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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. TRA-PCI Update on the New Antiplatelet Agents: PAR-1 Inhibitors. Platelet-Thrombin Interaction. Fibrinogen. Thrombus.

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TRA-PCI Update on the New Antiplatelet Agents: PAR-1 Inhibitors

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  1. David J. Moliterno, MD, MPHChief, Cardiovascular MedicineProfessor & Vice-Chair of MedicineUniversity of KentuckyCo-Director - Gill Heart InstituteLexington, KY TRA-PCI Update on the New Antiplatelet Agents: PAR-1 Inhibitors

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

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

  4. 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.

  5. 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 **Secondary Evaluable Cohort * Primary Evaluable Cohort

  6. Demographics

  7. PCI Cohort Medications

  8. PCI Cohort 3.3% 4.0% 2.5% 1.6% TIMI Major/Minor Bleeding 5% p = 0.73 4% p = 0.77 p = 0.70 2.8% 3% p = 0.35 2% 1% 0 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

  9. CABG Cohort Bleeding

  10. PCI Cohort MACE Results MACE = Major Adverse Cardiac Event (myocardial infarction, ischemia requiring hospitalization, coronary revascularization) MI = Myocardial Infarction * = primary efficacy endpoint

  11. PCI Cohort 5.9% 4.6% 5.0% 8.5% 8.6% 60-Day Death or MACE 10% p = 0.98 8% p = 0.26 p = 0.25 6% p = 0.15 4% 2% 0 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

  12. PCI Cohort 7.3% 4.0% 4.2% 5.4% 60-Day Death or MI 10% 8% p = 0.53 p = 0.19 6% p = 0.28 4.5% p = 0.20 4% 2% 0 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

  13. PCI Cohort 10% 8% 6% 4% 2% 0 Myocardial Infarction Placebo 10mg 20mg 40mg p = 0.52 p = 0.28 p = 0.12 0 1 2 3 4 5 6 7 Days

  14. Platelet Aggregation Substudy 30 minutes 60 minutes 90 minutes 120 minutes 0 0 0 0 0 0 Subjects with >80% IPA to 15 M TRAP 100% 96 82 80% 68 60% 54 53 46 43 40% 29 21 20% 6 0 Placebo n=23 10 mg n=15 20 mg n=18 40 mg n=33 SCH 530348

  15. PCI Cohort Results after Day 60

  16. 100 100 100 100 Subjects with >80% IPA to 15 M TRAP Platelet Aggregation 30 days 100% 91 91 60 days 80% 60% 40% 20% 11 9 0 Placebo 0.5 mg 1.0 mg 2.5 mg SCH 530348

  17. Conclusions TRA was not associated with an increase inTIMI 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

  18. 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

  19. 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

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