The US Food and Drug Administration (FDA) has granted accelerated approval for andexanet alfa (Andexxa®), the first antidote for the reversal of factor Xa inhibitors.
Andexanet alfa is approved for use in patients treated with rivaroxaban or apixaban when reversal of anticoagulation is needed due to life-threatening or uncontrolled bleeding.
Andexanet alfa was granted accelerated approval for this indication based on the drug’s anti-factor Xa activity in healthy volunteers.
Continued FDA approval of andexanet alfa may be contingent upon post-marketing study results to demonstrate an improvement in hemostasis in patients taking rivaroxaban or apixaban who require reversal of anticoagulation.
The post-marketing requirement is a trial in which patients will be randomized to receive either andexanet alfa or usual care. This study is scheduled to start in 2019, with results expected to be available in 2023.
Portola Pharmaceuticals, Inc., said it expects to launch andexanet alfa in early June. This drug will be produced using the generation 1 manufacturing process.
A broader commercial launch of andexanet alfa is anticipated in early 2019, dependent upon FDA approval of the generation 2 manufacturing process.
The FDA’s approval of andexanet alfa is supported by data from a pair of phase 3 studies—ANNEXA-R and ANNEXA-A.
These trials were designed to evaluate the safety and efficacy of andexanet alfa in reversing the anticoagulant activity of rivaroxaban and apixaban in healthy volunteers.
Results from both studies were published in NEJM in 2015.
The FDA also assessed interim data from the ongoing ANNEXA-4 study as part of the review and approval of andexanet alfa.
In ANNEXA-4, researchers are evaluating andexanet alfa in patients experiencing major bleeding while taking factor Xa inhibitors.
Interim results from this trial were presented at the American College of Cardiology’s 67th Annual Scientific Session & Expo in March.
About andexanet alfa
Andexanet alfa is a modified human factor Xa molecule that acts as a decoy to target and sequester both oral and injectable factor Xa inhibitors in the blood. Once bound, the factor Xa inhibitors are unable to bind to and inhibit native factor Xa, thus potentially allowing for the restoration of normal hemostatic processes.
Portola Pharmaceuticals first submitted the biologics license application (BLA) for andexanet alfa in December 2015. The FDA had already granted andexanet alfa orphan drug designation earlier in 2015 and breakthrough therapy designation in 2013.
With its first BLA submission, Portola was seeking approval for andexanet alfa as a reversal agent for patients anticoagulated with an oral or injectable factor Xa inhibitor—apixaban, rivaroxaban, edoxaban, or enoxaparin—who experience serious uncontrolled or life-threatening bleeding or who require urgent or emergency surgery.
In August 2016, the FDA issued a complete response letter explaining why the agency could not approve andexanet alfa for this indication.
The FDA requested additional information related to manufacturing of the drug and asked Portola for additional data to support the inclusion of edoxaban and enoxaparin on andexanet alfa’s label. This was because the ANNEXA-A and ANNEXA-R trials only included subjects who received apixaban or rivaroxaban.
In August 2017, Portola resubmitted the BLA for andexanet alfa. This time, the company sought approval of the drug only for patients on apixaban or rivaroxaban who are experiencing uncontrolled or life-threatening bleeding.
For additional information on andexanet alfa, visit https://www.andexxa.com/.