FDA issues CRL for Andexxa

Andexxa remains the only approved reversal agent for direct oral FXa inhibitors

AstraZeneca PLC’s anticoagulant reversal agent Andexxa (andexanet) will not convert to full approval, following the U.S. Food and Drug Administration’s (FDA) decision to issue a complete response letter (CRL) for the supplemental biologics license application.

The FDA decision was expected at the end of November. However, neither AstraZeneca nor the FDA provided additional information about the product’s regulatory standing. AstraZeneca stated that Andexxa will remain on the US market while discussions with the agency continue, but did not confirm whether those discussions include potential new trials.

Andexxa is currently the only treatment indicated to reduce the effects of direct oral factor Xa (FXa) inhibitors, including Bristol-Myers Squibb Co. / Pfizer Inc.’s Eliquis (apixaban) and Johnson & Johnson / Bayer AG’s Xarelto (rivaroxaban), when reversal of anticoagulation is needed due to life-threatening or uncontrolled bleeding.

The FDA raised efficacy and safety concerns about the drug’s confirmatory trial, ANNEXA-I, ahead of a November 21 advisory committee meeting. Among the concerns was an increased risk of thrombosis-related deaths. The Cellular, Tissue and Gene Therapies Advisory Committee (CTGTAC) suggested that the unfavorable risk–benefit balance observed in the trial may be due to the population studied — patients with acute intracranial hemorrhage. This group is generally older and sicker, and may be more susceptible to adverse events than other indicated populations.

The committee proposed modifying the indication to include patients more likely to have a favorable risk–benefit profile. Some members also suggested adjusting the Andexxa dose.

The lack of alternative products to reverse the effects of direct oral anticoagulants weighed heavily on committee members, who considered the trial data alongside public hearing testimony from emergency room doctors advocating for continued access to the drug.

Why did the FDA issue a complete response letter for Andexxa?

The FDA issued a CRL for Andexxa due to safety and efficacy concerns raised in the ANNEXA-I confirmatory trial, including an increased risk of thrombosis-related deaths.

What is Andexxa currently approved to treat?

Andexxa is approved to reverse the effects of direct oral factor Xa inhibitors, such as apixaban and rivaroxaban, in cases of life-threatening or uncontrolled bleeding.

Will Andexxa remain available in the USA?

Yes, AstraZeneca stated that Andexxa will remain on the US market while discussions with the FDA about next steps continue.

What concerns did the FDA advisory committee raise about Andexxa?

The Cellular, Tissue and Gene Therapies Advisory Committee raised concerns about the drug’s risk–benefit balance in patients with acute intracranial hemorrhage, who may be more susceptible to adverse events.

Are new clinical trials planned for Andexxa?

AstraZeneca has not confirmed whether new trials will be conducted, despite ongoing discussions with the FDA.