A recent FDA advisory committee meeting raised questions about the clinical benefit of andexanet alfa (Andexxa), marketed by AstraZeneca, despite evidence suggesting its ability to control hematoma volume in patients with intracerebral hemorrhage (ICH) taking direct oral anticoagulants (DOACs). The Cellular, Tissue, and Gene Therapies Advisory Committee acknowledged andexanet alfa's demonstrated ability to limit hematoma volume change within 12 hours, based on the ANNEXA-I trial. However, the panel expressed uncertainty regarding the clinical meaningfulness of this outcome, citing a lack of supporting evidence for improved patient outcomes.
The ANNEXA-I trial, a randomized controlled trial requested by the FDA, evaluated andexanet alfa in patients with acute ICH on factor Xa (FXa) inhibitors. While the trial met its primary endpoint by showing that the drug helped curb expansion of hematoma volume, it did not demonstrate improvements in neurologic status or survival. This discrepancy led to concerns among committee members about whether the observed effect on hematoma volume translated into tangible clinical benefits for patients.
Concerns Over Thrombotic Risks
Safety was a significant concern during the advisory committee meeting, as the ANNEXA-I trial linked andexanet alfa to an increased risk of thrombotic events. The trial reported that 14.6% of participants receiving andexanet alfa experienced thrombotic events by day 30, compared to 6.9% in the usual care group, which typically received a prothrombin complex concentrate (PCC). Thrombosis-related deaths occurred in 2.5% of the andexanet alfa group versus 0.9% in the usual care group. This safety signal had been previously observed in the 2016 ANNEXA-4 study.
Regulatory Context and Potential Refinement of Indications
Andexanet alfa received FDA accelerated approval in 2018 based on interim results from ANNEXA-4, which demonstrated a change in anti-activated FXa activity, a surrogate endpoint. Currently, andexanet alfa is indicated for the reversal of anticoagulation in patients treated with rivaroxaban (Xarelto) or apixaban (Eliquis) when life-threatening or uncontrolled bleeding occurs. Some panel members suggested refining the indications for andexanet alfa to better identify patients who would benefit most from the drug while minimizing the risk of thrombotic events.
Mechanism of Action and Trial Details
Andexanet alfa is a recombinant modified human FXa protein designed to bind FXa inhibitors and restore thrombin generation. In the ANNEXA-I trial, patients were randomized to either a low-dose or high-dose andexanet alfa regimen based on the timing and dosage of their last DOAC dose. The primary endpoint, hemostatic efficacy, was a composite of hematoma expansion of 35% or less, an increase of less than 7 points on the National Institutes of Health Stroke Scale, and no receipt of rescue therapy.
The FDA is not bound to follow the advice of its advisory committees but typically does so. The advisory panel members were not asked to vote on further regulatory action for andexanet alfa.
