Andexanet Alfa, First Reversal Agent for Factor Xa Inhibitors, Finally Gains FDA Approval

The US Food and Drug Administration (FDA) has cleared andexanet alfa (Andexxa) as a reversal agent for the anticoagulant effects of the two most commonly used factor Xa inhibitors in patients with life-threatening or uncontrolled bleeding, manufacturer Portola Pharmaceuticals announced late yesterday.

The antidote is indicated for use in patients who bleed while taking either rivaroxaban (Xarelto; Bayer/Janssen) or apixaban (Eliquis; Bristol-Myers Squibb), but the indication does not cover the other direct factor Xa inhibitors edoxaban (Savaysa; Daiichi Sankyo) and betrixaban (Bevyxxa)—which was approved last June for prevention of venous thromboembolism—or enoxaparin, an indirect factor Xa inhibitor.

The only other approved reversal agent for the non-vitamin K antagonist oral anticoagulants (NOACs)—given the FDA’s okay in October 2015—is idarucizumab (Praxbind), an antidote for the direct thrombin inhibitor dabigatran (Pradaxa; both Boehringer Ingelheim).

The FDA previously declined to approve andexanet alfa in August 2016, citing the need for more information related to manufacturing and more data to support inclusion of all of the factor Xa inhibitors on the label.

Jean Connors, MD (Brigham and Women’s Hospital, Boston, MA), told TCTMD the availability of andexanet alfa is critical because other strategies for reversing bleeding in patients treated with the factor Xa inhibitors are only partially effective. There was no specific reversal agent for this class of drugs until now.

Though idarucizumab has not been extensively used since its approval, Connors pointed out that the drug it reverses is not prescribed as frequently as rivaroxaban and apixaban. Andexanet alfa also will not have to be used that often, but the potential pool of patients is larger than for idarucizumab.

“It’s a small fraction of patients that develop major life-threatening bleeding on any of these anticoagulants, but when they do develop bleeding, the consequences can be severe,” Connors said.

It’s possible, she added, that the availability of andexanet alfa could have an impact on which oral anticoagulants physicians will use in their patients.

“There are still both patients and prescribing clinicians who are hesitant to use the direct oral anticoagulants because there are no reversal strategies,” she explained. “So andexanet may relieve that anxiety and we may see more people use those drugs.”

Andexanet alfa is a recombinant modified human factor Xa molecule that acts as a decoy, binding with factor Xa inhibitors in the bloodstream to allow the body’s own factor Xa to resume its normal coagulant activity. It was designated as a breakthrough therapy and an orphan drug by the FDA and cleared through the agency’s accelerated approval pathway, which means that continued approval may be contingent upon the antidote demonstrating improved hemostasis in a randomized trial versus usual care. Portola said that trial is scheduled to start in 2019, with results expected 4 years later.

The FDA granted approval based on evidence from the phase III ANNEXA-A and ANNEXA-R trials showing that andexanet alfa rapidly reverses the anticoagulant effects of factor Xa inhibitors in healthy volunteers. The agency also considered data from the ongoing phase IIb/IV ANNEXA-4 trial.

Andexanet alfa’s label will carry a boxed warning about thromboembolic risks, ischemic risks, cardiac arrest, and sudden deaths that advises clinicians to “monitor for thromboembolic events and initiate anticoagulation when medically appropriate. Monitor for symptoms and signs that precede cardiac arrest and provide treatment as needed.”

Connors said she does not have any concerns with using andexanet alfa. “When you’re faced with a patient who has life-threatening bleeding, you want to reverse the anticoagulant effect and if there are any downstream issues you can deal with them,” she said.

Though the underlying thrombotic risk of these patients is a concern and anticoagulation should be restarted as soon as possible after the bleeding has been resolved, she said, “if you don’t stop the bleeding and don’t reverse the anticoagulant effect up front you will never get to even being concerned about having any downstream effects.”

Asked about the boxed warning, a Portola spokesperson said in an email it “was not unexpected given this very high-risk patient population. We do not believe this will have an impact on the [uptake] of Andexxa. As a reminder, this division of the FDA also gave a boxed warning to KCentra for the reversal of warfarin and it did not have an impact on the uptake of KCentra for this indication. We will continue to provide data to the FDA from the ongoing ANNEXA-4 patient data that we believe supports both safety and efficacy of Andexxa.”

Portola said it expects to launch andexanet alfa in early June under an early supply program, with wider commercial availability expected early next year.

The reversal agent remains under review by the European Medicines Agency, with a final decision expected in early 2019.