New Anti-platelet Agents Toni L. Ripley, Pharm.D., BCPS, AQ-Card Associate Professor Cardiovascular Pharmacy Specialist American College of Cardiology Oklahoma Chapter, Annual Meeting April 10, 2010

Disclosures None

Overview Review mechanisms of platelet aggregation Summarize where current and investigational therapies fit in the physiology of platelet aggregation Review contemporary controversies of anti-platelet therapy

Dorsam and Kunapuli. J Clin Invest 2004;113:340-345. Gross and Weitz. Clin Pharmacol Ther 2009;86:139-146.

Eptifibatide Abciximab Tirofiban Clopidogrel Prasugrel Gross and Weitz. Clin Pharmacol Ther 2009;86:139-146.

New Anti-platelet Agents: An Overview

Prasugrel (Effient®) Oral thienopyridine P2Y12 irreversible inhibitor Approved for reduction of thrombosis in patients with ACS who are managed with PCI. TRITON-TIMI 38 Prodrug, requires biotransformation in a two-step process Wiviott, et all. NEJM 2007;357:2001-15

Metabolism (15%) (85%) From: J Clin Pharmacol 2008;48:53-59

Platelet inhibition: Prasugrel versus clopidogrel Maximal Platelet Inhibition (Light Transmission Aggregometry)1 P2Y12 Reaction Units (VerifyNow Assay)2 1Wallentin, et al. Eur Heart J 2008;29:21-30; 2Varenhorst, et al. Am Heart J 2009;157:e1-e9.

Ticagrelor (Brilinta®) Oral non-thienopyridine P2Y12 inhibitor Cyclopentyl-triazolo-pyrimidine (CPTP) Potent, reversible binding and non-competitive with ADP No biotransformation Metabolized to equipotent, active metabolite by CYP3A4 PLATO Wallentin et al. NEJM 2009;361:1045-57

Platelet inhibition: Ticagrelor versus clopidogrel Inhibition of platelet aggregation (Light Tranmission Aggregometry) P2Y12 Reaction Units (VerifyNow Assay) Platelet Reactivity Index, VASP-P Gurbel et al. Circulation 2009;120:2577-2585

Overview of other pipeline agents Cangrelor1, 2 Vorapaxar3 (SCH 530348) Elinogrel4 (PRT 060128) Drug class/chemistry Non-thienopyridine ATP analogue PAR-1 receptor blocker Direct P2Y12 ADP-receptor antagonist Effect on receptor Reversible FDA status Phase II/III Phase III Phase II Administration Intravenous Oral Intravenous and oral Clinical data CHAMPION – PLATFORM and PCI BRIDGE TRA●CER TIMI-50 ERASE MI INNOVATE-PCI 1NEJM 2009;361:2330-41; 2NEJM 2009;361:2318-29; 3Lancet 2009;373:919-28; 4Am Heart J 2009;158:998-1004

The Controversies

Limitations of current therapies Cardiovascular event rate1, 2, 3, 4 Aspirin resistance/failure5 Clopidogrel Variability of response6 Compliance Genetic polymorphisms Drug interactions Bleeding risk 1Yusuf, et al. NEJM 2001;345(7):494-502;2Mehta, et al. Lancet 2001;358:527-33;3Chen, et al. Lancet 2005;366:1607-21;4Bhatt et al. NEJM 2006;354:1706-17;5Patrono, et al. Chest 2008;133:199S-233S;6Angiolillo. Am J Cardiol 2009;103[suppl];27A-34A.

Pharmacogenetics Plavix (clopidogrel) label. Accessed from www.fda.gov on March 29, 2010

Polymorphism effects NEJM 2009;360:354-62; Circulation 2009;119:2553-2560

CYP2C19 Reduced-function Allele Carrier Status and Clinical Outcomes in Clopidogrel-treated Patients PRESENTATION TIP This slide presents the clopidogrel clinical outcome data in TRITON-TIMI 38 based on the CYP2C19 genotype in relation to clopidogrel metabolism. Emphasize that this slide shows the impact of genetic variation, not a comparison between prasugrel and clopidogrel. KEY POINTS DNA was collected from 1477 patients with ST-elevation myocardial infarction (MI) and non-ST-elevation ACS treated with prasugrel (60-mg/day loading dose, followed by a 10-mg/day maintenance dose) in the TRITON-TIMI 38 trial.1 395 patients carried at least one CYP2C19 reduced-function allele.1 Patients in this substudy are not reflective of the overall population. Thus, a direct comparison of the prasugrel data cannot be made to the clopidogrel data from this substudy.1 Clopidogrel-treated patients showed an association between CYP2C19 reduced-function allele carrier status and the primary efficacy endpoint of cardiovascular death, nonfatal MI, or nonfatal stroke (carriers, 12.1% vs non- carriers, 8.0%; 95% CI=1.07–2.19; P=0.01).1 Pharmacogenetic analyses were performed on 2943 patients enrolled in a pharmacogenetic substudy of TRITON- TIMI 38. In this genetic substudy, the rate of the primary efficacy endpoint (CV death, nonfatal MI, or nonfatal stroke) in the prasugrel arm (9.4%) was similar to the rate in the overall trial (9.9%); in contrast, the rate in the clopidogrel arm (9.3%) was lower than the rate observed in the overall trial (12.1%). The inconsistency between the observed rates for the pharmacogenetic substudy and those of the overall trial limits interpretation of between drug comparisons.2 BACKGROUND Of these patients, 71.0% presented with non-ST-elevation acute coronary syndromes, and 29.0% presented with ST-elevation MI. Patients carrying a CYP2C19 reduced-function allele had a higher rate of each component of the primary efficacy endpoint compared with non-carriers. This included death from cardiovascular causes (2.0% vs 0.4%; HR, 4.79; 95% CI, 1.40–16.37), nonfatal MI (10.1% vs 7.5%; HR, 1.38; 95% CI, 0.94–2.02), and nonfatal stroke (0.88% vs 0.24%; HR, 3.93; 95% CI=0.66–23.51). Rates of the endpoints were expressed as Kaplan-Meier estimates at 15 months, and were compared between carriers and non-carriers of at least 1 reduced-function CYP allele. REFERENCES Mega JL, Close SL, Wiviott SD, et al. Cytochrome P-450 polymorphisms and response to clopidogrel. N Engl J Med. 2009;360:354-362. Data on File: EFF20091219a, DSI/Lilly.

CYP2C19 Reduced-function Allele Carrier Status and Clinical Outcomes in Prasugrel-treated Patients PRESENTATION TIP This slide presents the prasugrel clinical outcome data in TRITON-TIMI 38 based on the CYP2C19 genotype in relation to prasugrel metabolism. Emphasize that this slide shows the impact of genetic variation, not a comparison between prasugrel and clopidogrel. KEY POINTS DNA was collected from 1466 patients with ST-elevation myocardial infarction and non–ST-elevation ACS treated with prasugrel (60-mg/day loading dose, followed by a 10-mg/day maintenance dose) in the TRITON-TIMI 38 trial. Four hundred seven patients carried at least 1 CYP2C19 reduced-function allele.1 Patients in this substudy are not reflective of the overall population. Thus, a direct comparison of the prasugrel data cannot be made to the clopidogrel data from this substudy. Pharmacogenetic analyses were performed on 2943 patients enrolled in a pharmacogenetic substudy of TRITON-TIMI 38. In this genetic substudy, the rate of the primary efficacy endpoint (CV death, nonfatal MI, or nonfatal stroke) in the prasugrel arm (9.4%) was similar to the rate in the overall trial (9.9%); in contrast, the rate in the clopidogrel arm (9.3%) was lower than the rate observed in the overall trial (12.1%). The inconsistency between the observed rates for the pharmacogenetic substudy and those of the overall trial limits interpretation of between drug comparisons.2 Prasugrel-treated patients showed no association between CYP2C19 reduced-function allele carrier status and the primary efficacy endpoint of cardiovascular death, nonfatal MI, or nonfatal stroke (carriers, 8.5% vs non-carriers, 9.8%; 95% CI=0.60–1.31; P=0.27).1 In healthy subjects, patients with stable atherosclerosis, and patients with ACS receiving prasugrel, there was no relevant effect of genetic variation in CYP2B6, CYP2C9, CYP2C19, or CYP3A5 on the pharmacokinetics of the active metabolite of prasugrel or its inhibition of platelet aggregation.3 BACKGROUND Of these patients, 69.8% presented with non–ST-elevation acute coronary syndromes, and 30.2% presented with ST-elevation myocardial infarction. No differences in hazard were observed for the individual components of the primary efficacy endpoint for carriers vs non-carriers for CV death (carriers, 0.99% vs non-carriers, 1.58%; HR, 0.80; 95% CI, 0.26–2.47; P=0.70); nonfatal MI (carriers, 6.6% vs non- carriers, 8.1%; HR, 0.82; 95% CI, 0.53–1.27; P=0.37); or nonfatal stroke (1.0% vs 0.82%; HR, 1.30; 95% CI, 0.39–4.31;P=0.67) in prasugrel treated patients. Rates of the endpoints were expressed as Kaplan-Meier estimates at 15 months, and were compared between carriers and non- carriers of at least 1 reduced-function CYP allele. No significant associations between any of the other CYP genotypes and the primary efficacy outcome were observed, nor did the rates of non–CABG-related TIMI major or minor bleeding differ significantly across any CYP genotype. REFERENCES Mega JL, Close SL, Wiviott SD, et al. Cytochrome P-450 genetic polymorphisms and the response to prasugrel: relationship to pharmacokinetic, pharmacodynamic, and clinical outcomes. Circulation. 2009;119:2553-2560. Data on File: EFF20091219a, DSI/Lilly USA, LLC. Effient Full Prescribing Information. Daiichi Sankyo, Inc. and Lilly USA, LLC.

Drug Interactions

Drug Interactions – What we know The mechanism: Strength of inhibition of PPIs on 2C19: Omeprazole = esomeprazole > pantoprazole > lansoprazole > rabeprazole CYP 2C19, 1A2, 2B6 CYP 2C19, 3A4, 2C9, 2B6 J Clinn Pharmacol 2008;48:53-59; Clin Pharmacokinet 2008;47:1-6

Death or re-hospitalization for ACS (%) VA Cohort Study Death or re-hospitalization for ACS (%) Adjusted OR 1.25, 95% CI, 1.11-1.41 Individual PPIs sub-study: omeprazole 59.7% (3132): OR 1.24, 95% CI 1.08-1.41; rabeprazole 2.9% (151): OR 2.83, 95% CI 1.96-4.09 Ho et al. JAMA 2009;301:937-944

Medco Outcomes Study: Effect of individual PPIs on risk of major CV events Number at Risk No PPI 9862 9235 8952 8818 8717 8622 8546 8459 8380 8318 8253 8197 8136 Omeprazole 2307 2117 2032 1992 1954 1915 1885 1860 1827 1803 1176 1758 1738 Esomeprazole 3257 3008 2891 2823 2782 2729 2694 2648 2596 2559 2529 2494 2460 Pantoprazole 1653 1501 1416 1378 1341 1312 1294 1276 1255 1235 1216 1194 1179 Lansoprazole 785 719 692 673 660 650 644 637 626 620 613 608 598 HR 1.61 (1.44-1.81 ), p<0.0001 29.2% Pantoprazole HR 1.39 (1.16-1.67 ), p=0.0004 24.3% Lansoprazole HR 1.57 (1.40-1.76 ), p<0.0001 24.9% Esomeprazole HR 1.39 ( 1.22-1.57), p<0.0001 25.1% Omeprazole Ref 17.9% No PPI http://www.theheart.org/article/967075.do

Drug Interactions – what we do not know Other potential mechanisms Shunting towards inactive pathway 2C19 competition Transport p-glycoprotein Clinical impact Clinical outcomes versus platelet inhibition

Drug interactions – new antiplatelets Effect with new antiplatelets Prasugrel Ticagrelor 3A4, 2D6 2C9, 2C19

Effect of separate administration of omeprazole with clopidogrel Bristol Myers Squibb Internal Data *No statistics provided MAI* *MAI – Maximum platelet aggregation intensity, % Concomitant administration 12-hour separate administration BMS unpublished data

Drug Interactions - Summary A clinically relevant drug interaction is a possibility. It may be a problem with all PPIs No good strategy to mitigate interaction Prasugrel Until this interaction is ruled out: H2-Blocker PPIs for patients at higher risk of GIB. Use PPIs that have the least effect on 2C19 (pantoprazole)

Risk of Bleeding

Bleeding risks – CURE1 *ACUITY definition, P<0.05 for all; no significant difference when TIMI or GUSTO definitions were applied 1Yusuf et al. NEJM 2001;345:494-502

For every 1000 patients treated: TIMI-381 - Prasugrel 6 patients will have a major bleed 5 will have a life-threatening bleed 3 will have a fatal bleed PLATO2 (similar definition to ACUITY) – Ticagrelor - No increased in overall major bleeding per study or TIMI criteria, but 1 patient will have a fatal intracranial bleed 6-7 patients will have major bleeding unrelated to CABG 1NEJM 2007;357:2001-2015; 2NEJM 2009;361:1045-57

New Antiplatelet Agents Improved CV event rates Less risk of drug interactions Less risk of variation Increased risk of bleeding

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