Charisma Genomics

8/14/2019 Charisma Genomics

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CHARISMA GenomicsCHARISMA Genomics

Deepak L. Bhatt MD, MPH, Katy L. Simonsen PhD, Eileen S.

Emison PhD, Keith A. A. Fox MBChB, P. Gabriel Steg MD,

Gilles Montalescot MD, PhD, Nihar Bhakta MD, Werner Hacke

MD, Marcus D. Flather MD, Patrice Cacoub MD, Mark A.

Creager MD, Peter B. Berger MD, Steven R. Steinhubl MD,

Gurunathan Murugesan PhD, Kandice Kottke-Marchant MD,

PhD, A. Michael Lincoff MD, Eric J. Topol MD, on Behalf of

the CHARISMA Executive Committee and Investigators


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Disclosure for Dr. Bhatt

Dr. Bhatt has served as a consultant to: Arena, Astra Zeneca, Bristol-Myers

Squibb, Cardax, Cogentus, Daiichi Sankyo, Eli Lilly, Eisai, Glaxo Smith Kline,

Johnson & Johnson, Medtronic, Millennium, Otsuka, Paringenix, PDL, Philips,

Portola, sanofi aventis, Schering Plough, Takeda, The Medicines Company,

Vertex.

Principal Investigator for several potentially related studies. His institution has

received funding from Bristol-Myers Squibb, Eisai, Ethicon, Heartscape, Sanofi

Aventis, The Medicines Company.

This presentation discusses off-label and/or investigational uses of various drugsand devices.

This CHARISMA study was funded by sanofi aventis and Bristol-Myers Squibb.

The genetic analyses were done by Bristol-Myers Squibbs Human Genetics and

Statistical Genetics Groups.


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Variability in Clopidogrel Responsiveness in a

Diverse Population of 544

Serebruany VL, Steinhubl SR, Berger PB, et al. JACC 2005; 45:246 51.


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Genetic Variations and Clopidogrel ResponseGenetic Variations and Clopidogrel Response

Mega JL, Close SL, Wiviott SD, et al. N Engl J Med. 2009;360:354-362.


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Genetic Variations and Clopidogrel ResponseGenetic Variations and Clopidogrel Response

Heterozygotes vs HomozygotesHeterozygotes vs Homozygotes

Simon T, et al. N Engl J Med. 2009;360:363-375.

Probability of all-cause death, recurrent myocardial infarction, and stroke (%) according to

CYP2C19 loss of function variant allele polymorphisms in the FAST MI registry


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Population RR (95% CI) p value

Qualifying CAD, CVD or PAD * 0.88 (0.77, 0.998) 0.046(n=12,153)

Multiple Risk Factors * 1.20 (0.91, 1.59) 0.20

(n=3,284)

Overall Population 0.93 (0.83, 1.05) 0.22(n=15,603)

Primary Efficacy Results (MI/Stroke/CV

Death) by Pre-Specified Entry Category

0.6 0.8 1.41.2

Clopidogrel + ASA

Better

Placebo + ASA

Better

1.60.4

* A statistical test for interaction showed marginally significant heterogeneity (p=0.045) in treatment response for these pre-

specified subgroups of patients 166 patients did not meet any of the main inclusion criteria

Bhatt DL, Fox KA, Hacke W, et al. NEJM 2006; 354:1706-17.


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Overall Population: Principal Secondary Efficacy

Outcome (MI/Stroke/CV Death/Hospitalization)

First Occurrence of MI, Stroke, CV Death, or Hospitalization for UA, TIA, or Revascularization

*All patients received ASA 75-162 mg/day

The number of patients followed beyond 30 months decreases rapidly to zero

Placebo + ASA*

17.9%

Clopidogrel + ASA*

16.7%

RRR: 7.7% [95% CI: 0.5%, 14.4%]

p = 0.04Cumulativee

ventrate(%)

0

5

10

15

20

Months since randomization0 6 12 18 24 30

Bhatt DL, Fox KA, Hacke W, et al. NEJM 2006; 354:1706-17.


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Primary Endpoint (MI/Stroke/CV Death) in

Patients With Previous MI, IS, or PAD*CAPRIE-like Cohort

* Post hoc analysis.

Bhatt DL, Flather MD, Hacke W, et al.J Am Coll Cardiol. 2007;49:1982-1988.


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Aims

To determine the effect of CYP2C19 polymorphisms on CV death, MI,

stroke in patients randomized to clopidogrel versus placebo in a stable CV

population

To assess the impact on severe or moderate GUSTO bleeding

To assess the impact on CV death, MI, stroke, or hospitalization for

ischemic events (more events)

To examine effects in higher risk subgroups

To assess the impact on any GUSTO bleeding (more events)


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Methods

A subset (N=4862) of the 15,603 patients enrolled into CHARISMA who consented were

genotyped for CYP2C19*2, *3, and *17 alleles

Genotyping details

*2 and *17 were genotyped by Restriction Fragment Length Polymorphism

*3 was genotyped by Taqman allelic discrimination assay

Accuracy: 11% of samples were genotyped in duplicate; no errors were identified in the

replicates

Statistical methods:

A Cox model of time to primary event, with treatment, genotype, and treatment by

genotype interaction terms, was used to elucidate the genotype effect

Covariates used in the genetic analyses were: inclusion criterion (symptomatic versus

asymptomatic), prior use of statins, prior use of calcium channel blockers, and smoking

Bleeding events were analyzed with logistic regression using the same terms


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Genotype Frequencies

n = 4862


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K-M Survival Curves by Genotype

Subjects with genotype frequencies < 5 were excluded from the analysis.

Survival curves are truncated at 30 months.

Uncorrectedp-value for testing the difference of time to

primary event between genotype groups, from the log-rank

test: 0.166

Uncorrectedp-value for testing the difference of time to

primary event between genotype groups, from the log-rank

test: 0.162


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Cox Model HRs by Treatment Arm

*2/*2 has

increased risk in

clopidogrel arm,

but much of this

risk is alsopresent in

placebo arm

(0.28, 1.74)0.6960.44*17/*17 vs WT/WT

(0.61, 1.40)0.9270.72*17/WT vs WT/WT(0.72, 2.42)1.3220.36*2/*17 vs WT/WT

(1.14, 5.00)2.3830.022*2/*2 vs WT/WT

(0.72, 1.71)1.1120.63*2/WT vs WT/WT

Effect of Genotype in Clopidogrel Group

(0.33, 2.11)0.8410.71*17/*17 vs WT/WT

(1.00, 2.21)1.4860.052*17/WT vs WT/WT

(0.65, 2.54)1.2850.47*2/*17 vs WT/WT

(0.74, 4.65)1.8520.19*2/*2 vs WT/WT

(0.51, 1.42)0.8520.54*2/WT vs WT/WT

Effect of Genotype in Placebo Group

(0.83, 1.77)1.2090.33Treatment vs Placebo

95% CI for HRHRp valueEffect


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Hazard Ratios

* Primary Analysis


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Caveat: Small Number of Primary Events

Clopidogrel

20 (0%)*2/*3

20 (0%)*3/WT

1135 (4.42%)*17/*17

64337 (5.75%)*17/WT

17013 (7.65%)*2/*17

588 (13.79%)*2/*2

49033 (6.73%)*2/WT

95057 (6%)WT/WT

TotalNumber (%) of

Subjects with

Primary Event

Genotype

Placebo

20 (0%)*2/*3

10 (0%)*3/WT

1135 (4.42%)*17/*17

64248 (7.48%)*17/WT

15910 (6.29%)*2/*17

575 (8.77%)*2/*2

48921 (4.29%)*2/WT

97149 (5.05%)WT/WT

TotalNumber (%) of

Subjects with

Primary Event

Genotype


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Secondary Endpoint: Hazard Ratios


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Symptomatic Subpopulation (N=3666):

Hazard Ratios


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CAPRIE-like Subpopulation (N=2773):

Hazard Ratios


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GUSTO moderate and severe:

Logistic Regression ORs by Treatment Arm

Significantly

decreased bleeding

risk for *2/wt

compared with wt/wt

on placebo

Result is based on

very few events

No conclusions for*2/*2 (3 vs 0 events)

(0.012, 1.018)0.2170.054*17/*17 vs WT/WT

(0.619, 1.714)1.0310.906*17/WT vs WT/WT

(0.339, 2.029)0.9050.823*2/*17 vs WT/WT

0.0000.033*2/*2 vs WT/WT

(0.777, 2.214)1.3220.297*2/WT vs WT/WT


(0.190, 2.291)0.8010.709*17/*17 vs WT/WT

(0.377, 1.330)0.7230.302*17/WT vs WT/WT

(0.231, 2.018)0.7850.644*2/*17 vs WT/WT

(0.400, 4.985)1.7070.420*2/*2 vs WT/WT

(0.106, 0.742)0.3130.007*2/WT vs WT/WT


(0.756, 2.007)1.2280.407Treatment vs Placebo

95% CI for ORORp valueEffect


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All GUSTO bleeding events:

Logistic Regression ORs by Treatment Arm

Significantly more

bleeding events in

wt/wt subjects on

clopidogrel

compared with

placebo

Significantly

reduced risk of

bleeding events for

the *2/*2 genotypevs wt/wt on

clopidogrel

Risk in *2/*2 is not

significantlydifferent between

(0.860, 1.891)1.27700.2236*17/*17 vs WT/WT

(0.824, 1.238)1.01000.9222*17/WT vs WT/WT

(0.513, 1.020)0.72700.0652*2/*17 vs WT/WT

(0.160, 0.619)0.32904 x 10-4*2/*2 vs WT/WT

(0.683, 1.070)0.85500.1712*2/WT vs WT/WT


(0.469, 1.278)0.79100.3477*17/*17 vs WT/WT

(0.769, 1.243)0.97900.8618*17/WT vs WT/WT

(0.748, 1.641)1.11800.5803*2/*17 vs WT/WT

(0.340, 1.400)0.72500.3528*2/*2 vs WT/WT

(0.821, 1.374)1.06400.6392*2/WT vs WT/WT


(1.978, 2.943)2.4110


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Limitations

Genotyped patients differed from non-genotyped patients

Overall trial was negative for the primary endpoint, so power is somewhat limited

Secondary endpoint was positive and more than doubles events, but still no

relationship with heterozygotes and outcomes

Higher risk subgroups also did not find relationship with heterozygotes and

outcomes

Still, more events in a placebo controlled trial than any other study to date

Stable population, so results seen here may not apply to ACS

But perhaps more relevant for chronic therapy


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Conclusions

No relationship seen between CYP2C19*2 heterozygotes and outcomes

Small % of homozygotes may have worse outcome, though this is noted

to an extent in the placebo arm as well

First large study to establish potential relationship between less bleeding

and genotype

Further prospective study needed to determine clinical relevance of

CYP2C19 polymorphisms on efficacy/bleeding - and appropriate clinical

action to take - before routine testing can be recommended


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Acknowledgements

Bristol-Myers Squibb Human Genetics Group for the genotyping

Terrye A. DelMonte, B.S.

Lester E. Hui, B.S.

Bristol-Myers Squibb Statistical Genetics and Biomarkers Group

for statistical analyses Oksana Mokliatchouk, Ph.D.

Lisa R. Denogean, Ph.D.

Lionel Thevathasan, M.D., sanofi aventis, for reviewing

Stuart Wakelin, Ph.D. and George Clarkson, Ph.D. from Alpha-Plus

Medical Communications Ltd for graphical support (funded by

sanofi aventis)


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Q+A


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Backup Slides


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All GUSTO bleeding events:

Counts and Interactions by Treatment Arm

Significantly more

bleeding events in

wt/wt subjects on

clopidogrel

compared withplacebo

Significantly

reduced risk of

bleeding events forthe *2/*2 genotype

vs wt/wt on

clopidogrel

Risk in *2/*2 is notsignificantly

2(50%)1Placebo

2(50%)1Clopidogrel*2/*3

1(100%)1Placebo

2(0%)0Clopidogrel*3/WT

0.348113(18.6%)21Placebo0.134

0.224113(46.9%)53Clopidogrel

*17/*17

0.862642(22.3%)143Placebo0.845

0.922643(41.4%)266Clopidogrel*17/WT

0.580159(24.5%)39Placebo0.107

0.065170(34.1%)58Clopidogrel*2/*17

0.35357(17.5%)10Placebo0.1130.000458(19.0%)11Clopidogrel*2/*2

0.639489(23.7%)116Placebo0.211

0.171490(37.6%)184Clopidogrel*2/WT

971(22.7%)220Placebo

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Charisma Genomics