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Portola Pharmaceuticals late on Wednesday evening that it had received a complete response letter (CRL) from the FDA regarding its Biologics License Application (BLA) for its NOAC reversal agent AndexXa (andexanet alfa).
Approval for the drug had been widely expected earlier in the day, which was the drug's PDUFA date. The drug had been on an accelerated approval pathway after having been designated by the FDA as an orphan drug and as a breakthrough therapy.
The lack of a reversal agent has been considered a major limitation of the new Factor Xa oral anticoagulants rivaroxaban (Xarelto, Bayer and Johnson & Johnson) and apixaban (Eliquis, Bristol-Myers Squibb and Pfizer).
Unlike warfarin, which they are designed to supplant, the new drugs don't require monitoring and don't have numerous interactions with food and other drugs. But a reversal agent is available for warfarin. Reversal agent for anticoagulants are not used frequently but physicians like to have them available in cases of major bleeding or when patients require immediate surgery.
Portola said that the FDA asked the company to "provide additional information primarily related to manufacturing." In addition, the FDA also "asked for additional data to support inclusion" in the label of two additional anticoagulants, edoxaban and enoxaparin. The FDA also indicated to the company that "it needs to finalize its review of the clinical amendments to Portola's post-marketing commitments that recently were submitted."
It is unclear how long it will take Portola to respond to the FDA's and gain approval. The Portola press release does not appear to suggest that the FDA has raised a major or insurmountable obstacle to approval.
"Because AndexXa addresses an urgent unmet medical need, we and the FDA are committed to resolving the outstanding questions and determining appropriate next steps. Portola's goal is to define the most expedient path to approval so we can meet the needs of these patients who have no alternative," said Bill Lis, Portola's CEO. "We plan to meet with the FDA as soon as possible."
The BLA for AndexXa relied on data from two Phase 3 ANNEXA studies in healthy volunteers published last year in the New England Journal of Medicine. The FDA also analyzed data from the ongoing ANNEXA-4 study, which the company described as a "Phase 3b/4 single-arm, open-label confirmatory study in patients receiving apixaban, rivaroxaban, edoxaban or enoxaparin who present with an acute major bleed."
Last October the FDA approved idarucizumab (Praxbind), a monoclonal antibody designed to reverse the anticoagulant effects of dabigatran Pradaxa), a direct thrombin inhibitor. Both Prabind and Pradaxa are manufactured by Boehringer Ingelheim.