The results of the Phase 3 ANNEXATM (Andexanet Alfa a Novel Antidote to the Anticoagulant Effects of FXa Inhibitors) studies by Portola Pharmaceuticals have been published online by The New England Journal of Medicine.
The safety and efficacy of andexanet alfa were evaluated by the ANNEXA-R and ANNEXA-A trials. The investigational reversal agent, for reversing the anticoagulant activity of the Factor Xa inhibitors rivaroxaban and apixaban, respectively, in healthy volunteers, was designated a breakthrough therapy by the US Food and Drug Administration (FDA).
Results showed that both ANNEXA Part 1 (bolus only) and Part 2 (bolus plus continuous infusion) met all primary and secondary efficacy endpoints, including the measurement of reversal Anti-Xa activity (p<0.0001) for both rivaroxaban and apixaban.
In Part 1, andexanet alfa given as an IV bolus reversed the anticoagulant effect of the Factor Xa inhibitors to no-effect levels, as measured by anti-Factor Xa activity, within two to five minutes of administration (p<0.0001). In Part 2, andexanet alfa was administered as an intra-venous bolus followed by a continuous two-hour infusion sustained that reversal for the duration of the infusion, reducing anticoagulant activity (p<0.0001). Andexanet alfa was well tolerated, with no serious or severe adverse events, no thrombotic events, and no antibodies observed to Factor X or Xa.
Full results of Part 2 of ANNEXA-R also were presented today during a Late Breaking Clinical Trial session at the American Heart Association’s (AHA) Scientific Sessions 2015 in Orlando, Florida.
Four-factor PCCs, are not approved to reverse the anticoagulant effects of Factor Xa inhibitors, and no known label-enabling studies are ongoing. Additionally, the FDA and the European Medicines Agency do not view four-factor PCCs, which are only approved to reverse the effects of vitamin K and include a black box warning for blood clots, as a standard of care therapy for this patient population.
“The ANNEXA studies demonstrated that andexanet alfa can rapidly reverse the anticoagulant effect of Factor Xa inhibitors for both short and sustained periods with a good safety profile. This means that andexanet alfa, by allowing for flexible and controlled reversal, could address different clinical scenarios in which a reversal agent is needed,” says John T Curnutte, executive vice president of research and development for Portola.
