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

  • Br J Clin Pharmacol. 2018 May;84(5):876-887. doi: 10.1111/bcp.13520.
Vidya Perera  1 ,  Joseph M Luettgen  2 ,  Zhaoqing Wang  1 ,  Charles E Frost  1 ,  Cynthia Yones  1 ,  Cesare Russo  1 ,  John Lee  1 ,  Yue Zhao  1 ,  Frank P LaCreta  1 ,  Xuewen Ma  1 ,  Robert M Knabb  3 ,  Dietmar Seiffert  1 ,  Mary DeSouza  1 ,  Pierre Mugnier  4 ,  Brenda Cirincione  1 ,  Takayo Ueno  5 ,  Robert J A Frost  1
Affiliations
  • 1. Early Clinical and Translational Research, Bristol-Myers Squibb Company, Princeton, NJ, 08540, USA.
  • 2. Cardiovascular Drug Discovery Biology, Bristol-Myers Squibb Company, Princeton, NJ, 08543, USA.
  • 3. Global Clinical Research, Bristol-Myers Squibb Company, Princeton, NJ, 08540, USA.
  • 4. Global Regulatory Safety and Biometrics, Bristol-Myers Squibb Company, Princeton, NJ, 08540, USA.
  • 5. Translational Research, Bristol-Myers Squibb K.K, Tokyo, Japan.
PMID: 29346838 DOI: 10.1111/bcp.13520
Abstract

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.

Keywords
Japanese; anticoagulation; factor XIa inhibition; pharmacodynamics; pharmacokinetics.
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