Dominick J. Angiolillo, MD, PhD, FACC, FESC Director of Cardiovascular Research Assistant Professor of Medicine Update on Novel Antiplatelet Agents Under Advanced Clinical Development CRT 2008 Wednesday February 13 th, 2008

Presenter Disclosure Information Name: Dominick J Angiolillo Within the past 12 months, the presenter or their spouse/partner have had a financial interest/arrangement or affiliation with the organization listed below. Company Name:Relationship: Bristol Myers SquibbConsultant/Speaker bureau Sanofi-AventisConsultant/Speaker bureau Eli LillyConsultant/Speaker bureau Daiichi SankyoConsultant/Speaker bureau PortolaConsultant GSKEducational Grant

Novel ADP P2Y 12 receptor antagonist PrasugrelAZD6140Cangrelor

PrasugrelAZD6140Cangrelor

Ticlopidine (1 st generation) N S Cl Clopidogrel (2 nd generation) N S Cl O O CH 3 C Prasugrel (CS-747) (LY640315) (3 rd generation) N F O S O O CH 3 The Thienopyridine Family

Active Metabolite Formation HOOC * HS N N O O F F N N S S O O C C H H 3 3 C C O O F F Active Metabolite Prasugrel Sankyo Ann Report 51:1,1999Clopidogrel Pro-drugPro-drug Hepatic Metabolism Cytochrome P450 Active Metabolite N N S S O O F F O O HOOC * HS N N O O Cl OCH 3 Sem Vasc Med 3:113, 2003 Pre-hepatic metabolism Esterases in blood (? Small Intestine) O O 85% Inactive Metabolites Esterases in blood O O N N S S O O Cl O O CH 3 CC N N S S O O Cl O O CH 3 CC N N S S O O Cl O O CH 3 CC

Healthy volunteer crossover study IPA (20  M ADP) at 24 hours Brandt J et al. AHJ 2006 – Inhibition of platelet aggregation (%) Response to prasugrel 60 mg Response to clopidogrel 300 mg N=64

HR 0.81 ( ) P= Prasugrel Clopidogrel Days Endpoint (%) HR 1.32 ( ) P=0.03 Prasugrel Clopidogrel events 35 events Balance of Efficacy and Safety CV Death / MI / Stroke TIMI Major NonCABG Bleeds NNT = 46 NNH = 167 Wiviott et al NEJM 2007

Stent Thrombosis (ARC Definite + Probable) HR 0.48 P < Prasugrel Clopidogrel 2.4 (142) NNT= (68) Days Endpoint (%) Any Stent at Index PCI N= 12,844

Diabetic Subgroup HR 0.70 P<0.001 Days Endpoint (%) CV Death / MI / Stroke TIMI Major NonCABG Bleeds NNT = 21 N= Prasugrel Clopidogrel Prasugrel Clopidogrel Wiviott et al NEJM 2007

Net Clinical Benefit Bleeding Risk Subgroups OVERALL >=60 kg < 60 kg < 75 >=75 No Yes Prior Stroke / TIA Age Wgt Risk (%) Prasugrel BetterClopidogrel Better HR P int = P int = 0.18 P int = 0.36 Post-hoc analysis Wiviott et al NEJM 2007

Safety Significant increase in serious bleeding (32% increase) Avoid in pts with prior CVA/TIA Efficacy 1. A significant reduction in: CV Death/MI/Stroke 19% Stent Thrombosis52% uTVR 34% MI 24% 2. An early and sustained benefit 3. Across ACS spectrum Prasugrel 60 mg LD/10mg MD vs Clopidogrel 300 mg LD/ 75 mg MD Conclusions Higher IPA to Support PCI Net clinical benefit significantly favored Prasugrel Optimization of Prasugrel maintenance dosing in a minority of patients may help improve the benefit : risk balance

PRINCIPLE – TIMI 44 Comparison with Higher Dose Clopidogrel P< for each IPA (%; 20  M ADP) Hours14 Days IPA (%; 20  M ADP) P< Prasugrel 10 mg Clopidogrel 150 mg Wiviott et al Circulation N=201 Prasugrel 60 mg Clopidogrel 600 mg

Prasugrel studies in the pipeline S.W.A.P. – Phase II: Switching antiplatelet therapy (clopidogrel to prasugrel) S.W.A.P. – Phase II: Switching antiplatelet therapy (clopidogrel to prasugrel) ACAPULCO – Phase II: Prasugrel ( vs high dose clopidogrel (900mg LD/150mg MD) in ACS/PCI ACAPULCO – Phase II: Prasugrel ( vs high dose clopidogrel (900mg LD/150mg MD) in ACS/PCI TRILOGY – Phase III: Prasugrel vs clopidogrel in non- revascularized ACS TRILOGY – Phase III: Prasugrel vs clopidogrel in non- revascularized ACS OPTIMUS-3 – Phase II: Prasugrel vs high dose clopidogrel (600mg LD/150mg MD) in diabetes mellitus OPTIMUS-3 – Phase II: Prasugrel vs high dose clopidogrel (600mg LD/150mg MD) in diabetes mellitus

Novel ADP P2Y 12 receptor antagonist PrasugrelAZD6140Cangrelor

AZD6140 (Ticagrelor)  A non-thienopyridine, in the chemical class CPTP (CycloPentylTriazoloPyrimidine)  First oral reversible ADP P2Y 12 receptor antagonist  Direct acting via the P2Y 12 receptor - metabolism not required for activity  More potent platelet inhibitor than clopidogrel  A non-thienopyridine, in the chemical class CPTP (CycloPentylTriazoloPyrimidine)  First oral reversible ADP P2Y 12 receptor antagonist  Direct acting via the P2Y 12 receptor - metabolism not required for activity  More potent platelet inhibitor than clopidogrel HO HN HO OH OS F F N N N N N

DISPERSE: Faster, Greater and More Consistent IPA with AZD6140 vs clopidogrel Time, hours AZD6140 (100 mg bd) 8128 Inhibition, % 24 Clopidogrel Inhibition, % Day 1Day 14Day 1Day Husted SE et al Eur Heart J 2006; 27:

DISPERSE2 Study Design DISPERSE2 was a double-blind, randomized study of AZD6140 compared with clopidogrel, both on a background of aspirin (75–100 mg od) 50% of patients in each AZD6140 arm received a loading dose of 270 mg In the clopidogrel arm, thienopyridine treatment-naïve patients received a 300-mg loading dose Randomization Visit 1 Day 1 Visit 2Visit 3Visit 4Follow-up Week 4Week 8Week 12Final Visit +7 days AZD mg bid AZD mg bid Clopidogrel 75 mg qd NSTE-ACS patients with onset of chest pain <48 hours n = 334 n = 329 n = 327 Cannon CP et al. J Am Coll Cardiol 2007

DISPERSE2 Adjudicated Bleeding Rates (%) Week 4 and Overall Week 4 Total Bleeding Rate (%) 0 Overall Total Bleeding Rate (%) % 7.7% 8.0% 10.2% 9.2% AZD mg bid N = 334 AZD mg bid N = 323 Clopidogrel 75 mg qd N = 327 AZD mg bid N = 334 AZD mg bid N = 323 Clopidogrel 75 mg qd N = 327 Minor bleeding*Major bleeding Adjudicated total bleeding rates were similar for all groups No evidence of dose-response for major bleeds * Minor bleeding without major bleeding Cannon CP et al. J Am Coll Cardiol 2007

DISPERSE-2: Non-bleeding adverse events Clop AZD mg AZD mg Clop AZD mg AZD mg 4.4% 5.6% 9.9% 6.4% 10.5% 15.8% Ventricular Pauses >2.5 Seconds Dyspnea % % Discontinuation rates from non-bleeding adverse events were low and similar between groups

Primary endpoint:CVD/MI/stroke Secondary endpoint:CVD/MI/stroke/revascularization with PCI; CVD/MI/stroke, severe recurrent ischemia 12-month maximum exposure (Min = 6 mo, Max = 12 mo, Mean = 11 mo) (N=18,000) ASA + Clopidogrel 300 mg ld/75 mg qd 600 mg ld allowed in PCI ASA + AZD mg ld/90 mg bid Moderate- to high-risk ACS patients (UA/NSTEMI/STEMI, PCI, medically managed, or CABG) ASA = acetylsalicylic acid; bid = twice daily; CVD = cardiovascular disease; ld = loading dose; MI = myocardial infarction; NSTEMI = non-ST- segment elevation MI; qd = once daily; STEMI = ST-segment elevation MI; UA = unstable angina. ClinicalTrials.gov Identifier: NCT

Novel ADP P2Y 12 receptor antagonist PrasugrelAZD6140Cangrelor

Cangrelor (AR-C69931MX)  Parenteral ADP-P2Y 12 receptor antagonist  ATP analogue  Direct and Reversible P2Y 12 inhibitor  More potent than clopidogrel ~90% inhibition of platelet aggregation at mcg/kg/min iv  Plasma half-life of 5-9 min.; 20 min. for return to normal platelet function O - O - O - O - OO HOOH PPPOO N HN N N N N S S CF 3 O Cl - O

% Inhibition of Aggregation Fold Increase in Bleeding Time Aggregation Bleeding time + aspirin/heparin/GTN + placebo AR-C69931 (ng.kg -1.min -1 ) Stepped infusion period Recovery period min Key Phase I result Rapid reversal of dose-dependent effect

Phase II clinical data: Compared with Abciximab in PCI Double-blind randomized trial performed in US 5.7% 5.4% 2.1% 1.0% Death, MI, revascularizationMajor bleed (TIMI criteria) Incidence of events up to 7-days AR-C69931MX report number SC Part 2 Abciximab (N=94) Cangrelor (N=105) Greenbaum et al. Am Heart J. 2006;151:689.e1-689.e10

CHAMPION-PCI PCI (with or without stent) 1:1 Double blind, double dummy Placebo capsules (to match) Cangrelor bolus (30µg/kg) & infusion (4µg/kg/hour) Clopidogrel capsules (600mg) Placebo bolus & infusion (to match) 1º Endpoint: Death, MI, and uRevasc at 48 hours 2 º Endpoints: Death, MI, uRevasc at 30 days Death at 6 months and 1 year Index Procedure Study drug infusion (for at least 2 hours or the duration of the procedure, whichever is longer) Clopidogrel capsules (600 mg) Placebo capsules (to match) Clopidogrel Maintenance (at physician discretion) ++

Platelet Stimuli GP IIb/IIIa integrin ADP Epinephrine Collagen Thrombin Platelet Aggregation Serotonin Shear rate AA TxA 2 COX-1 ThrombinThrombinThrombin TxA 2

Thrombin ADP TXA 2 ADP P2Y 12 ADP (fibrinogenreceptor) GP IIb/IIIa Activation COX-1 clopidogrel bisulfate aspirin cAMP Oral Anti-PAR-1 receptors SCH E 5555 adapted from Schafer AI. Am J Med. 1996;101:

TRA (SCH ) Program (29,500 pts) 1 o EP: Composite of CV death, MI, Stroke, and urgent revascularization TRA (SCH ) Program Evaluation of Efficacy and Safety in Acute and Chronic Atherothrombosis NSTEACS 10,000 pts 2º Prevention 19,500 pts SCH PlaceboSCH Placebo F/U: 30 days, 4,8,12 months, and 6 months thereafter F/U 1 yr minimum 1 o EP: Composite of CV death, MI, Stroke, urgent revascularization and Recurrent Ischemia w/ Rehosp

……. to be continued !!!!!!!!!!!