Introduction: Direct FXa inhibitors have demonstrated convincing anticoagulant efficacy. However, risk of major bleeding is a concern and no specific antidotes are available for reversal. Andexanet alfa (AnXa), a recombinant modified FXa, is an investigational specific antidote for FXa inhibitors. We report data from the ANNEXA™ Phase 3 registration studies in older healthy subjects anticoagulated with apixaban (apix) or rivaroxaban (riva).
Methods: ANNEXA–A&R were two Phase 3, randomized, double-blind, placebo-controlled studies of AnXa in healthy subjects age 50 to 75 administered either apixaban or rivaroxaban. Andexanet dose selection was based on Phase 2 data and PK/PD modeling, which will be presented. In ANNEXA™-A, subjects were treated with apix 5mg BID for 4 days to achieve steady state concentrations. AnXa (Part 1: 400mg bolus; Part 2: 400mg bolus plus 4mg/min x 2hr infusion) or placebo was administered on Day 4, 3 hrs after the last apix dose. In ANNEXA™-R, subjects were treated with riva 20mg QD for 4 days to achieve steady state concentrations. AnXa (Part 1: 800mg bolus; Part 2: 800mg bolus plus 8mg/min x 2hr infusion) or placebo was administered on Day 4, 4 hrs after the last riva dose. Safety data were collected through Day 43.
Results: ANNEXA-A&R enrolled 63 and 82 subjects, respectively. The primary efficacy endpoint, percent change from baseline in anti-FXa activity to nadir (Part 1: between 2-5 min post-bolus; Part 2: between 10 min prior to and 5 min after the end of the continuous infusion) was met for each part with high statistical significance (p<0.0001 vs. placebo). Additional efficacy endpoints, including reduction in plasma free inhibitor concentration and restoration of thrombin generation, were also met. There were no serious adverse events, thrombotic events, or antibodies to FX or FXa. The andexanet PK/PD model accurately predicted the riva and apix anti-FXa activity observed in this study.
Conclusions: ANNEXA-A&R achieved all primary and secondary endpoints with high statistical significance. AnXa treatment resulted in rapid and sustained reversal of both apix and riva-induced anticoagulation. A Phase 3b/4 confirmatory study (ANNEXA-4) in patients with acute major bleeds is ongoing.
Patient Care: Provide a treatment option for patients treated with Factor Xa inhibitors that experience a major bleed, including intracranial hemorrhages
Learning Objectives: Provide a treatment option for patients treated with Factor Xa inhibitors that experience a major bleed, including intracranial hemorrhages