Pharmacogenomic Clinical Studies

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Michael S. Phillips Ph.D. …

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

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  • This is our new model and there are major trends shaping it Instead of relying on a description of a disease we will have certainty about the molecular characteristics of the disease Instead of empirical intervention we’ll have rationale intervention directed by the better understanding of the disease Instead of treating all people as uniform we’ll begin to treat as individuals Instead of practising “reactive” medicine, we’ll practise “pro-active disease management” based on risk assessment, in short information based targeted care The days of exploratory operations have gone; the days of the average medicine being prescribed to everyone is no longer going to be acceptable

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  • 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    
  • 11.
    • Development of a Markov model for statins
    • Developed a Discrete Event Simulation model to allow for a more realistic economic modeling for statin testing
    • Developed a template that can be used for the economic evaluation of other pharmacogenomic tests.
    • Received additional funding ($1.4M) from CIHR for a prospective study focusing on the true effect of statin toxicity on compliance.
    • ( M Choinière, JC Tardif and J LeLorier)
    Pharmaco-economics Dr. Jacques LeLorier Universit é de Montéal
  • 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
  • 15. 10mg arm 2,000 patients Project 2: Study Design Fixed torcetrapib / atorvastatin arm
    • blood pressure,
    • potassium,
    • aldosterone,
    • mortality,
    • CVD events,
    • LDL,
    • HDL,
    • pathways involved in the adverse outcomes
    Evaluate: On-Target effects Off-Target effects Genome Wide Scan Illumina 610K Non-hypothesis-based analysis Candidate Gene Panel iSelect with custom content ADME CVD Statin (Mevalonate pathway) Hypertension
  • 16. Optimising Patient Care by Incorporating PGx Data into the Clinic: Testing and Guidance
    • The primary objective: create a prototype informatics pipeline to inform family practise physicians of an available pharmacogenomic test at the time of prescribing Warfarin in the clinic.
    • Physicians can then opt to receive test results and guidance, incorporated into the patient’s Electronic Health Record (EHR), (OSCAR).
    • Cost/Benefit Analysis (economics & patient outcomes.
    Tibor Van Rooij - PGx Centre Martin Dawes & Gillian Bartlett - McGill
  • 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
  • 24. An Integrative Approach
    • Clinical Utility
      • Probability Assessment
      • Economics
      • Clinical Guidance
      • Education
    Technology Analysis and Interpretation Clinical Practice “ Guidelines” and Algorithms
  • 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