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

2. 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

3. Platelet-Thrombin Interaction Thrombin X a +V a +II Thrombus Fibrin Fibrinogen

4. Platelet Receptors Platelet Thrombin ADP Epinephrine Collagen Anionic phospholipid surfaces GPIIb/IIIa Platelet Fibrinogen GP Ia P2Y 1 GP VI PAR-4 TBX A 2 TBXA 2 -R Serotonin5HT 2 A P2Y 12 PAR-1GPIIb/IIIa EPI-R

5. TRA Background SCH 530348 is an oral, potent, selective thrombin receptor antagonist (TRA) being developed for the prevention and treatment of atherothrombosis. 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). 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). SCH 530348 is an oral, potent, selective thrombin receptor antagonist (TRA) being developed for the prevention and treatment of atherothrombosis. 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). 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.

6. 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 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 Safety: TIMI Major plus Minor Bleeding Efficacy: Death/MACE Safety: TIMI Major plus Minor Bleeding * Primary Evaluable Cohort **Secondary Evaluable Cohort Cardiac Catheterization Planned PCI (All Receive Clopidogrel and Antithrombin) CABG Quantify Postoperative Chest-Tube Drainage, Transfusions, and Re-exploration Medical Management 0.5 mg n~100 1 mg n~100 2.5 mg n~100 Placebo n~100 SCH 530348

7. Placebo All 10 mg 20 mg 40 mg All Randomized 257773222238313 Primary Cohort (PCI) Primary Cohort (PCI)151422129120173 Secondary Cohort Secondary Cohort10635193118140 with CABG with CABG2452101824 Male80%70%72%66%72% Age (mean, years) 6263656363 Weight (mean, kg) 9190899290 Diabetes Mellitus 30%34%37%32%33% Prior MI 37%35%35%38%32% Prior Revascularization 47%48%50%46%48% Demographics

8. 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 All All 146 (97%) 408 (97%) 127 (98%) 117 (98%) 164 (95%) 75 mg 75 mg 73 (48%) 73 (48%) 191 (45%) 56 (43%) 56 (43%) 52 (43%) 52 (43%) 83 (48%) 83 (48%) 300 mg 300 mg 30 (20%) 30 (20%) 85 (20%) 85 (20%) 34 (26%) 34 (26%) 21 (18%) 21 (18%) 30 (17%) 30 (17%) 600 mg 600 mg 40 (26%) 40 (26%) 125 (30%) 36 (28%) 36 (28%) 39 (33%) 39 (33%) 50 (29%) 50 (29%) Antithrombin Agent Heparin Heparin 61 (40%) 181 (43%) 53 (41%) 53 (41%) 52 (43%) 52 (43%) 76 (44%) 76 (44%) Bivalirudin Bivalirudin 76 (50%) 196 (46%) 65 (50%) 65 (50%) 51 (43%) 51 (43%) 80 (46%) 80 (46%) GP IIb/IIIa 7 (5%) 37 (9%) 7 (5%) 7 (5%) 14 (12%) 14 (12%) 16 (9%) 16 (9%) PCI Cohort Medications

9. TIMI Major/Minor Bleeding 4% 0 2% All TRA n=422 2.8% PCI Cohort 1% 3% 5% Placebon=151 3.3% 10 mg n=129 20 mg n=120 40 mg n=173 1.6% 2.5% 4.0% SCH 530348 p = 0.77 p = 0.35 p = 0.70 p = 0.73 p- value relative to placebo

10. Placebo(n=24) SCH 530348 All(n=52) 10 mg (n = 10) 20 mg (n = 18) 40 mg (n=24) Any Bleed 2452101824 TIMI Major/Minor 19 (79%) 48 (92%) 9 (90%) 17 (94%) 22 (92%) Non-TIMI 8 (33%) 8 (33%) 18 (35%) 3 (30%) 6 (33%) 6 (33%) 9 (39%) 9 (39%) Transfusion PRBC PRBC 11 (46%) 32 (62%) 8 (80%) 9 (50%) 15 (63%) >2 Units >2 Units59225 Chest Tube Drainage (ml) 99698813931015870 Re-exploration32101 CABG Cohort Bleeding

11. Placebo Placebo n= 151 SCH 530348 Alln=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* 13 (8.6%) 25 (5.9%) 11 (8.5%) 6 (5.0%) 8 (4.6%) Death/MI 11 (7.3%) 19 (4.5%) 7 (5.4%) 7 (5.4%) 5 (4.2%) 7 (4.0%) Death0 2 (0.5%) 2 (0.5%) 1 (0.8%) 0 1 (0.6%) MACE 13 (8.6%) 24 (5.7%) 11 (8.5%) 6 (5.0%) 7 (4.0%) MI 11 (7.3%) 18 (4.3%) 7 (5.4%) 7 (5.4%) 5 (4.2%) 6 (3.5%) Recurrent ischemia 1 (0.7%) 1 (0.7%) 1 (0.2%) 1 (0.2%) 1 (0.8%) 1 (0.8%)00 Revascularization 1 (0.7%) 1 (0.7%) 6 (1.4%) 6 (1.4%) 3 (2.3%) 3 (2.3%) 1 (0.8%) 2 (1.2%) Stroke0 1 (0.2%) 1 (0.2%) 1 (0.8%) 1 (0.8%)00 MACE = Major Adverse Cardiac Event (myocardial infarction, ischemia requiring hospitalization, coronary revascularization) MI = Myocardial Infarction * = primary efficacy endpoint PCI Cohort MACE Results

12. 60-Day Death or MACE 8% 0 4% All TRA n=422 PCI Cohort 2% 6% 10% Placebon=151 8.6% 10 mg n=129 20 mg n=120 40 mg n=173 8.5% 5.0% 4.6% SCH 530348 5.9% p = 0.26 p = 0.98 p = 0.25 p = 0.15 p- value relative to placebo

13. 60-Day Death or MI 8% 0 4% All TRA n=422 4.5% PCI Cohort 2% 6% 10% Placebon=151 7.3% 10 mg n=129 20 mg n=120 40 mg n=173 5.4% 4.2% 4.0% SCH 530348 p = 0.19 p = 0.53 p = 0.28 p = 0.20 p- value relative to placebo

14. PCI Cohort Myocardial Infarction 8% 0 4% 2% 6%10%Placebo40mg20mg10mg 1 723456 0 Days p = 0.52 p = 0.28 p = 0.12

15. 80% 0 40% Platelet Aggregation Substudy 20% 60% 100% Placebon=23 10 mg n=15 20 mg n=18 40 mg n=33 29 SCH 530348 00000053 68 82 96 46 54 6 43 21 30 minutes 60 minutes 90 minutes 120 minutes Subjects with >80% IPA to 15  M TRAP

16. Placebo Placebo SCH 530348 All 0.5 mg 1.0 mg 2.5 mg Number149413136139138 TIMI Major/Minor 0 4 (1.0%) 4 (1.0%) 2 (1.5%) 0 2 (1.4%) TIMI Major 0 2 (0.5%) 2 (0.5%) 1 (0.7%) 0 TIMI Minor 0 2 (0.5%) 2 (0.5%) 1 (0.7%) 0 Non-TIMI bleeding 8 (5.4%) 25 (6.1%) 8 (5.9%) 6 (4.3%) 11 (8.0%) PCI Cohort Results after Day 60

17. 80% 0 40% Platelet Aggregation 20% 60% 100% 0.5 mg 1.0 mg 2.5 mg SCH 530348 100100 30 days 60 days Subjects with >80% IPA to 15  M TRAP 1001009191 Placebo 11 9

18. Conclusions TRA was not associated with an increase in TIMI major, minor, or non-TIMI bleeding TRA was not associated with an increase in TIMI major, minor, or non-TIMI bleeding Using 15  M TRAP-induced platelet aggregation: 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: While not statistically significant, SCH 530348 was associated with:  Death/MACE:  32% overall;  46% with 40 mg  MI:  41% overall;  52% with 40 mg

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

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