Andexanet alfa reverses rivaroxaban-induced anticoagulation in phase 3 ANNEXA-R trial
Intravenous administration of andexanet alfa rapidly and significantly reversed the anticoagulant effect of Factor Xa inhibitor rivaroxaban, according to phase 3 results presented at the American College of Cardiology Scientific Sessions.
Results from ANNEXA-R evaluating andexanet alfa (AnXa, Portola Pharmaceuticals) after rivaroxaban (Xarelto, Janssen Pharmaceuticals) showed a significant reduction in plasma levels of the unbound Factor Xa inhibitor and thrombin generation restored to within normal baseline range.
“We believe that andexanet alfa has the potential to become the first approved universal antidote for Factor Xa inhibitors and the standard of care to manage bleeding associated with these novel anticoagulants,” John T. Curnutte, MD, PhD, executive vice president of research and development for Portola, said in a news release.
In a randomized, double blind, placebo-controlled trial, Mark Crowther, MD, MSc, FRCPC, of McMaster University, Canada, and colleagues evaluated the safety and efficacy of andexanet alfa in reversing anticoagulation induced by rivaroxaban in 41 healthy adults aged 50 to 75 years.
After receiving rivaroxaban (20 mg) once daily over 4 days, participants were randomized at peak concentration in a 2:1 ratio to andexanet alfa (800-mg intravenous bolus; n = 27, 66.7% men) or placebo (n = 14, 57.2% men).
The investigators evaluated efficacy using biomarker endpoints; anti-Factor Xa levels were the primary endpoint, and secondary endpoints included plasma levels of free rivaroxaban and endogenous thrombin potential (ETP) as a measure of thrombin generation.
Andexanet alfa reduced the anti-Factor Xa activity of rivaroxaban from baseline by more than 90% (P < .0001), with 26 of 27 participants treated with the drug demonstrating a decrease vs. 0 participants with placebo.
From baseline, unbound rivaroxaban concentration decreased with andexanet alfa compared with placebo, and ETP increased (P < .0001 for both)
With andexanet alfa, normal range of thrombin generation was achieved by 26 of 27 participants within 10 minutes of the end of the bolus administration.
Andexanet alfa was well-tolerated, with no serious or severe adverse events, no thrombotic events and no antibodies to Factor X or Xa observed.
Approximately 40 healthy adults are expected to participate in the second part of ANNEXA-R, which would add a continuous infusion of andexanet alfa (8 mg/min for 120 minutes) to the bolus regimen; results are anticipated in mid-2015.
“Andexanet alfa is the only Factor Xa inhibitor antidote in development shown to directly and significantly impact definitive markers of coagulation, such as anti-Factor Xa levels, in clinical studies,” Curnutte said.
The company anticipates submitting data to the FDA by the end of 2015 for its Biologics License Application, according to the release.
“With andexanet alfa and betrixaban, our investigational Factor Xa inhibitor, we are building a robust thrombosis franchise of potentially life-saving medicines that could benefit millions of patients worldwide,” Curnutte said.
Gold AM, et al. Abstract 912-08. Presented at: American College of Cardiology Scientific Sessions; March 14-16, 2015; San Diego.
Gold AM, et al. J Am Coll Cardiol. 2015;doi:10.1016/S0735-1097(15)60023-7.
Disclosure: Crowther reports advisory board roles with AKP America, Janssen, Leo Pharma, and Portola, and receiving funding for presentations from Bayer, Celgene, CSL Behring Leo Pharma, and Shire. Please see the full study for a list of all other authors’ relevant financial disclosures.