PharmacogenomicClinical Studies

PharmacogenomicClinical Studies

Oct. 2, 2009Oct. 2, 2009

Michael S. Phillips Ph.D.Michael S. Phillips Ph.D.Dir. of Pharmacogenomics, Genome QuebecDir. of Pharmacogenomics, Genome QuebecAssociate Professor, Associate Professor, Université de MontrUniversité de Montrééalal

Criteria for Evaluation ofCriteria for Evaluation ofNew Genetic Tests/BiomarkersNew Genetic Tests/Biomarkers

• Analytic validity• Clinical validity• Clinical utility (Evidence based medicine)

- probability assessment- economics- clinical guidance- education

Need outcomes data!Need outcomes data!(large cohorts in the clinic)(large cohorts in the clinic)

Pharmacogenomics Centre

U de MontrealQuebec/Canadian Clinical Networks

Patients &Patients &ClinicClinic

ToolsTools

Genome QuebecTechnologyPlatforms

R & DR & D ClinicalClinical

Guidance/Guidance/Dosing AlgorithmsDosing Algorithms

Genomic Analysis/Genomic Analysis/Phenotype InferencePhenotype Inference

PharmacogenomicsPharmacogenomicsCentreCentre

Epidemiology

Stat Genetics

Pharmaco-economics

GELS

Genome Canada ProjectGenome Canada Project

Pharmacogenomics of Pharmacogenomics of Drug Efficacy and Toxicity in the Drug Efficacy and Toxicity in the

Treatment of Cardiovascular DiseaseTreatment of Cardiovascular DiseasePI’s:PI’s:Dr. Jean-Claude TardifDr. Jean-Claude Tardif MHI, UdeM MHI, UdeMDr. Michael S. PhillipsDr. Michael S. Phillips GQ, UdeM GQ, UdeM

Project 1. Project 1.

Pharmacogenomics of the Toxicity of Pharmacogenomics of the Toxicity of Lipid-Lowering Agents Lipid-Lowering Agents

Identify biomarkers that are predictive of myotoxicityIdentify biomarkers that are predictive of myotoxicityrelated to statin treatmentrelated to statin treatment

Rh

abd

om

ylR

hab

do

myl

. <1%

Myo

toxi

city

3-5

%M

yoto

xici

ty 3

-5%

Mya

lgia

s 10

%M

yalg

ias

10%

Response to statin treatmentResponse to statin treatment

Project 1: Statin Adverse ReactionsClinical Rationale

PK & PDProteomics

PhenotypeCharacterization

Statin Myotoxicity: Study Design

Statin Users

2383 Patients(myalgia, myotoxicity, rhabdo)

2287 ControlsTaking Statins 46704670

patientspatients

Genome Wide ScanIllumina 610K

Non-hypothesis-based analysis

Candidate Gene PaneliSelect with custom content

ADMECVD

Statin (Mevalonate pathway)

Hypertension

Association of SLCO1B1 (OATPC) to Statin MyotoxicityAssociation of SLCO1B1 (OATPC) to Statin Myotoxicity

      nn CasesCases ControlsControlsNumbersNumbers    262262 401401Current statinCurrent statin            AtorvastatinAtorvastatin    207207 331331   SimvastatinSimvastatin    5555 7070MenMen    663663 164 (62.6%)164 (62.6%) 319 (79.9%)319 (79.9%)AgeAge    663663 61.161.1 64.464.4Ethnic BackgroundEthnic Background 660660         CaucasianCaucasian    257 (98.1%)257 (98.1%) 395 (98.5%)395 (98.5%)   BlackBlack    00 1 (0.3%)1 (0.3%)   Native americanNative american    1 (0.4%)1 (0.4%) 00   HispanicHispanic    1 (0.4%)1 (0.4%) 1 (0.3%)1 (0.3%)   AsianAsian    1 (0.4%)1 (0.4%) 00   OtherOther    2 (0.8%)2 (0.8%) 1 (0.3%)1 (0.3%)Self-identified as Self-identified as French-CanadianFrench-Canadian 658658 233 (88.9%)233 (88.9%) 360 (89.8%)360 (89.8%)BMIBMI    662662 28.928.9 28.728.7Blood pressureBlood pressure            SystolicSystolic 661661 134.1134.1 130.5130.5

   DiastolicDiastolic 662662 76.776.7 74.574.5

      nn CasesCases ControlsControlsHeart RateHeart Rate 662662 68.568.5 66.166.1Years of schoolingYears of schooling 662662 12.912.9 13.213.2Living situationLiving situation 662662         At HomeAt Home    258258 391391   OtherOther    44 99CVD medical historyCVD medical history            Previous MIPrevious MI 663663 5151 138138   Previous PCIPrevious PCI 662662 5555 120120   AnginaAngina 663663 8989 151151   Stroke/TIAStroke/TIA 663663 2020 1616   Previous CABGPrevious CABG 663663 4040 8989   ArrhythmiaArrhythmia 662662 2929 5353   Valvular diseaseValvular disease 662662 99 2929   Congestive Heart FailureCongestive Heart Failure 658658 44 1616

  Peripheral vascular Peripheral vascular diseasedisease 662662 2424 3434

   HypertensionHypertension 663663 154154 229229   History of DiabetesHistory of Diabetes 663663 4444 8282Ever SmokerEver Smoker 661661 160160 256256CKCK       117.5117.5 107.3107.3

Selected Patients from the Montreal Statin CohortSelected Patients from the Montreal Statin Cohort

No association identified between SLCO1B1 No association identified between SLCO1B1 and statin-induced myopathy.and statin-induced myopathy.

      CasesCases ControlsControls

Total Patients:Total Patients: 262262 401401

Type of statin takenType of statin taken      

   AtorvastatinAtorvastatin 207207 331331

   SimvastatinSimvastatin 5555 7070

Evaluation of SLCO1B1 Myotoxicity Association Evaluation of SLCO1B1 Myotoxicity Association in our Cohortin our Cohort

No association was also observed in No association was also observed in Dr. Robert Hegele’sDr. Robert Hegele’s Cohort evaluating Cohort evaluating126 cases with high CK values against126 cases with high CK values against144 controls.144 controls.

663663patientspatients

270270patientspatients

• Development of a Markov model for statinsDevelopment of a Markov model for statins

• Developed a Discrete Event Simulation model to allow for a more Developed a Discrete Event Simulation model to allow for a more realistic economic modeling for statin testingrealistic economic modeling for statin testing

• Developed a template that can be used for the economic evaluation Developed a template that can be used for the economic evaluation of other pharmacogenomic tests.of other pharmacogenomic tests.

• Received additional funding ($1.4M) from CIHR for a prospective Received additional funding ($1.4M) from CIHR for a prospective study focusing on the true effect of statin toxicity on compliance.study focusing on the true effect of statin toxicity on compliance.

((M Choinière, JC Tardif and J LeLorier) M Choinière, JC Tardif and J LeLorier)

Pharmaco-economicsPharmaco-economics

Dr. Jacques LeLorierDr. Jacques LeLorierUniversitUniversitéé de Montéal de Montéal

Study 2. Study 2. Pharmacogenomics of Novel Pharmacogenomics of Novel Anti-Atherosclerotic AgentsAnti-Atherosclerotic Agents

Torcetrapib PGx studyTorcetrapib PGx study(Pfizer)(Pfizer)

Project 2: Clinical RationaleProject 2: Clinical Rationale

Statins lower LDL-cholesterol, but prevent only 30% of Statins lower LDL-cholesterol, but prevent only 30% of myocardial infarction and stroke.myocardial infarction and stroke.

TorcetrapibTorcetrapib (Pfizer) is a potent and selective inhibitor of (Pfizer) is a potent and selective inhibitor of cholesterol-ester transfer protein (cholesterol-ester transfer protein (CETPCETP), a plasma glycoprotein ), a plasma glycoprotein that transfers cholesteryl esters from high-density lipoprotein that transfers cholesteryl esters from high-density lipoprotein (HDL) particles to very low density (VLDL) and LDL particles. (HDL) particles to very low density (VLDL) and LDL particles. CETP inhibition with torcetrapib results in increases of HDL-C of CETP inhibition with torcetrapib results in increases of HDL-C of 20% to 100% in patients.20% to 100% in patients.

Trial halted due to primarily off target events.Trial halted due to primarily off target events.

Project 2 Objectives:Project 2 Objectives: - identify biomarkers that are genetic predictors of response to- identify biomarkers that are genetic predictors of response to the combination of torcetrapib and atorvastatin therapy. the combination of torcetrapib and atorvastatin therapy. - De-risk follow-on compounds- De-risk follow-on compounds

““IllUMINATE” Study DesignIllUMINATE” Study Design

4 - 10 weeks4 - 10 weeks

Atorvastatin10 - 80 mg

Fixed combinationtorcetrapib/atovastatin

984 primary events984 primary events~ 4.5 years~ 4.5 years

LDL-C <2.6 mmol/LLDL-C <2.6 mmol/L

15,000 randomized patients at 250 sites in North America, 15,000 randomized patients at 250 sites in North America, Europe and AustraliaEurope and Australia

Study halted in December 2006Study halted in December 2006

Atorvastatin10 – 80 mg

RandomizationDouble-blindDouble-blind

Treatment periodTreatment periodScreen

Visit

Open-labelOpen-labelRun-In periodRun-In period

ScreeningScreeningperiodperiod

~10 days~10 days

10mg arm 2,000 patients10mg arm 2,000 patients

Project 2: Study Design

Fixed torcetrapib / atorvastatin armFixed torcetrapib / atorvastatin arm

• blood pressure,• potassium, • aldosterone, • mortality, • CVD events,• LDL, • HDL, • pathways involved in the

adverse outcomes

Evaluate:On-Target effectsOff-Target effects

Genome Wide ScanIllumina 610K

Non-hypothesis-based analysis

Candidate Gene PaneliSelect with custom content

ADMECVD

Statin (Mevalonate pathway)

Hypertension

Optimising Patient Care by Incorporating PGx Optimising Patient Care by Incorporating PGx

Data into the Clinic:Data into the Clinic: Testing and GuidanceTesting and Guidance

The primary objective: create a prototype The primary objective: create a prototype informatics pipeline to inform informatics pipeline to inform family practisefamily practise physiciansphysicians of an available pharmacogenomic test of an available pharmacogenomic test at the time of prescribing Warfarin in the clinic.at the time of prescribing Warfarin in the clinic.

Physicians can then opt to receive test results and Physicians can then opt to receive test results and guidance, incorporated into the patient’s guidance, incorporated into the patient’s Electronic Health Record (EHR), (OSCAR).Electronic Health Record (EHR), (OSCAR).

Cost/Benefit Analysis (economics & patient Cost/Benefit Analysis (economics & patient outcomes.outcomes.

Tibor Van Rooij - PGx Centre

Martin Dawes & Gillian Bartlett - McGill

PHIMS

Beacon

Sherpa

Castor QC

Pharmacogenomics HealthPharmacogenomics HealthInformation Management SystemInformation Management System

Dr. Brian F. Gage, Washington University

No PGx Test Available

PGx Test Available

Order Test & Results PendingOrder Test & Results Pending

Test Results AvailableTest Results Available

confidential

An Integrative ApproachAn Integrative Approach

Clinical UtilityClinical Utility• Probability AssessmentProbability Assessment• EconomicsEconomics• Clinical GuidanceClinical Guidance• EducationEducation

TechnologyTechnology

Analysis and Analysis and InterpretationInterpretation

Clinical PracticeClinical Practice““Guidelines” Guidelines”

and Algorithmsand Algorithms

DevelopmentDevelopmentSharon MarshSharon MarshJulia AdamsJulia AdamsGenevieve DufourGenevieve DufourAndrew BrownAndrew BrownSteve GeoffroySteve GeoffroyMathieu Langlois Mathieu Langlois Ian MongrainIan MongrainValerie NormandValerie NormandYannick RenaudYannick Renaud

Bio-InformaticsBio-InformaticsTibor Van RooijTibor Van RooijChris BeckChris BeckMarc BouffardMarc BouffardMichal BlazejczykMichal BlazejczykPaul GuelpaPaul Guelpa

Genome QuebecGenome Quebec

Childrens Mercy Hospital, Kansas City, MOChildrens Mercy Hospital, Kansas City, MOAndrea GaedigkAndrea Gaedigk

LavalLavalPhilippe RigaultPhilippe Rigault

Illumina Inc.Illumina Inc.Crane HarrisCrane HarrisMark HansonMark HansonRichard ChenRichard ChenCharles LinCharles Lin

AutogenomicsAutogenomicsNani DattaguptaNani DattaguptaPaul HujsakPaul HujsakKen FuKen Fu

GATC ProjectGATC ProjectMichael HaydenMichael HaydenBruce CarletonBruce CarletonColin RossColin Ross

CollaboratorsCollaborators

PharmacogenomicClinical Studies

PharmacogenomicClinical Studies

Oct. 2, 2009Oct. 2, 2009

Michael S. Phillips Ph.D.Michael S. Phillips Ph.D.Dir. of Pharmacogenomics, Genome QuebecDir. of Pharmacogenomics, Genome QuebecAssociate Professor, Associate Professor, Université de MontrUniversité de Montrééalal