FDA Declines to Approve Portola’s Reversal Agent for Factor Xa Inhibitors

The US Food and Drug Administration (FDA) has declined to approve andexanet alfa (AndexXa), a reversal agent for the anticoagulant effects of factor Xa inhibitors. 

Portola Pharmaceuticals, the manufacturer of andexanet alfa, reported late last night they had received a complete response letter (CRL) from the FDA regarding their Biologics License Application.

The agent, which was designated as a breakthrough therapy and an orphan drug by the FDA and was cleared through the agency’s accelerated approval pathway, reverses the effects of the direct factor Xa inhibitors—apixaban (Eliquis; Bristol-Myers Squibb), rivaroxaban (Xarelto; Janssen Pharmaceuticals), and edoxaban (Savaysa; Daiichi Sankyo)—and enoxaparin, an indirect factor Xa inhibitor.

In the CRL, the FDA stated they want the company to provide additional information related to manufacturing, as well as additional data to support the inclusion of edoxaban and enoxaparin in the label. In addition, the agency stated they need to finalize their review of recently submitted clinical amendments to Portola’s postmarketing commitments.

In a statement, Portola said they “are committed to resolving the outstanding questions and determining appropriate next steps” to gain approval. They plan to meet with the FDA to address the issues.

The biologics license application for andexanet alfa was based on data from the two phase III ANNEXA-A and ANNEXA-R trials. Those studies, published in the New England Journal of Medicine, showed andexanet alfa effectively reversed the anticoagulant activity of apixaban and rivaroxaban in healthy volunteers with no serious adverse events.

The FDA also analyzed limited data from the ongoing phase IIIb/IV ANNEXA-4 study, which is enrolling patients presenting with acute major bleeding while taking any of the factor Xa inhibitors. An interim analysis of ANNEXA-4 will be presented at the European Society of Cardiology Congress in Rome, Italy, at the end of the month.

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 dabigatran (Pradaxa; both Boehringer Ingelheim).

Related Stories:

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