Prasugrel Background and PRINCIPLE – TIMI 44 Stephen D. Wiviott, MD Cardiovascular Division Brigham and Women’s Hospital Assistant Professor of Medicine Harvard Medical School Investigator, TIMI Study Group

Adhesion 1 Platelets Lipid core Collagen GP la/lla bind von Willebrand Factor/GP lb bind Activation 2 Thrombin ADP 5 HT TXA 2 Aggregation 3 Fibrinogen Activated GP llb/llla Handin RI. Harrison’s Principles of Internal Medicine. Vol 1. 14th ed. NY, NY: McGraw-Hill; 1998:339. Schafer AI. Am J Med. 1996;101: Platelet Cascade in Thrombus Formation

Inhibition of Platelet Purinergic Receptors Storey F, et al. Platelets. 2001;12:197. Receptorsubtype Molecularstructure Secondarymessengersystem Functionalresponse P2Y 12 Inhibitor P2X 1 P2Y 1 P2Y 12 P2X 1 P2Y 1 P2Y 12 G proteinG protein Intrinsic ion GPCR GPCR channel G q G i ↓ ↓↓ ↑[Na + /Ca 2+ ] i ↑PLC/IP 3 ↓AC ↑[Ca 2+ ] i ↓[cAMP] ↑[Ca 2+ ] i ↓[cAMP] ↓↓↓ Shape change Shape change Sustained aggregation transient aggregation aggregation aggregation transient aggregation aggregation secretion secretion

Clopidogrel Across Spectrum of CAD COMMIT † (CCS-2) CAPRIE § Lancet 1996 MI/S troke/PAD High-Risk Vascular Disease STEMI Acute STEMI Long-term 2 o (1º) prevention UA/NSTEMI PCI UA/NSTEMI + Benefit 1 Year + Benefit 1-3 Years 30 Days + Benefit CLARITY * CURE † CREDO † CHARISMA † *Clopidogrel vs. placebo. † Clopidogrel + ASA. § Clopidogrel vs. ASA. CLARITY  20%CV death/MI/ re-isch COMMIT  9%death/MI/stroke  18.4%CV death/MI/ stroke  26.9% death/MI/ stroke  8.7% risk reduction death/MI/ stroke  7%CV death/MI/ stroke PCI Up to 3.5 years Benefit in symptomatic patients only

The First Clopidogrel Resistance Study (300 mg): A “Fingerprint” of Clopidogrel Response Variability Gurbel PA et al. Circulation. 2003;107: Hours 5 Days  Aggregation (%) Resistance = 63% Resistance = 31% Resistance Resistance = 31% Resistance Resistance = 15%  Aggregation (%) Resistance Patients (%) ≤ -30 (-30,-20] (-20,-10] (-10,0] (0,10] (10,20] (20,30] (30,40] (40,50] (50,60] >60 Patients (%) ≤ -10(-10,0](0,10](10,20](20,30](30,40](40,50](50,60]> ≤ -30 (-30,-20] (-20,-10] (-10,0] (0,10] (10,20] (20,30] (30,40] (40,50] (50,60] > ≤ -30 (-30,-20] (-20,-10] (-10,0] (0,10] (10,20] (20,30] (30,40] (40,50] (50,60] >60  Aggregation (%) Resistance Patients (%) 24 Hours 30 Days

GP IIb/IIIa receptor expression P2Y 12 receptor (irreversible inhibition) Active metabolite Hepatic metabolism Cytochrome P450 pathway Intestinal absorption Variable absorption Drug-drug interactions Genetic polymorphisms CYP enzymes Drug-drug interactions Genetic polymorphisms P2Y 12 receptor Alternate pathways of platelet activation ↑ release of circulating ADP Higher baseline platelet reactivity Genetic polymorphisms Poor compliance Inadequate administration Potential Sites for Response Variability O’Donoghue M and Wiviott SD Circulation 2007

Clopidogrel Response Variability: Increase the Dose (300 mg vs. 600 mg) Gurbel PA et al. J Am Coll Cardiol. 2005;45: ≤-30 (-30,-20] (-20,-10] (-10,0] (0,10] (10,20] (20,30] (30,40] (40,50] (50,60] (60,70] > mg Clopidogrel 600 mg Clopidogrel   Aggregation (5 µM ADP-induced Aggregation) at 24 Hr Patients (%) Resistance = 28% (300 mg) Resistance = 8% (600 mg)

Clopidogrel Response Variability: Change the Agent? Prasugrel Pro-drug Oxidation (Cytochrome P450) HOOC * HS N O F Active Metabolite N S O F O Hydrolysis(Esterases) N S O CH 3 C O F O N S O ClO CH 3 C Clopidogrel 85% Inactive Metabolites Esterases N S O Cl O CH 3 C O N S O Cl O C Active Metabolite HOOC * HS N O Cl OCH 3 Herbert JM, Savi P. Sem Vasc Med. 2003;3:

Inhibition of Platelet Aggregation (IPA) at 24 Hours (Healthy Volunteers) Inhibition of Platelet Aggregation (%) Response to Prasugrel Response to Clopidogrel Clopidogrel Responder Clopidogrel Non-responder *Responder =  25% IPA at 4 and 24 h Interpatient Variability Brandt JT et al. Am Heart J. 2007;153:66.e9-e16.

In Vitro Antiplatelet Effects of Active Metabolites in PRP * P < 0.05 ** P < 0.01 vs. control Ogawa, et al ESC 2005.

Prasugrel 60 mg Time in Hr Plasma Concentration (ng/ml) Clopidogrel 300 mg ISTH 2005 Payne et al, P0952 Insights into Potency : Active Metabolite Levels in Humans (Crossover Study)

Copyright ©2007 American Heart Association Wiviott SD et al, Circulation 2007 Copyright ©2007 American Heart Association Wiviott SD et al, Circulation 2007 PRasugrel IN Comparison to Clopidogrel for Inhibition of PLatelet Activation and AggrEgation (PRINCIPLE) – TIMI 44

Copyright ©2007 American Heart Association Wiviott SD et al, Circulation 2007 Copyright ©2007 American Heart Association Wiviott SD et al, Circulation 2007 Study Design Loading Phase N=201 Maintenance Phase N=100 No PCI 6h* Labs, 15d Events Coronary Angiography Post-Angiography Labs Planned Elective PCI Baseline Laboratory Measures Prasugrel 60 mg Clopidogrel 600 mg 0.5 h Post-Loading Dose Labs PCI 6h* Labs, 18-24h Labs Clopidogrel 150 mg x 14d Prasugrel 10 mg x 14d Prasugrel 10 mg x 14d Clopidogrel 150 mg x 14d 15d Clinical Events, Labs, † CROSSOVER 29d Clinical Events, Labs † Clopidogrel naïve No planned GP IIb/IIIa use 1º EPs: *Loading = 6h IPA (20 µM ADP); † Maintenance = 15d or 29d IPA (20 µM ADP) Copyright ©2007 American Heart Association Wiviott SD et al, Circulation 2007

PRINCIPLE – TIMI Trial Organization US Lead and PI: S Wiviott ROW Lead: FJ Neumann US Sites (4) D. Angiolillo E. Bates M. Furman D. Purdy US Sites (4) D. Angiolillo E. Bates M. Furman D. Purdy France Lead: G. Montalescot France Lead: G. Montalescot Israel Lead: H. Hod Israel Lead: H. Hod German Lead: FJ Neumann German Lead: FJ Neumann France Sites (3) J-L Bonnet B Charbonnier E Van Belle France Sites (3) J-L Bonnet B Charbonnier E Van Belle German Sites (5) M Gawaz A Schomig R Voss B Witzenblicher FJ Neumann German Sites (5) M Gawaz A Schomig R Voss B Witzenblicher FJ Neumann Israel Sites (3) L Gruberg H Danenberg S Matetsky Israel Sites (3) L Gruberg H Danenberg S Matetsky Study Chairman: Eugene BraunwaldDirector: Carolyn McCabe

Copyright ©2007 American Heart Association Wiviott SD et al, Circulation 2007 Copyright ©2007 American Heart Association Wiviott SD et al, Circulation 2007 PRIMARY EP Acute Phase: IPA 20 uM ADP Prasugrel 60 mg P< for each IPA (%; 20  M ADP) Copyright ©2007 American Heart Association Wiviott SD et al, Circulation 2007 Hours

Copyright ©2007 American Heart Association Wiviott SD et al, Circulation 2007 Copyright ©2007 American Heart Association Wiviott SD et al, Circulation 2007 Maximal Platelet Aggregation (MPA) Prasugrel 60 mg P< for each MPA (%; 20  M ADP) Hours

Copyright ©2007 American Heart Association Wiviott SD et al, Circulation 2007 Copyright ©2007 American Heart Association Wiviott SD et al, Circulation 2007 Prasugrel 10 mg Difference Between Treatments: 14.9 [95% CI 10.6 – 19.3], P< IPA (%; 20  M ADP) Days PRIMARY EP Chronic Phase: IPA 20 uM ADP

Copyright ©2007 American Heart Association Wiviott SD et al, Circulation 2007 Copyright ©2007 American Heart Association Wiviott SD et al, Circulation 2007 Maximal Platelet Aggregation (MPA) Prasugrel 10 mg Difference Between Treatments: 11.3 [95% CI 8.1 – 14.5], P< Clopidogrel 150 mg MPA (%; 20  M ADP) Days

Copyright ©2007 American Heart Association Wiviott SD et al, Circulation 2007 Copyright ©2007 American Heart Association Wiviott SD et al, Circulation 2007 Thienopyridine Hyporesponsiveness: IPA 20 uM ADP < 20% P =0.06 P =0.18 P = P = P < P = Clopidogrel Prasugrel Hours Percent of Subjects

Copyright ©2007 American Heart Association Wiviott SD et al, Circulation 2007Implications PRINCIPLE – TIMI 44 extends the pharmacologic superiority of the TRITON – TIMI 38 dose of prasugrel (60 mg/10 mg) to higher doses of clopidogrel (600 mg/150mg) in PCI. TRITON – TIMI 38 1 tested hypothesis that an agent with higher and more consistent IPA than standard approved clopidogrel (300 mg/ 75 mg) will improve clinical outcomes 1 Wiviott SD, Braunwald E, McCabe CH et al NEJM2007