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Increasing Clopidogrel Based on CYP2C19 Genotype in Patients with Cardiovascular Disease JL Mega, W Hochholzer, AL Frelinger III, MJ Kluk, S Isserman, WJ Rogers, DJ Angiolillo, DJ Kereiakes, CT Ruff, DD Berg, J Cyr, BM Scirica, L Grip, RA Mesa,

SLIDE 1

Increasing Clopidogrel Based on CYP2C19 Genotype in Patients with Cardiovascular Disease

JL Mega, W Hochholzer, AL Frelinger III, MJ Kluk, S Isserman, WJ Rogers, DJ Angiolillo, DJ Kereiakes, CT Ruff, DD Berg, J Cyr, BM Scirica, L Grip, RA Mesa, JF Mattimore, JA Longtine, AD Michelson, MS Sabatine

SLIDE 2

Trial Organization

TIMI Study Group

Brigham and Women’s Hospital Harvard Medical School

M Sabatine, MD, MPH (Chairman) J Mega, MD, MPH (PI) W Hochholzer, MD & C Ruff, MD, MPH (Co-Inv) L Grip, BA (Project Director) R Mesa, BS & J Mattimore, BA (Research Monitors) J Cyr, PA & D Berg, MD (Medical Monitors) C Contant, PhD (Director of Biostats) S Mohanavelu, MS & K Crowley, MS (Stats)

Clinical Events Adjudicator

B Scirica, MD, MPH

Independent Data Monitor

UT Southwestern

J de Lemos, MD

Platelet Function Laboratory

Children’s Hospital

A Michelson, MD A Frelinger, PhD

Genotyping Laboratory

Brigham and Women’s Hospital

J Longtine, MD, PhD M Kluk, MD, PhD

Independent Biostatistics

Harvard Clinical Research Institute

M Pencina, PhD L Lei & G Doros, PhD

Supported by an Investigator-Initiated Grant from Bristol-Myers Squibb & Sanofi-Aventis. Research Supplies from Accumetrics and Nanosphere.

SLIDE 3

PI: Goldberg RC: Barrett

La Mesa, CA

Dr. Blonder

RC: Gneiting

Colorado Springs, CO

PI: Ferrier RC: Hockett

Rapid City, SD

PI: Peart RC: Stephens

Tucson, AZ

PI: Peterson RC: Pape

Spokane, WA

PI: Chandna RC: Holly

Victoria, TX

PI: Bhagwat RC: Winterrowd

Hammond, IN

PI: Ginete RC: Gunderson

Duluth, MN

PI: Hamroff RC: Fuerst-Carter

Cortland Manor, NY

PI: Albirini RC: Campbell

Zanesville, OH

PI: Bertolet RC: McDuffie

Tupelo, MS

PI: Korban RC: Manns

Jackson, TN

PI: Fastabend RC: Bruney

Lake Charles, LA

PI: Kereiakes RC: White

Cincinnati, OH

PI: Staniloae RC: Pinassi

New York, NY

PI: Wefald RC: Moore

Smithfield, NC

PI: Isserman RC: Moore

Hickory, NC

PI: Gips RC: Davis

Haddon Heights, NJ

PI: Rogers RC: Thorington

Birmingham, AL

PI: Vicari RC: St. Cyr

Melbourne, FL

PI: Sotolongo RC: Jones

Jacksonville Beach, FL

PI: Iteld RC: Stevenson

Slidell, LA

PI: Katopodis RC: Knap

Tallahassee, FL

PI: Doty RC: Parsons

Pensacola, FL

PI: Angiolillo RC: McElveen

Jacksonville, FL

PI: Reddy RC: Qureshi

Atlanta, GA

PI: Cole RC: Fisher

Baltimore, MD

PI: Haskel RC: Powell

Baltimore, MD

PI: Denning RC: Cuenot

Canton, OH

PI: Aycock RC: Tatum

Pensacola, FL

PI: Jones RC: Stover

Birmingham, AL

PI: Katopodis RC: Hernandez

Huston, TX

SLIDE 4

24 Hours After 300mg Clopidogrel

Gurbel PA et al. Circulation 2003;107:2908-13.

10 20 ≤ -30 (-30,-20) (-20,-10) (-10,0) (0,10) (10,20) (20,30) (30,40) (40,50) (50,60) >60

 Platelet Aggregation Before and After Clopidogrel (%) Patients (%)

N=96, Elective PCI

Variable Response to Clopidogrel

SLIDE 5

N S O Cl O CH3 C

Clopidogrel (pro-drug)

Clopidogrel → Active Metabolite

85% Inactive Metabolites

hCE1 Active Metabolite

HOOC * HS N O Cl OCH

CYPs: 2C19 1A2 2B6 CYPs: 2C19 3A 2B6 2C9

O N S O Cl O CH3 C

26%

Clopidogrel Metabolite (Log AUC0-t)

Clopidogrel 75 mg

CYP2C19 Reduced- Function Alleles

(non-carriers/ wild-type)

1

(heterozygotes)

2

(homozygotes)

28% Carriers 2%

Mega JL, Close SL, Wiviott SD et al. N Eng J Med. 2009;360:354-62.

SLIDE 6

Increasing the daily maintenance

dose of clopidogrel in patients who carry a CYP2C19*2 allele will reduce platelet reactivity.

Among carriers of CYP2C19*2, a

higher maintenance dose of clopidogrel will reduce platelet reactivity to the levels achieved in non-carriers treated with the standard 75 mg daily dose of clopidogrel.

Hypotheses

SLIDE 7

Each dose given for ~14 days followed by platelet function testing (VASP and VerifyNow P2Y12 assays) and assessment for events 335 Patients Enrolled

Stable CAD Pts on Clopidogrel 75 mg daily (>4 Weeks and <6 Months Post-MI or PCI)

333 Blinded Genotyping 86 CYP2C192 Carriers (80 Heterozygotes; 6 Homozygotes) 247 CYP2C192 Non-Carriers

75 mg

2 Not Genotyped

Study Design

Investigator-Initiated Study IND #: 107635 Randomized to various blinded sequences

f daily doses of clopidogrel

Randomized to various blinded sequences

f daily doses of clopidogrel

75 mg 150 mg 150 mg 75 mg 225 mg 300 mg 150 mg

SLIDE 8

58 70 87 50 55 60 65 70 75 80 85 90 95

Squares represent the means and vertical lines the 95% confidence intervals.

75 mg Clopidogrel Daily

VASP PRI

Non- Carriers CYP2C19*2 Heterozygotes CYP2C19*2 Homozygotes

164 226 329 100 150 200 250 300 350 400

PRU

VerifyNow PRU

<0.001 <0.001 <0.001 <0.001

Non- Carriers CYP2C19*2 Heterozygotes CYP2C19*2 Homozygotes

SLIDE 9

70 61 53 49 40 45 50 55 60 65 70 75 75 150 225 300

Clopidogrel Daily Dose (mg) %

Ptrend<0.001

Squares represent the means and vertical lines the 95% confidence intervals.

CYP2C19*2 Heterozygotes

226 188 153 128 100 150 200 250 75 150 225 300

PRU

Ptrend<0.001

VASP PRI VerifyNow PRU

SLIDE 10

P<0.001

52% 26% 10% 10%

0% 10% 20% 30% 40% 50% 60%

75 150 225 300

P=0.002 P=0.90 Percent

Clopidogrel Daily Dose (mg)

Ptrend<0.001

CYP2C19*2 Heterozygotes

Non-Responders (PRU≥230)

SLIDE 11

CYP2C19*2 Heterozygotes 164 226 188 153 128 100 125 150 175 200 225 250 75 75 150 225 300 Non- Carriers

PRU

Squares represent the means and vertical lines the 95% confidence intervals. Differences are reported as least squares differences.

 Clopidogrel in CYP2C19*2 Heterozygotes

vs. 75 mg in Non-Carriers

Clopidogrel Daily Dose (mg)

PRUdiff +61 P<0.001 PRUdiff +24 P=0.02 PRUdiff -10 P=0.31 PRUdiff -37 P<0.001

SLIDE 12

50 100 150 200 250 300 350 400 75 75 150 225 300 75 150 225 300 CYP2C192 Homozygotes CYP2C192 Heterozygotes Non- Carriers

Clopidogrel Daily Dose (mg) PRU

Squares represent the means and vertical lines the 95% confidence intervals.

Platelet Reactivity with  Clopidogrel

SLIDE 13

Clopidogrel Doses (mg) 75 150 225 300 Compliance (%) 97.3% 98.1% 98.6% 98.3% Adverse Events (n) 12 10 2 6 Serious Adverse Events (n) 2 1 TIMI Bleeding Requiring Medical Attention (n) 1 1 1 Cardiac Ischemic Events (n) 1

Compliance and Events

CYP2C19*2 Carriers

There were no deaths, cerebrovascular events, or TIMI major or minor bleeding events.

SLIDE 14

Among patients with stable CV disease:

– CYP2C192 heterozygotes: tripling the maintenance dose of clopidogrel to 225 mg daily achieved levels of platelet reactivity similar to the standard 75 mg dose in non-carriers. – CYP2C192 homozygotes: even 300 mg of clopidogrel daily, is unlikely to result in

ptimal degrees of platelet inhibition.

Conclusion

SLIDE 15

Increasing Clopidogrel Based on CYP2C19 Genotype in Patients with Cardiovascular Disease

JL Mega, W Hochholzer, AL Frelinger III, MJ Kluk, S Isserman, WJ Rogers, DJ Angiolillo, DJ Kereiakes, CT Ruff, DD Berg, J Cyr, BM Scirica, L Grip, RA Mesa, JF Mattimore, JA Longtine, AD Michelson, MS Sabatine

Trial Organization

TIMI Study Group

Brigham and Women’s Hospital Harvard Medical School

Clinical Events Adjudicator

Independent Data Monitor

UT Southwestern

Platelet Function Laboratory

Children’s Hospital

Genotyping Laboratory

Brigham and Women’s Hospital

Independent Biostatistics

Harvard Clinical Research Institute

 Platelet Aggregation Before and After Clopidogrel (%) Patients (%)

Variable Response to Clopidogrel

Clopidogrel → Active Metabolite

26%

Clopidogrel 75 mg

1

2

28% Carriers 2%

dose of clopidogrel in patients who carry a CYP2C19*2 allele will reduce platelet reactivity.

higher maintenance dose of clopidogrel will reduce platelet reactivity to the levels achieved in non-carriers treated with the standard 75 mg daily dose of clopidogrel.

Hypotheses

Each dose given for ~14 days followed by platelet function testing (VASP and VerifyNow P2Y12 assays) and assessment for events 335 Patients Enrolled

333 Blinded Genotyping 86 CYP2C19*2 Carriers (80 Heterozygotes; 6 Homozygotes) 247 CYP2C19*2 Non-Carriers

75 mg

Study Design

75 mg 150 mg 150 mg 75 mg 225 mg 300 mg 150 mg

75 mg Clopidogrel Daily

VASP PRI

VerifyNow PRU

Ptrend<0.001

CYP2C19*2 Heterozygotes

Ptrend<0.001

VASP PRI VerifyNow PRU

P<0.001

52% 26% 10% 10%

P=0.002 P=0.90 Percent

Ptrend<0.001

CYP2C19*2 Heterozygotes

Non-Responders (PRU≥230)

CYP2C19*2 Heterozygotes 164 226 188 153 128 100 125 150 175 200 225 250 75 75 150 225 300 Non- Carriers

 Clopidogrel in CYP2C19*2 Heterozygotes

50 100 150 200 250 300 350 400 75 75 150 225 300 75 150 225 300 CYP2C19*2 Homozygotes CYP2C19*2 Heterozygotes Non- Carriers

Platelet Reactivity with  Clopidogrel

Clopidogrel Doses (mg) 75 150 225 300 Compliance (%) 97.3% 98.1% 98.6% 98.3% Adverse Events (n) 12 10 2 6 Serious Adverse Events (n) 2 1 TIMI Bleeding Requiring Medical Attention (n) 1 1 1 Cardiac Ischemic Events (n) 1

Compliance and Events

CYP2C19*2 Carriers

There were no deaths, cerebrovascular events, or TIMI major or minor bleeding events.

Among patients with stable CV disease:

– CYP2C19*2 heterozygotes: tripling the maintenance dose of clopidogrel to 225 mg daily achieved levels of platelet reactivity similar to the standard 75 mg dose in non-carriers. – CYP2C19*2 homozygotes: even 300 mg of clopidogrel daily, is unlikely to result in

Conclusion

Published Online First November 16, 2011 Available at www.jama.com

333 Blinded Genotyping 86 CYP2C192 Carriers (80 Heterozygotes; 6 Homozygotes) 247 CYP2C192 Non-Carriers

50 100 150 200 250 300 350 400 75 75 150 225 300 75 150 225 300 CYP2C192 Homozygotes CYP2C192 Heterozygotes Non- Carriers

– CYP2C192 heterozygotes: tripling the maintenance dose of clopidogrel to 225 mg daily achieved levels of platelet reactivity similar to the standard 75 mg dose in non-carriers. – CYP2C192 homozygotes: even 300 mg of clopidogrel daily, is unlikely to result in