Reversal of Betrixaban-Induced Anticoagulation in Healthy Volunteers By Andexanet Alfa

Abstract Introduction: Andexanet alfa (andexanet) is a modified, recombinant human factor Xa (FXa) molecule that acts as a decoy to bind and sequester FXa inhibitors. We previously reported Phase 2 data with apixaban, rivaroxaban, edoxaban, and enoxaparin in healthy volunteers, and demonstrated that andexanet rapidly reversed pharmacodynamic (PD) markers of anticoagulation. Here, we report new clinical data demonstrating 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 an ongoing, Phase 2, randomized, double-blind study in healthy subjects, andexanet (n=12) or placebo (n=6) was administered intravenously following dosing of 80 mg qd po betrixaban to steady state (7 days). In Cohort 1 (andexanet bolus only), subjects (n=6) received an 800 mg bolus of andexanet 3 hours after the last dose of betrixaban on day 7 or matching placebo (n=3). In Cohort 2 (andexanet bolus plus 2-hour infusion), subjects (n=6) received an 800 mg bolus of andexanet 4 hours after the last betrixaban dose, followed immediately by a 2-hour infusion of andexanet (8 mg/min), or matching placebo (n=3). Study endpoints included assessments of safety and multiple PD markers of anticoagulation reversal, including reduction in anti-FXa activity, decrease in unbound betrixaban plasma concentration, and restoration of thrombin generation. Results: Following treatment with betrixaban in Cohort 1, andexanet rapidly (2 minutes after the bolus) decreased anti-FXa activity from 29.9 ± 11.6 to 6.5 ± 4.5 ng/mL while the anti-FXa levels following placebo were largely unchanged (45.2 ± 44.8 to 43.6 ± 37.7 ng/mL). Unbound betrixaban plasma concentration decreased from 12.3 ± 5.6 to 3.6 ± 2.7 ng/mL with andexanet, but remained constant following placebo administration (18.3 ± 17.9 to 19.3 ± 18.1 ng/mL). Similar results were observed in Cohort 2 following andexanet bolus (2 minutes after the bolus), and the effects were maintained during the 2-hour infusion of andexanet. For Cohort 1, thrombin generation was restored (within the mean pre-anticoagulant value ± 2 standard deviations) in 6/6 (100%) of the andexanet-administered subjects vs. 1/3 (33.3%) of the placebo subjects. For Cohort 2, thrombin generation was restored in 5/6 (83.3%) of the andexanet subjects vs. 1/3 (33.3%) of the 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 indicate that andexanet could be a universal antidote for all four direct FXa inhibitors (apixaban, rivaroxaban, edoxaban, and betrixaban) as well as indirect FXa inhibitors. An ongoing Phase 3b/4 study (ANNEXA™-4) study 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. Disclosures Crowther: Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Leo Pharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Alexion: Consultancy, Speakers Bureau; AKP America: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb - Pfizer alliance: Honoraria; Portola: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb - Pfizer alliance: Honoraria; Leo Pharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Portola: Consultancy, Membership on an entity's Board of Directors or advisory committees; Portola: Consultancy, Membership on an entity's Board of Directors or advisory committees; Ortho Clinical Diagnostics: Honoraria; Daichii: Honoraria; Alexion: Consultancy, Speakers Bureau; Celgene: Honoraria; Celgene: Honoraria; Octapharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; AKP America: Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Alexion: Consultancy, Speakers Bureau; Octapharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Octapharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Alexion: Consultancy, Speakers Bureau; Bayer AG: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Boehringer-Ingelheim: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Leo Pharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Honoraria; Boehringer-Ingelheim: Honoraria, Membership on an entity's Board of Directors or advisory committees; Octapharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria; Ortho Clinical Diagnostics: Honoraria; CSL Behring: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Portola: Consultancy, Membership on an entity's Board of Directors or advisory committees; Daichii: Honoraria; Boehringer-Ingelheim: Honoraria, Membership on an entity's Board of Directors or advisory committees; CSL Behring: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Leo Pharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Boehringer-Ingelheim: Honoraria, Membership on an entity's Board of Directors or advisory committees; Leo Pharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bayer AG: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bayer AG: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Boehringer-Ingelheim: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Boehringer-Ingelheim: Honoraria, Membership on an entity's Board of Directors or advisory committees; Boehringer-Ingelheim: Honoraria, Membership on an entity's Board of Directors or advisory committees; Ortho Clinical Diagnostics: Honoraria; Octapharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer AG: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Alexion: Consultancy, Speakers Bureau; Boehringer-Ingelheim: Honoraria, Membership on an entity's Board of Directors or advisory committees; Portola: Consultancy, Membership on an entity's Board of Directors or advisory committees; Portola: Consultancy, Membership on an entity's Board of Directors or advisory committees; Portola: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria; Ortho Clinical Diagnostics: Honoraria; Bayer AG: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; CSL Behring: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Portola: Consultancy, Membership on an entity's Board of Directors or advisory committees; Boehringer-Ingelheim: Honoraria, Membership on an entity's Board of Directors or advisory committees; AKP America: Membership on an entity's Board of Directors or advisory committees; Alexion: Consultancy, Speakers Bureau; Alexion: Consultancy, Speakers Bureau; Leo Pharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; AKP America: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb - Pfizer alliance: Honoraria; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Portola: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb - Pfizer alliance: Honoraria; CSL Behring: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bristol-Myers Squibb - Pfizer alliance: Honoraria; Leo Pharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Octapharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria; Ortho Clinical Diagnostics: Honoraria; Ortho Clinical Diagnostics: Honoraria; Bayer AG: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Ortho Clinical Diagnostics: Honoraria; Pfizer: Co

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