Michael S. Phillips Ph.D. Dir. of Pharmacogenomics, Genome Quebec Associate Professor, Université de Montréal

1. Pharmacogenomic Clinical Studies Oct. 2, 2009 Michael S. Phillips Ph.D. Dir. of Pharmacogenomics, Genome Quebec Associate Professor, Université de Montr é al

2. Criteria for Evaluation of New Genetic Tests/Biomarkers • Analytic validity • Clinical validity • Clinical utility (Evidence based medicine) - probability assessment - economics - clinical guidance - education Need outcomes data! (large cohorts in the clinic)

3. Pharmacogenomics Centre U de Montreal Quebec/Canadian Clinical Networks Patients & Clinic Tools Genome Quebec Technology Platforms R & D Clinical Guidance/ Dosing Algorithms Genomic Analysis/ Phenotype Inference Pharmacogenomics Centre Epidemiology Stat Genetics Pharmaco-economics GELS

4. Pharmacogenomics of Drug Efficacy and Toxicity in the Treatment of Cardiovascular Disease Genome Canada Project PI’s: Dr. Jean-Claude Tardif MHI, UdeM Dr. Michael S. Phillips GQ, UdeM

5. Project 1. Pharmacogenomics of the Toxicity of Lipid-Lowering Agents

6. Identify biomarkers that are predictive of myotoxicity related to statin treatment Rhabdomyl . <1% Myotoxicity 3-5% Myalgias 10% Response to statin treatment Project 1: Statin Adverse Reactions Clinical Rationale

7. PK & PD Proteomics Phenotype Characterization Statin Myotoxicity: Study Design Statin Users 2383 Patients (myalgia, myotoxicity, rhabdo) 2287 Controls Taking Statins 4670 patients Genome Wide Scan Illumina 610K Non-hypothesis-based analysis Candidate Gene Panel iSelect with custom content ADME CVD Statin (Mevalonate pathway) Hypertension

8. Association of SLCO1B1 (OATPC) to Statin Myotoxicity

9. Selected Patients from the Montreal Statin Cohort n Cases Controls Numbers 262 401 Current statin Atorvastatin 207 331 Simvastatin 55 70 Men 663 164 (62.6%) 319 (79.9%) Age 663 61.1 64.4 Ethnic Background 660 Caucasian 257 (98.1%) 395 (98.5%) Black 0 1 (0.3%) Native american 1 (0.4%) 0 Hispanic 1 (0.4%) 1 (0.3%) Asian 1 (0.4%) 0 Other 2 (0.8%) 1 (0.3%) Self-identified as French-Canadian 658 233 (88.9%) 360 (89.8%) BMI 662 28.9 28.7 Blood pressure Systolic 661 134.1 130.5 Diastolic 662 76.7 74.5 n Cases Controls Heart Rate 662 68.5 66.1 Years of schooling 662 12.9 13.2 Living situation 662 At Home 258 391 Other 4 9 CVD medical history Previous MI 663 51 138 Previous PCI 662 55 120 Angina 663 89 151 Stroke/TIA 663 20 16 Previous CABG 663 40 89 Arrhythmia 662 29 53 Valvular disease 662 9 29 Congestive Heart Failure 658 4 16 Peripheral vascular disease 662 24 34 Hypertension 663 154 229 History of Diabetes 663 44 82 Ever Smoker 661 160 256 CK 117.5 107.3

10. No association identified between SLCO1B1 and statin-induced myopathy. Evaluation of SLCO1B1 Myotoxicity Association in our Cohort No association was also observed in Dr. Robert Hegele’s Cohort evaluating 126 cases with high CK values against 144 controls. 663 patients 270 patients 70 55 Simvastatin 331 207 Atorvastatin Type of statin taken 401 262 Total Patients: Controls Cases

12. Study 2. Pharmacogenomics of Novel Anti-Atherosclerotic Agents Torcetrapib PGx study (Pfizer)

13. Project 2: Clinical Rationale Statins lower LDL-cholesterol, but prevent only 30% of myocardial infarction and stroke. Torcetrapib (Pfizer) is a potent and selective inhibitor of cholesterol-ester transfer protein ( CETP ), a plasma glycoprotein that transfers cholesteryl esters from high-density lipoprotein (HDL) particles to very low density (VLDL) and LDL particles. CETP inhibition with torcetrapib results in increases of HDL-C of 20% to 100% in patients. Trial halted due to primarily off target events. Project 2 Objectives: - identify biomarkers that are genetic predictors of response to the combination of torcetrapib and atorvastatin therapy. - De-risk follow-on compounds

14. “ IllUMINATE” Study Design Atorvastatin 10 - 80 mg Fixed combination torcetrapib/atovastatin 984 primary events ~ 4.5 years LDL-C <2.6 mmol/L 15,000 randomized patients at 250 sites in North America, Europe and Australia Study halted in December 2006 Atorvastatin 10 – 80 mg Randomization Double-blind Treatment period Screen Visit Open-label Run-In period Screening period ~10 days 4 - 10 weeks

17. Pharmacogenomics Health Information Management System PHIMS Beacon Sherpa Castor QC

18. Dr. Brian F. Gage, Washington University

19. No PGx Test Available

20. PGx Test Available

21. Order Test & Results Pending

22. Test Results Available

23. confidential

25. Development Sharon Marsh Julia Adams Genevieve Dufour Andrew Brown Steve Geoffroy Mathieu Langlois Ian Mongrain Valerie Normand Yannick Renaud Bio-Informatics Tibor Van Rooij Chris Beck Marc Bouffard Michal Blazejczyk Paul Guelpa Genome Quebec Childrens Mercy Hospital, Kansas City, MO Andrea Gaedigk Laval Philippe Rigault Illumina Inc. Crane Harris Mark Hanson Richard Chen Charles Lin Autogenomics Nani Dattagupta Paul Hujsak Ken Fu GATC Project Michael Hayden Bruce Carleton Colin Ross Collaborators

26. Pharmacogenomic Clinical Studies Oct. 2, 2009 Michael S. Phillips Ph.D. Dir. of Pharmacogenomics, Genome Quebec Associate Professor, Université de Montr é al