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

Abstract

Aims

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 hour (Part A) and 5 day (Part B) intravenous (IV) infusions of BMS-962212. Part A used 4 doses (1.5, 4, 10, and 25 mg h^-1) assigned to BMS-962212 or placebo in a 3:1 ratio per dose. Part B used 4 doses (1, 3, 9, and 20 mg h^-1) enrolling Japanese (n = 4 active, n = 1 placebo) and non-Japanese subjects (n = 4 active, n = 1 placebo) 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 Part A and B, BMS-962212 demonstrated dose-proportionality. The mean half-life in Part A and B ranged from 2.04 - 4.94 h and 6.22 - 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), respectively. 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.

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