Update on the New Antiplatelet Agents: TRA-PCI Update on the New Antiplatelet Agents: PAR-1 Inhibitors David J. Moliterno, MD, MPH Chief, Cardiovascular Medicine Professor & Vice-Chair of Medicine University of Kentucky Co-Director - Gill Heart Institute Lexington, KY

Update on the New Antiplatelet Agents: PAR-1 Inhibitors David J. Moliterno, Richard C. Becker, Lisa Jennings, Gail Berman, Bo Yang, John Strony, Enrico Veltri, and Robert A. Harrington on behalf of the TRA–PCI Investigators University of Kentucky Gill Heart Institute

Platelet-Thrombin Interaction Thrombus Xa+Va+II Fibrin Fibrinogen Thrombin

Platelet Receptors Platelet Platelet PAR-1 Thrombin PAR-4 GP IIb/IIIa Fibrinogen GP IIb/IIIa P2Y1 ADP P2Y12 GP IIb/IIIa TBX A2 TBXA2-R Epinephrine EPI-R Serotonin 5HT2A GP VI Collagen Anionic phospholipid surfaces GP Ia

TRA Background SCH 530348 is an oral, potent, selective thrombin receptor antagonist (TRA) being developed for the prevention and treatment of atherothrombosis. Preclinical and early clinical studies have demonstrated SCH 530348 to have antithrombotic properties, with no increase in bleeding time or clotting times (aPTT, PT, ACT). Galbulimima baccata Himbicine derivative Bark of the Australian Rhododendron Found in the tropical zones of eastern Malaysia, New Guinea, northern Australia and the Solomon Islands.

Study Design Non-Urgent PCI or Cath possible PCI (All Receive Aspirin) Randomization #1 — 3:1 SCH530348:Placebo (Single Loading Dose) Sequential Groups: 1=10 mg; 2=20 mg; 3=40 mg, or Placebo Cardiac Catheterization Planned PCI (All Receive Clopidogrel and Antithrombin) No PCI** Randomization #2 1:1:1 Maintenance Therapy Once Daily for ~ 60 days SCH 530348 Loading Dose  SCH 530348 Or Placebo Loading Dose  Placebo CABG Medical Management Quantify Postoperative Chest-Tube Drainage, Transfusions, and Re-exploration SCH 530348 0.5 mg n~100 1 mg n~100 2.5 mg n~100 Placebo n~100 Safety: TIMI Major plus Minor Bleeding Efficacy: Death/MACE Safety: TIMI Major plus Minor Bleeding * Primary Evaluable Cohort **Secondary Evaluable Cohort

Demographics Placebo SCH 530348 All 10 mg 20 mg 40 mg 257 773 222 238 All Randomized 257 773 222 238 313 Primary Cohort (PCI) 151 422 129 120 173 Secondary Cohort 106 351 93 118 140 with CABG 24 52 10 18 Male 80% 70% 72% 66% Age (mean, years) 62 63 65 Weight (mean, kg) 91 90 89 92 Diabetes Mellitus 30% 34% 37% 32% 33% Prior MI 35% 38% Prior Revascularization 47% 48% 50% 46%

PCI Cohort Medications Placebo (n = 151) SCH 530348 All n = 422 10 mg n = 129 20 mg n = 120 40 mg n = 173 Aspirin 148 (98%) 416 (99%) 127 (98%) 117 (98%) 172 (99%) Clopidogrel 146 (97%) 408 (97%) 164 (95%) 75 mg 73 (48%) 191 (45%) 56 (43%) 52 (43%) 83 (48%) 300 mg 30 (20%) 85 (20%) 34 (26%) 21 (18%) 30 (17%) 600 mg 40 (26%) 125 (30%) 36 (28%) 39 (33%) 50 (29%) Antithrombin Agent Heparin 61 (40%) 181 (43%) 53 (41%) 76 (44%) Bivalirudin 76 (50%) 196 (46%) 65 (50%) 51 (43%) 80 (46%) GP IIb/IIIa 7 (5%) 37 (9%) 14 (12%) 16 (9%)

TIMI Major/Minor Bleeding PCI Cohort TIMI Major/Minor Bleeding 5% p = 0.73 4.0% 4% 3.3% p = 0.77 p = 0.70 2.8% 3% 2.5% p = 0.35 2% 1.6% 1% Placebo n=151 All TRA n=422 10 mg n=129 20 mg n=120 40 mg n=173 SCH 530348 p- value relative to placebo

CABG Cohort Bleeding Placebo (n=24) SCH 530348 All (n=52) 10 mg Any Bleed 24 52 10 18 TIMI Major/Minor 19 (79%) 48 (92%) 9 (90%) 17 (94%) 22 (92%) Non-TIMI 8 (33%) 18 (35%) 3 (30%) 6 (33%) 9 (39%) Transfusion PRBC 11 (46%) 32 (62%) 8 (80%) 9 (50%) 15 (63%) >2 Units 5 9 2 Chest Tube Drainage (ml) 996 988 1393 1015 870 Re-exploration 3 1

PCI Cohort MACE Results Placebo n= 151 SCH 530348 All n=422 10 mg n= 129 20 mg n=120 40 mg n=173 Death/MACE/Stroke 13 (8.6%) 26 (6.2%) 12 (9.3%) 6 (5.0%) 8 (4.6%) Death/MACE* 25 (5.9%) 11 (8.5%) Death/MI 11 (7.3%) 19 (4.5%) 7 (5.4%) 5 (4.2%) 7 (4.0%) Death 2 (0.5%) 1 (0.8%) 1 (0.6%) MACE 24 (5.7%) MI 18 (4.3%) 6 (3.5%) Recurrent ischemia 1 (0.7%) 1 (0.2%) Revascularization 6 (1.4%) 3 (2.3%) 2 (1.2%) Stroke MACE = Major Adverse Cardiac Event (myocardial infarction, ischemia requiring hospitalization, coronary revascularization) MI = Myocardial Infarction * = primary efficacy endpoint

PCI Cohort 60-Day Death or MACE SCH 530348 8.6% 8.5% 5.9% 5.0% 4.6% 10% p = 0.98 8.6% 8.5% 8% p = 0.26 5.9% p = 0.25 6% 5.0% p = 0.15 4.6% 4% 2% Placebo n=151 All TRA n=422 10 mg n=129 20 mg n=120 40 mg n=173 SCH 530348 p- value relative to placebo

PCI Cohort 60-Day Death or MI SCH 530348 7.3% 5.4% 4.5% 4.2% 4.0% 10% 8% 7.3% p = 0.53 p = 0.19 6% 5.4% p = 0.28 4.5% p = 0.20 4.2% 4.0% 4% 2% Placebo n=151 All TRA n=422 10 mg n=129 20 mg n=120 40 mg n=173 SCH 530348 p- value relative to placebo

Myocardial Infarction PCI Cohort Myocardial Infarction 8% 4% 2% 6% 10% Placebo 10mg 20mg 40mg p = 0.52 p = 0.28 p = 0.12 1 2 3 4 5 6 7 Days

Platelet Aggregation Substudy Subjects with >80% IPA to 15 M TRAP 100% 96 30 minutes 60 minutes 90 minutes 120 minutes 82 80% 68 60% 54 53 46 43 40% 29 21 20% 6 Placebo n=23 10 mg n=15 20 mg n=18 40 mg n=33 SCH 530348

PCI Cohort Results after Day 60 Placebo SCH 530348 All 0.5 mg 1.0 mg 2.5 mg Number 149 413 136 139 138 TIMI Major/Minor 4 (1.0%) 2 (1.5%) 2 (1.4%) TIMI Major 2 (0.5%) 1 (0.7%) TIMI Minor Non-TIMI bleeding 8 (5.4%) 25 (6.1%) 8 (5.9%) 6 (4.3%) 11 (8.0%)

Subjects with >80% IPA to 15 M TRAP Platelet Aggregation Subjects with >80% IPA to 15 M TRAP 100 100 100% 30 days 91 91 60 days 80% 60% 40% 20% 9 11 Placebo 0.5 mg 1.0 mg 2.5 mg SCH 530348

Conclusions TRA was not associated with an increase in TIMI major, minor, or non-TIMI bleeding Using 15 M TRAP-induced platelet aggregation: 40 mg loading dose of SCH 530348 achieved ≥ 80% IPA in 1-2 hours in 68-96% subjects 1 mg and 2.5 mg maintenance doses sustained ≥ 80% IPA at 30 and 60 days in all subjects While not statistically significant, SCH 530348 was associated with: Death/MACE: 32% overall; 46% with 40 mg MI: 41% overall; 52% with 40 mg

TRA•CER Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome NSTEACS N = 10,000 SCH 530348 40 mg bolus, 2.5 mg daily n=5000 Placebo (and usual therapy) n=5000 • 1-Year Cardiovascular Death, MI, Stroke, Recurrent Ischemia with Rehosp, Urgent Coronary Revas • www.clinicaltrials.gov

Thrombin Receptor Antagonist TRA•2P—TIMI 50 Thrombin Receptor Antagonist for 2º Prevention Hx MI, CVA, PVD N ~ 18,000 SCH 530348 2.5 mg daily N~9,000 Placebo (and usual therapy) N~9000 • 1-Year Cardiovascular Death, MI, Stroke, Recurrent Ischemia with Rehosp, Urgent Coronary Revas • www.clinicaltrials.gov