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.
Conclusions: 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.
Patient Care: The results of the current, completed, and ongoing studies evaluate and validate clinical data that may change the approach to VTE prophylaxis as well as to the management of major bleeding associated with direct oral anticoagulants.
Learning Objectives: - Andexanet is an investigational reversal agent for factor Xa inhibitors
- Betrixaban is a direct factor Xa inhibitor that was investigated for extended-duration thromboprophylaxis
- Andexanet rapidly reversed anticoagulation effects of betrixaban in healthy subjects