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

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 < .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). CONCLUSIONS: BMS-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.