Pharmacogenomic Clinical Studies
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Transcript of Pharmacogenomic Clinical Studies
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