Utility of Pharmacogenomics to Identify and Limit CV Risk. Christopher B. Granger, MD

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1 Utility of Pharmacogenomics to Identify and Limit CV Risk Christopher B. Granger, MD

2 Disclosure Research contracts: AstraZeneca, Novartis, GSK, Sanofi-Aventis, BMS, Pfizer, The Medicines Company, and Boehringer Ingelheim Consulting/Honoraria: AstraZeneca, GSK, BMS, Pfizer, Lilly, Diaichi Sankyo, Novartis, Roche, Boehringer Ingelheim, The Medicines Company, and Sanofi-Aventis For full listing see

3 Pharmacogenomics and Drug Safety Rationale Examples Clopidogrel Warfarin Statins What is the way forward?

4 Where are we in 2013? Elegant and convincing pharmacology evidence that genetic variants relate to treatment effect and/or risk of adverse events No clinical data to support that measuring/ using any of these variants results in treatment selection that improves clinical outcome Examples of where pharmacogenetics might allow improved use of a drug that has been superseded by a new drug that obviates the need for the testing Regulatory agencies that promote pharmacogenetic data in drug labels without evidence of how or whether that information will improve care

5 Summary of target organ contributions to drug withdrawals Stevens JL. Drug Discovery Today 2009;14:162-

6 Clopidogrel Story as Case Study Clopidogrel response (platelet function testing) is variable Less response relates to higher thrombotic risk Less response relates to lower plasma concentrations of active metabolite CYP 2C19 loss of function (LOF) variants (25-50% hetero, 2-14% homozygous) are associated with lower levels of active metabolite and less platelet inhibition on clopidogrel Thrombotic events more common with LOF alleles for patients on clopidogrel

7 Association of 2C19 Genotype with Antiplatelet Effect of Clopidogrel ADP response highly heritable 12% of clopidogrel response accounted for by CYP 2C19*2 variant Twice as likely to have death or MI Shuldiner JAMA. 2009;302(8):

8 FDA Box Warning

9 J. Am. Coll. Cardiol. 2010;56;

10 But is the treatment effect of clopidogrel modified by CYP2C19 status?

11 CURE Loss-of-Function Carrier Status No heterogeneity for the first primary (P=0.84), second primary (P=0.87) or safety (P=0.74) endpoint Pare G. N Engl J Med 2010;363:

12 Lancet 2012; 379: JAMA 2011; 306(20): Alexopoulos JACC Intv 2011; 4: Bonello JACC 2010; 56:1630 6

13 Clopidogrel PG Randomized trials fail to show that the treatment effect of clopidogrel is different according to gene variant status There is inconsistent evidence that prasugrel and/or ticagrelor may provide greater advantage in LOF allele population

14 Warfarin: #1 drug implicated for adverse events leading to emergency hospitalization in US N Engl J Med 2011; 365:

15 Warfarin Dosing Prototypical Case for Pharmacogenetic Testing Variants in CYP2C9 (*2, *3) and VKORC1 genes explain up to ~1/3 of variability in response to warfarin (~1/2 with clinical characteristics age, sex, weight) and are associated with bleeding events in observational studies Dose-response relationship Variants are common 66% of Caucasians, 90% of east Asians have at least one CYP2C9 or VKORC1 variant Impact of testing potentially large Kangelaris, et al. J Gen Int Med 2009; Anderson, et al. Circulation 2007; Gage B, et al Clin Pharmacol Ther 2008; Schwartz UI, et al. NEJM 2008.

16 Association with warfarin dose Takeuchi F et al. PLoS Genet 2009;5(3):e

17 FDA Prescribing Information

18 The COAG Clinical Trial C O A G A multicenter, double-blinded, stratified RCT of 1,015 participants, comparing two approaches: 1) initiation of warfarin therapy based on algorithms using only clinical information (Clinical-guided dosing arm) 2) initiation of warfarin therapy based on algorithms using clinical information and an individual s genotype (PGx-guided dosing arm) 18

19 Maintenance Dose Prediction C O A G Pharmacogeneticguided Clinicalguided Dose-initiation algorithm R Dose-revision algorithm R PGx demonstrated better maintenance dose prediction the clinical algorithm Dose prediction as expected based on prior studies 19

20 Primary Outcome - PTTR at 4 Weeks C O A G Genotypeguided dosing Mean (SD) Clinical-guided dosing Mean (SD) Mean difference (95% CI) * P-value PTTR All participants (n=955) 45.2 (26.6) 45.4 (25.8) (-3.4, 3.1) 0.91 Algorithms Difference 0.63** 1mg/d (n=392) 45.1 (25.5) 46.5 (27.1) -1.1 (-6.2, 4.0) 0.67 < 1 mg/d (n=563) 45.2 (27.4) 44.7 (24.8) 0.52 (-3.7, 4.8) * Mean difference in PTTR between genotype-guided and clinical-guided dosing groups, estimated from multivariable linear regression models that adjusted for race and clinical center **Interaction P value to evaluate equality of mean difference between subgroups

21 Conclusions C O A G COAG trial does not support the hypothesis that adding genetic information to determine dosing for the first five days of warfarin therapy improves anticoagulation control compared to initiating warfarin using only clinical information COAG highlights the importance of performing randomized trials for pharmacogenetics, particularly for complex medicine regimens such as warfarin 21

22 EU-PACT Warfarin RCT AIM To determine whether genotype-guided dosing of warfarin was superior to standard clinical care over 3 months in patients with AF or VTE previously naïve to warfarin DESIGN Pragmatic single-blind two-arm parallel group randomized controlled trial (455 patients)

23 Primary Outcome Measure Percent time within therapeutic INR range (TTR) during 12 weeks following the initiation of warfarin therapy Genotyped arm %TTR Standard dosing (control) arm %TTR Adjusted Difference ITT ANALYSIS (n= 211 vs 216) P value 67.4% 60.3% 7% P<0.001 PER-PROTOCOL (n=166 vs 184) 68.9% 62.3% 6.6% P=0.001 Sensitivity analyses did not change the conclusions of the primary analysis

24 N= 1015 N= 548 N= 455 N Engl J Med 2013;369

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26 Statins: Muscle symptoms and toxicity

27 SLCO1B1: EMR-based study and overview OR: 2.1 per allele variant for myopathy, 4.1 for severe myopathy (CK> 10X or rhabdo) Carr DF et al. Clinical Pharm Ther: 2013;94:

28 Validation of SLCO1B1*5: GWAS of severe simvastatin-induced myopathy Link et al, N Engl J Med. 2008;359(8):789-99

29 The way forward? These recent programs are depressing given the initial promise Defining clinical role is even more difficult than making the pharmacologic discoveries Further randomized trials to define some clinical benefit are needed to justify promotion and use of these tests Collection of genetic and biomarker material in large clinical trials is key to have ability to define potential roles

30 FDA List of 160 Pharmacogenomic Biomarkers in Drug Labeling Drug exposure and clinical response variability Risk for adverse events Genotype-specific dosing Mechanisms of drug action Polymorphic drug target and disposition genes

31 FDA Letter to 23andMe