1. Improved efficacy/safety profile of factor XIa inhibitor BMS‐724296 versus factor Xa inhibitor apixaban and thrombin inhibitor dabigatran in cynomolgus monkeys
- Author
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Pancras C. Wong and Mimi L. Quan
- Subjects
anticoagulant ,antithrombotic agent ,apixaban ,blood coagulation ,dabigatran ,factor XIa inhibitor ,Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
Abstract Background Inhibition of activated factor XI (FXIa) is a promising antithrombotic drug target. BMS‐724296 is a selective, reversible, small‐molecule inhibitor of human FXIa (Ki 0.3 nM). Objectives This study assessed effects of BMS‐724296 versus standard‐of‐care oral anticoagulants apixaban (activated factor X inhibitor) and dabigatran (thrombin inhibitor) on arterial thrombosis, kidney bleeding time (KBT), and clotting time (CT) in nonhuman primate (NHP) cynomolgus monkey models. Methods Carotid artery thrombosis was produced by electrical stimulation in anesthetized NHPs. Hemostasis was assessed with a provoked KBT model. Thrombosis, KBT, and CT were monitored. Vehicle and various doses of BMS‐724296, apixaban, and dabigatran were administered as bolus (intravenous [i.v.]) followed by infusion starting 30 minutes before initiation of thrombosis and continued until the experiment’s end (n = 3‐8/group). Primary end points included thrombus weight reduction (TWR), KBT, and CT (activated partial thromboplastin time [aPTT], prothrombin time [PT], and thrombin time [TT]). Results BMS‐724296 at 0.025 + 0.05, 0.05 + 0.1, 0.102 + 0.2, and 0.4 + 0.8 mg/kg+mg/kg/h i.v. (bolus + infusion) reduced thrombus weight by 0 ± 0, 35 ± 7*, 72 ± 4*, and 86 ± 4%*, respectively (*P
- Published
- 2021
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