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Factor Xa inhibitor antidote shows promise in phase 2 study
New phase 2 data presented at the American Society of Hematology Annual Meeting demonstrate that andexanet alfa effectively reversed the anticoagulation activity of rivaroxaban.
For the double blind, placebo-controlled, cohort, dose-escalation study, researchers administered 20 mg rivaroxaban (Xarelto, Janssen Pharmaceuticals) once daily for 6 days to 36 healthy volunteers. Participants were then randomly assigned in a 6:3 ratio to receive a single IV bolus of andexanet alfa (PRT4445, Portola Pharmaceuticals) at a dose of 210 mg, 420 mg or 600 mg, or a 720 mg bolus followed by a 4 mg/minute infusion for 1 hour.
“Andexanet alfa is the only agent that has been shown to reverse the anticoagulation effect of Factor Xa inhibitors by directly impacting anti-Factor Xa activity,” researcher John T. Curnutte, MD, PhD, executive vice president of research and development for Portola Pharmaceuticals, told Healio.com. “This is important because no antidote or reversal agent is approved for use against Factor Xa inhibitors. Additionally, andexanet alfa provides either short-term reversal of anti-Factor Xa activity through the administration of an intravenous bolus, or sustained reversal by the addition of an extended infusion. This is critical in covering the multiple clinical scenarios in which a reversal agent would be needed.”
Patients in all four groups experienced dose-dependent reductions in anti-Factor Xa activity. A 20% reduction was observed in the 210-mg group, 53% reduction in the 420-mg group, 70% reduction in the 600-mg group and 81% reduction in the 720-mg group. Activity returned to placebo levels approximately 2 hours after participants received treatment. The researchers also reported decreases in unbound rivaroxaban plasma concentrations of 32% in the 210-mg group, 51% in the 420-mg group, 75% in the 600-mg group and 70% in the 720-mg group.
In addition, the data demonstrate a dose-dependent effect on the inhibition of thrombin generation and the increase in prothrombin and active clotting time induced by rivaroxaban.
No participants in any group experienced serious adverse events or thrombotic events, and no participants developed Factor Xa or Factor X antibodies during the study.
“With these new phase 2 data, we now know that andexanet alfa sequesters Xarelto and Eliquis (apixaban, Bristol-Myers Squibb) in a consistent and similar stoichiometric manner, resulting in dose-dependent reversal of anti-Factor Xa activity,” Curnutte said. “This information will be instrumental in selecting doses for upcoming phase 3 studies of andexanet alfa, which we anticipate initiating in the first half of 2014.” – by Adam Taliercio
For more information:
Crowther M. Abstract #3636. Presented at: American Society of Hematology Annual Meeting and Exposition; Dec. 7-10, 2013; New Orleans.
Disclosure: All researchers report serving as employees or consultants for, and/or having equity ownership in, Portola Pharmaceuticals.