A Novel Orally-Active Small-Molecule Antagonist of the Platelet Protease-Activated Receptor-4, BMS986120, Inhibits Arterial Thrombosis With Limited Impact on Hemostasis in Cynomolgus Monkeys

Introduction: BMS-986120 (BMS) is a novel orally-active antagonist of protease-activated receptor-4 (PAR4), a human platelet thrombin receptor, and is in phase I clinical trial. The antithrombotic potential of BMS was studied in models of electrically-mediated carotid artery thrombosis and bleeding time (BT) in cynomolgus monkeys, which have platelet thrombin receptors similar to human. Methods: Individual anesthetized monkeys were given orally of BMS (0.2, 0.5,1 mg/kg) or vehicle (n=8/group) 2 hour before a combination of thrombosis, BT and ex vivo biomarker experiments. Aspirin alone (ASA, 4 mg/kg/h IV) or in combination with BMS (0.5, 1 mg/kg) was also studied (n=8/group). Thrombus weight (TW) reduction, BT increase over vehicle in kidney (KBT) and mesenteric artery (MBT), and platelet aggregation (PA) inhibition were determined. Peak PA responses to activation peptides selective for PAR4 (PAR4-AP, 12.5 μM) and PAR1 (PAR1-AP, 18 μM), ADP (20 μM), and collagen (5 μg/ml) were determined by whole blood aggregometry. Results: BMS comparably inhibited PA induced by PAR4-AP in human and monkey blood in vitro (IC 50 of 9.5±2.7 and 2.1±0.4 nM, respectively). In monkeys, BMS produced parallel rightward shifts in the log PA dose response to PAR4-AP without affecting maximum response, suggesting surmountable antagonism. BMS (1 mg/kg) did not inhibit PA induced by PAR1-AP, ADP and collagen, supporting selectivity. BMS (0.2, 0.5, 1 mg/kg) reduced TW by 35±5, 49±4, and 83±4%, respectively. Maximum KBT and MBT increases were only 2.2-fold and 1.8-fold, respectively. A maximum antiplatelet dose of ASA (4 mg/kg/h, n=8) slightly reduced TW by 12±2% and increased KBT and MBT by 2.2- and 2.7-fold, respectively. Co-administration of ASA and BMS (0.5 or 1 mg/kg) reduced TW by 54±3 and 95±2%, increased KBT by 3.1- and 3.6-fold, and increased MBT by 2.6- and 3.3-fold, respectively (n=8/group). In companion monkey studies, clopidogrel (0.3 mg/kg/day, n=6) alone reduced TW by 49±6%, but increased KBT and MBT by 7.3- and 8.1-fold, respectively. Conclusion: In monkeys, BMS alone or combined with ASA prevents occlusive carotid artery thrombosis with limited impact on BT, demonstrating a wider therapeutic window than the standard of care antiplatelet drugs, aspirin and clopidogrel.