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Andexanet Alfa Reverses Anti-Clotting Effect of Apixaban in Late-Stage Study
A phase III study of andexanet alfa (Portola Pharmaceuticals), a potential universal factor Xa inhibitor antidote and an FDA-designated “breakthrough therapy,” has met its primary and secondary endpoints.
Andexanet alfa was well tolerated, with no serious adverse events reported.
Top-line efficacy data from the first of two ANNEXA-A (Andexanet Alfa, a Novel Antidote to the Anticoagulant Effects of FXa Inhibitors — Apixaban) trials demonstrated that an intravenous (IV) bolus of andexanet alfa immediately reversed the anticoagulation activity of the direct factor Xa inhibitor apixaban (Eliquis, Bristol-Myers Squibb/Pfizer).
The new findings will be presented November 17 at the American Heart Association 2014 Scientific Sessions, to be held in Chicago.
The ongoing randomized, double-blind, placebo-controlled ANNEXA-A studies are evaluating the safety and efficacy of andexanet alfa in reversing apixaban-induced anticoagulation in older healthy volunteers. Efficacy is being evaluated using biomarker endpoints, including anti-factor Xa levels, as the primary endpoint. Secondary endpoints include levels of unbound (free-fraction) apixaban in plasma and thrombin generation.
In the first ANNEXA-A study, 33 older healthy volunteers were treated with apixaban 5 mg twice daily for 4 days and were then randomly assigned to receive andexanet alfa (administered as a 400-mg IV bolus) or placebo. The study met its primary and secondary endpoints with high statistical significance. The results showed that andexanet alfa immediately and significantly reversed the anticoagulation activity of apixaban.
In the second ANNEXA-A study, 32 healthy volunteers will be given apixaban 5 mg twice daily for 4 days and will then be randomly assigned to receive andexanet alfa (administered as a 400-mg IV bolus, followed by a continuous infusion of 4 mg/min for 120 minutes) or placebo. Data from this study are expected in early 2015.
In addition, the ability of andexanet alfa to reverse the anticoagulation effects of the direct factor Xa inhibitors rivaroxaban (Xarelto, Bayer HealthCare/Janssen) and edoxaban (Daiichi Sankyo) is being evaluated in the phase III ANNEXA-R and ANNEXA-E trials, respectively. Results from three phase II proof-of concept studies with apixaban, rivaroxaban, and enoxaparin (Lovenox, Sanofi), a low-molecular-weight heparin and indirect factor Xa inhibitor, in healthy volunteers demonstrated that andexanet alfa immediately reversed the anticoagulation activity of each factor Xa inhibitor and that the reversal could be sustained.
Andexanet alfa has been shown to be well tolerated in phase I and phase II clinical studies, which included more than 100 healthy volunteers, with no thrombotic events or antibodies to factor Xa or factor X observed.
A phase II proof-of-concept study with edoxaban is ongoing, and a phase II proof-of-concept study with the direct factor Xa inhibitor betrixaban (Portola Pharmaceuticals) is planned.
Source: Portola Pharmaceuticals; October 1, 2014.