314 Reversal of Betrixaban-Induced Anticoagulation in Healthy Volunteers by Andexanet Alfa

Abstract

Abstract INTRODUCTION Andexanet alfa (andexanet) is a modified, recombinant human factor Xa (FXa) that acts as a decoy to bind and sequester FXa inhibitors, thus reversing their anticoagulation effects. Here, we report the efficacy of andexanet in reversing the anticoagulant activity of betrixaban, a direct FXa inhibitor which has recently completed a large Phase 3 clinical trial in acute medically ill patients (APEX). METHODS In this Phase 2, randomized, double-blind study, healthy subjects were dosed with 80 mg qd po betrixaban to steady state (7 days). In Cohort 1, subjects (n = 6) received 800-mg andexanet bolus 3 hours after the last dose of betrixaban, or matching placebo (n = 3). In Cohort 2, subjects (n = 6) received 800-mg andexanet bolus 4 hours after the last betrixaban dose, followed immediately by a 2-hour andexanet infusion (8 mg/min), or matching placebo (n = 3). Study endpoints included assessments of safety and pharmacodynamic markers of anticoagulation reversal. RESULTS >Following dosing with betrixaban, andexanet rapidly (2 minutes after the bolus) decreased anti-FXa activity by ∼80% in both cohorts (P < 0.001 vs. placebo) and decreased unbound betrixaban plasma concentration by 73% and 83% in Cohorts 1 and 2, respectively (P < 0.001 vs. placebo). The effects were maintained during the 2-hour infusion of andexanet. Thrombin generation was restored in 11/12 (91.7%) subjects administered andexanet vs. 2/6 (33.3%) placebo subjects. Andexanet was well-tolerated; there were no thrombotic events or other serious/severe adverse events. CONCLUSION Andexanet was well-tolerated and rapidly reversed anticoagulation effects of betrixaban in healthy subjects. The results of this and previous studies in healthy subjects indicate the potential of andexanet as a universal antidote for FXa inhibitors. An ongoing Phase 3b/4 study (ANNEXA-4) in patients receiving a FXa inhibitor who present with acute major bleeding and require urgent reversal of anticoagulation will provide efficacy and safety information on andexanet in this target patient population.