Abstract 13794: An Orally-Active Small-Molecule Antagonist of the Platelet Protease-Activated Receptor-4, BMS-986141, Prevents Aeterial Thrombosis With Low Bleeding Liability in Cynomolgus Monkeys

Introduction: BMS-986141 (BMS) is a small-molecule platelet thrombin receptor antagonist selective for the protease-activated receptor-4 (PAR4), and is under clinical investigation. Hypothesis: Blockade of PAR4 provides robust antithrombotic activity with low bleeding. Methods: We examined effects of BMS alone and in combination with aspirin (ASA) in models of electrically-mediated carotid artery thrombosis (ECAT) and mesenteric artery bleeding time (MBT) in monkeys. Monkeys were given a single oral dose of BMS (0.05, 0.1, 0.5 mg/kg) or vehicle (n=8/group). At 2 hr post-dose, in vivo ECAT, MBT as well as ex vivo platelet aggregation were monitored in the same animal, under anesthesia. ASA (4 mg/kg/h IV) alone or in combination with BMS was also studied (n=8/group). Thrombus weight reduction, MBT increase over vehicle, and platelet aggregation inhibition were determined. Peak platelet aggregation responses to activation peptides selective for PAR4 (PAR4 AP, 12.5 μM) and PAR1 (PAR1 AP, 18 μM), to collagen (5 μg/ml) and to ADP (20 μM) were determined by whole blood aggregometry. Results: BMS inhibited platelet aggregation induced by PAR4-AP in human and monkey blood in vitro with comparable IC 50 of 1.8±0.3 and 1.2±0.3 nM, respectively. BMS at 0.5 mg/kg completely inhibited ex vivo platelet aggregation induced by PAR4-AP, but not those by PAR1-AP, ADP and collagen, suggesting PAR4 receptor selectivity. In the ECAT model, BMS at 0.05, 0.1 and 0.5 mg/kg reduced thrombus weight by 36±7, 63±8, and 88±3%, respectively. BMS increased MBT by up to 1.2-fold. In a separate study, ASA slightly reduced thrombus weight by 12% and increased MBT by 2.2-fold in ECAT monkeys. Co-administration of ASA with BMS at 0.1 and 0.5 mg/kg reduced thrombus weight by 50 and 89%, and increased MBT by 2.6- and 3-fold, respectively. In companion monkey studies, clopidogrel (0.3 mg/kg/day) alone reduced thrombus weight by 48%, but increased MBT by 8.1-fold (n=6). Conclusion: BMS alone or combined with ASA prevents occlusive arterial thrombosis with low MBT increases in monkeys, demonstrating a wider therapeutic window than the standard antiplatelet agents, clopidogrel and ASA. This study suggests that PAR4 antagonism provides a potentially safer treatment to prevent arterial thrombosis.