Phase I Assessment of the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of the Oral Protease-activated Receptor-4 Antagonist BMS-986120

Introduction: BMS-986120 is a potent and selective oral antagonist of protease-activated receptor-4 (PAR4), a thrombin-activated platelet receptor thought to be important in thrombus propagation and pathological vascular occlusion. PAR4 antagonism has potential therapeutic utility in the treatment and prevention of thrombotic diseases. Preclinical arterial thrombosis models showed greater efficacy than current antithrombotics, including aspirin, clopidogrel and vorapaxar, with lower bleeding risk. Hypothesis: This report presents results from the initial Phase I randomized, double-blind, placebo-controlled single- and multiple-ascending oral dose studies of BMS-986120. Methods: To assess the pharmacokinetics (PK), pharmacodynamics (PD), safety profile and tolerability of BMS-986120, single doses of BMS-986120 from 0.5-180 mg were administered to 42 healthy subjects and multiple doses of 2.5-100 mg daily for up to 14 days to 24 subjects, randomized with placebo. Results: BMS-986120 PK showed rapid absorption and distribution with slow terminal elimination. Exposures increased in a dose related manner. BMS-986120 selectively inhibited PAR4 agonist peptide (PAR4-AP) induced ex-vivo platelet aggregation and p-selectin expression in a dose- and concentration-dependent manner. Complete inhibition of induced platelet aggregation for at least 24 hours was observed in all subjects with doses ≥10 mg daily. PAR1 platelet activation was unaffected. Treatment-emergent adverse events (AEs) were reported at a frequency similar to placebo. There were no drug-related discontinuations or bleeding-related clinical findings or AEs. Laboratory assessments, including routine coagulation tests and template bleeding times, showed no clinically relevant trends. Conclusions: BMS-986120 was safe and well tolerated by healthy subjects. These results represent the first reported clinical experience of a selective oral PAR4 antagonist.