First‐in‐human study to assess the safety, pharmacokinetics and pharmacodynamics of BMS‐962212, a direct, reversible, small molecule factor XIa inhibitor in non‐Japanese and Japanese healthy subjects

AIMS: The aims of the present study were to assess the safety, pharmacokinetics (PK) and pharmacodynamics (PD) of BMS‐962212, a first‐in‐class factor XIa inhibitor, in Japanese and non‐Japanese healthy subjects. METHODS: This was a randomized, placebo‐controlled, double‐blind, sequential, ascending‐dose study of 2‐h (part A) and 5‐day (part B) intravenous (IV) infusions of BMS‐962212. Part A used four doses (1.5, 4, 10 and 25 mg h(−1)) of BMS‐962212 or placebo in a 6:2 ratio per dose. Part B used four doses (1, 3, 9 and 20 mg h(−1)) enrolling Japanese (n = 4 active, n = 1 placebo) and non‐Japanese (n = 4 active, n = 1 placebo) subjects per dose. The PK, PD, safety and tolerability were assessed throughout the study. RESULTS: BMS‐962212 was well tolerated; there were no signs of bleeding, and adverse events were mild. In parts A and B, BMS‐962212 demonstrated dose proportionality. The mean half‐life in parts A and B ranged from 2.04 to 4.94 h and 6.22 to 8.65 h, respectively. Exposure‐dependent changes were observed in the PD parameters, activated partial thromboplastin time (aPTT) and factor XI clotting activity (FXI:C). The maximum mean aPTT and FXI:C change from baseline at 20 mg h(−1) in part B was 92% and 90%, respectively. No difference was observed in weight‐corrected steady‐state concentrations, aPTT or FXI:C between Japanese and non‐Japanese subjects (P > 0.05). CONCLUSION: BMS‐962212 has tolerability, PK and PD properties suitable for investigational use as an acute antithrombotic agent in Japanese or non‐Japanese subjects.