;57:

14 Frequency 12/8/2011 Skewed Distribution The Mean is Not the Same as the Mode Activity (Phenotype) 14

15 Example of a Skewed Distribution: Heterogeneity in response to Inhaled Corticosteroids Weiss ST et al. Hum Molec Genetics 2004; 13:

16 Magnitude 12/8/2011 The Problem with Mean Response Data : Heterogeneity in Response to Medicines In Clinical Trials Benefit Large Benefit with little harm (10%) Mixed Benefit and Harm (30%). Small benefit for most. Neither harm or benefit --Nonresponders(50%) Harm Harm Without Benefit (10%) Frequency of various responses in the RCT treated population Evans B, Flockhart DA et al. (2010) 16

17 Consequences of Variable Treatment Response -- The Unmet Medical Need 1. Cancer: Poor outcomes due to poor therapeutic efficacy and the development of resistance 2. Cardiovascular Disease: High morbidity and mortality due to persistent disease progression 3. Psychiatry: Inadequate treatment due to side effects, poor compliance and lack of efficacy biomarkers 17

18 Consequences of Variable Treatment Response -- The Unmet Medical Need 1. Cancer: Poor outcomes due to limited therapeutic efficacy and the development of resistance 2. Cardiovascular Disease: High morbidity and mortality due to persistent disease progression 3. Psychiatry: Inability to select optimal therapy due to lack of biomarkers, and poor compliance due to adverse events 18

19 Pharmacogenomic Opportunities in Cancer Tamoxifen for Breast Cancer as an example Therapeutic ceiling in endocrine therapy Imperfect prediction of response Roadmap for prognostic tests ER, PR, HER2 Precedent for multiplex arrays Highly organized tissue collection (tumor) Multiple retrospective trials to study 19

20 Recurrence (%) 12/8/2011 Variability in Tamoxifen Therapy Outcome Control 45% 10,386 women Absolute benefit 18% Tamoxifen for 5 years NNT = Years EBCTCG: Lancet 365:1687,

21 Existing Biomarkers of Endocrine Treatment Response For ~70% of breast cancer patients Clinical Grade and stage of tumor Menopausal status Osteoporosis Genetic Pharmacogenetic effect Cytochrome P450 enzyme: CYP2D6Ongoing studies: TCL1A, UGT2B7, ABCC2 21

22 A Mechanistic Basis for a Tamoxifen Biomarker: CYP2D6 Generates the Active Tamoxifen Metabolites Desta et al, J Pharmacol Exp Ther Sep;310(3):

23 Number of subjects Subjects 12/8/2011 CYP2D6 Pharmacogenetics Subjects EMs UMs IMs cutoff PMs Rate of Debrisoquin Metabolism Parent drug to metabolite ratio Dahl ML et al. J Pharmacol Exp Ther Jul;274(1):

24 Tamoxifen CYP2D6 Pharmacogenetic Testing Analytical Validity OK if sufficient variants genotyped Clinical Validity OK Clinical Utility Not Demonstrated Inconsistent Validation in Clinical Trials Inconsistent genotyping methodology, trial design, dose, indication and analysis. 24

25 PharmGKB as a Tool: Irinotecan Pathway 25

26 % grade 4/5 neutropenia Objective response (%) 12/8/2011 UGT1A1 TA Repeat Genotype Altered Irinotecan Neutropenia and Activity in Colon Cancer P= /6 6/7 7/7 UGT1A1 genotype P= /6 6/7 7/7 UGT1A1 genotype N=524 McLeod H. et al,

27 Irinotecan Pharmacogenomic Testing Analytical Validity OK Clinical Validity OK Clinical Utility unclear because the tests value is limited to specific dosing regimes Not in widespread use 27

28 Thiopurine Methyl Transferase Cause of Highly Variable Toxicity : Granulocytopenia with Mercaptopurines:Azathioprine and 6-Mercaptopurine Used in: Acute Lymphocytic Leukemia in Children Inflammatory Bowel Disease in Adults Homozygous mutants are 0.2% of Caucasian Populations Heterozygotes are ~ 10% Homozygous wild type is 90% Metabolism of 28

29 Variability in Thiopurine Methyl Transferase From: Weinshilboum et al. JPET;222:

30 TPMT Pharmacogenomic Testing Analytical Validity OK Clinical Validity OK Clinical Utility Variable Depending on Practice Setting 30

31 Biotech Pharmacogenomics Bevacizumab (Avastin ) Interferon and IL 28b Erlotinib and K-Ras 31

32 Bevacizumab in Breast Cancer Improvement in PFS/ORR did not translate into OS benefit ORR (measurable disease) 49.2% vs. 25.2% P<0.001 Miller et al. NEJM 357:2666;

33 GOOD NEWS=all subgroups gained benefit We need something better! BAD NEWS= our common clinical variables were unable to identify an effect group Miller et al. NEJM 357:2666;

34 Pharmacogenetic Biomarkers VEGF AA & AA genotypes in combination arm outperformed control p= mo p= mo 25.2 mo 46.5 mo Median OS Control arm=25.2 mo Combination arm=26.7 mo Combination arm AA=37.0 mo Median OS Control arm=25.2 mo Combination arm=26.7 mo Combination arm AA=46.5 mo 34

35 Bevacizumab Pharmacogenomic Testing Analytical Validity OK Clinical Validity OK Clinical Utility Requires Validation in Other Trials Could a Pharmacogenomics Approach bring Avastin Back? 35

36 Current Pharmacogenomic Testing in Cancer Established Tests: Imatinib (Gleevec ) and BCR-ABL Erlotinib (Tarceva) and K-Ras (somatic, monogenic) Oncotype Dx and Mammaprint Evolving Tests: Irinotecan and UGT1A1 Tamoxifen and 2D6 Bevacizumab and VEGF Vincristine and CYP3A5 Cyclophosphamide and CYP2B6 Azathioprine and TPMT 36

37 Consequences of Variable Treatment Response -- The Unmet Medical Need 1. Cancer: Poor outcomes due to limited therapeutic efficacy and the development of resistance 2. Cardiovascular Disease: High morbidity and mortality due to persistent disease progression 3. Psychiatry: Inability to select optimal therapy due to lack of biomarkers, and poor compliance due to adverse events 37

38 Pharmacogenomics Opportunities in Cardiovascular Disease Clopidogrel for Coronary Thrombosis as an example A large population of patients treated Great variability in both efficacy and bleeding outcomes Samples from many large prospective trials available Available pharmacokinetic biomarkers for research Platelet aggregation testing widely available Alternative dosing a possibility An alternative drug is available: prasugrel 38

39 CYP2C19 generates the active metabolite of Clopidogrel (Plavix ) Simon et al. NEJM December 23 rd,

40 Comparison of prasugrel 60 mg and clopidogrel 600 mg loading dose exposure of active metabolite by CYP2C19 genetic classification. Box represents median, 25th, and 75th percentiles and whiskers represent the most extreme values within 1.5 times interquartile range of the box. AUC, area under the concentration time curve; EM, extensive metabolizer; RM, reduced metabolizer. Eur Heart J (2009) 30 (14):

41 CV Death, MI, or Stroke (%) 12/8/2011 Carriers of a CYP2C19 Genetic Variant Experienced More Cardiovascular Events Mega JL et al, NEJM, April,

42 CYP2C19 Effect Significant in PCI Patient Populations Simon T et al: Clinical Pharmacology & Therapeutics (2011) 90 4,

43 Pharmacogenomics Opportunities in Cardiovascular Disease Warfarin for Deep Venous Thrombosis and Atrial Fibrillation as an example A large population of patients treated Great variability in both efficacy and bleeding outcomes Samples from many large prospective trials available International Normalized Ratio available as an existing biomarker 43

44 VKORC1 Haplotype and CYP2C9 Genotype changed Warfarin Dose Primary cohort: UW (N=185); Replication cohort: Wash U (N=368). All participants were Caucasian. Rieder et al. N. Eng J. Med 2005;352: [ 44

45 Pharmacogenomics Opportunities in Cardiovascular Disease :Warfarin Analytical Validity OK Clinical Validity OK Clinical Utility limited because a viable alternative (INR) is available in many, but not all practice settings. Not in widespread use. 45

46 2SNPs: 10 possible hapoltypes Haplotypes Diplotypes Ser Arg Ser Arg Ser Arg Ser Arg Ser Arg Ser Arg Ser Arg Ser Ser Ser Ser Arg Ser Arg Arg Arg Arg Ying-Hong Wang PhD, Indiana University School of Medicine 46

47 Observed 1AR Haplotypes in Caucasians and African American Women (WISE study) Terra et al. Clin. Pharmacol. Ther. 71:70 (2002) 47

48 Of 10 theoretical diplotypes, only 4 were present in the study population Haplotypes Diplotypes Ser Arg Ser Arg Ser Arg Ser Arg Ser Arg Ser Arg Ser Arg Ser SR/SR SR/SG SR/GR Ser Ser Ser Arg Ser Arg SG/GR Arg Arg Arg Ying-Hong Wang PhD, Indiana University School of Medicine 48

49 Diplotype Predicted Beta-blocker effect: Single SNP analysis Would Miss It. Johnson et al. Clin Pharmacol & Ther. 2003,74:

50 Consequences of Variable Treatment Response -- The Unmet Medical Need 1. Cancer: Poor outcomes due to limited therapeutic efficacy and the development of resistance 2. Cardiovascular Disease: High morbidity and mortality due to persistent disease progression 3. Psychiatry: Inability to select optimal therapy due to lack of biomarkers, and poor compliance due to adverse events 50

51 51 51

52 Pharmacogenomic Opportunities in Psychiatry Venlafaxine for Depression as an example Blockbuster drug for a common disease Variability in efficacy and toxicity Prolonged time before efficacy is evident Need for biomarkers of treatment response Exclusive Metabolism by CYP2D6 Large prospective trials with germline DNA available 52

53 Venlafaxine (VEN) Is Metabolized To O-Demethylated-Venlafaxine (ODV) By CYP2D6 CYP2D6 ODV : VEN To assess CYP2D6 status VEN + ODV Total active compound Br J Clin Pharmacol. 1996;41(2):

54 CYP2D6 Genotype Associated with Venlafaxine Efficacy Lobello KW et al. J Clin Psychiatry 71:11, Nov

55 Promising pharmacogenomic opportunities exist in cancer, cardiovascular disease and psychiatry. How to implement? 55

56 Pharmacogenomic Pitfalls to Avoid 1. Inadequate testing of genetic variation 2. Inadequate analysis of known genetic variants 3. Poorly defined biomarker phenotypes 4. Inappropriate attempts to validate associations in the wrong populations 5. Ineffective communication with the clinical community 56

57 57

58 58

59 Iterative Statistical Analyses From Discovery To Clinic Validation Normit plot: discriminates between single or multiple normal components within the population Mixture normal model: identifies number of normal components within the population Membership assignment of each subject according to the probability of belonging to each subgroup Lang Li and David A. Flockhart,

60 Outline Pharmacogenomics and rationale for the use of pharmacogenomics in the clinic Basic principals for the value of pharmacogenomics The unmet disease burden and the opportunity. Pharmacogenomic opportunities in cancer, cardiovascular disease and psychiatry Avoiding pitfalls and optimizing clinician uptake 60

61 Optimizing Clinical Uptake 1. Simple and user-friendly informatic approaches 2. Education and raising awareness 3. Team approaches involving the whole therapeutic alliance 4. Prospective trials of pharmacogenomic-guided therapy versus standard-of-care 5. Act local, think global 61

62 A Tool to Aid Clinical Implementation 62

63 Optimizing Clinical Uptake 1. Simple and user-friendly informatic approaches 2. Education and raising awareness 3. Team approaches involving the whole therapeutic alliance 4. Prospective trials of pharmacogenomic-guided therapy versus standard-of-care 5. Act local, think global 63

64 Role Models for Pharmacogenetics Concorde? Nuclear Power? The Longitude Problem? 64