First antidote for reversal of Factor Xa inhibitors receives FDA approvalNews - May 7, 2018
The U.S. Food and Drug Administration (FDA) has approved andexanet alfa, the first and only antidote indicated for patients treated with rivaroxaban and apixaban, when reversal of anticoagulation is needed due to life-threatening or uncontrolled bleeding.
Andexanet alfa is a recombinant coagulation factor Xa protein specifically designed to bind to Factor Xa inhibitors and rapidly reverse their anticoagulant effect. Andexanet alfa works by acting as a decoy for oral and injectable Factor Xa inhibitors, which target and bind to Factor Xa, which allows them to exert their anticoagulant effect.
Andexanet alfa received both U.S. Orphan Drug and FDA Breakthrough Therapy designations and was approved under the FDA's Accelerated Approval pathway based on the change from baseline in anti-Factor Xa activity in healthy volunteers. Continued approval for this indication may be contingent upon post-marketing study results to demonstrate an improvement in hemostasis in patients.
The use of Factor Xa inhibitors is rapidly growing because of their efficacy and safety profile compared to enoxaparin and warfarin in preventing and treating thromboembolic conditions such as stroke, pulmonary embolism and venous thromboembolism (VTE). This growth has come with a related increase in the incidence of hospital admissions and deaths related to bleeding, the major complication of anticoagulation. In the U.S. alone in 2016, there were approximately 117,000 hospital admissions attributable to Factor Xa inhibitor-related bleeding and nearly 2,000 bleeding-related deaths per month.
The approval of andexanet alfa is supported by data from two Phase 3 ANNEXA studies (ANNEXA-R and ANNEXA-A) published in The New England Journal of Medicine, which evaluated the safety and efficacy of andexanet alfa in reversing the anticoagulant activity of the Factor Xa inhibitors rivaroxaban and apixaban in healthy volunteers. As described in the label, results demonstrated that andexanet alfa rapidly and significantly reversed anti-Factor Xa activity. The median decrease in anti-Factor Xa activity from baseline was 97 percent for rivaroxaban and 92 percent for apixaban.
Interim data from the ongoing ANNEXA-4 single-arm, open-label study in patients with major bleeding also were assessed by the FDA as part of its review and approval. Data from 185 evaluable patients showed that andexanet alfa rapidly and significantly reversed anti-Factor Xa activity when administered as a bolus and sustained this reversal when followed by a 120-minute infusion. The median decrease from baseline was 90 percent for rivaroxaban and 93 percent for apixaban.
The Marketing Authorization Application (MAA) for andexanet alfa is also under review by the European Medicines Agency. The Committee for Medicinal Products for Human Use (CHMP) communicated a positive trend vote on the MAA in February 2018. A formal opinion from the CHMP is expected by the end of 2018, and the European Commission is expected to issue a decision in early 2019.