Improved efficacy/safety profile of factor XIa inhibitor BMS‐724296 versus factor Xa inhibitor apixaban and thrombin inhibitor dabigatran in cynomolgus monkeys

Abstract

BackgroundInhibition 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). ObjectivesThis 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. MethodsCarotid 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]). ResultsBMS‐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< .05 vs vehicle; n = 5‐6/group). BMS‐724296 at the highest dose (0.4 + 0.8 mg/kg+mg/kg/h) did not increase KBT compared to vehicle (109 ± 6 vs 113 ± 20 seconds, respectively) and increased ex vivo aPTT by 2.9 ± 0.1‐fold without changing PT and TT. In companion NHP studies, high doses of apixaban and dabigatran produced similar TWR as BMS‐724296, but increased KBT 4.3 ± 0.5‐fold and 5.8 ± 0.5‐fold, respectively (n = 3‐4/group). ConclusionsBMS‐724296 produced similar antithrombotic efficacy as apixaban and dabigatran but with no increase in KBT in NHPs. These findings suggest that FXIa inhibitors may provide safe and effective antithrombotic therapy.