Portola Pharmaceuticals has announced positive topline results from the second part of the phase 3 ANNEXA-A (Andexanet Alfa a Novel Antidote to the Anticoagulant Effects of FXa Inhibitors – Apixaban) study, which evaluated the safety and efficacy of andexanet alfa, an investigational antidote, with the Factor Xa inhibitor Eliquis (apixaban) in healthy volunteers.
Andexanet alfa, a US Food and Drug Administration (FDA)-designated breakthrough therapy, was administered as an intravenous bolus followed by a continuous two-hour infusion to sustain the reversal of anticoagulation activity. This registration-enabling study achieved all primary and secondary endpoints with high statistical significance. Andexanet alfa produced rapid reversal of the anticoagulant effect of apixaban, as measured by anti-Factor Xa activity, which was sustained for the duration of the infusion. In the study, andexanet alfa was well tolerated, with no serious adverse events, thrombotic events, or antibodies to Factor X or Xa reported. The full data from this second part of the ANNEXA-A study will be presented at an upcoming scientific meeting.
“Andexanet alfa has now demonstrated its ability to rapidly and significantly reverse the anticoagulant effect of apixaban administered as a bolus only or bolus plus continuous infusion in ANNEXA-A parts 1 and 2. These important findings show that andexanet alfa has the potential to treat a broad group of patients who require an antidote, including those requiring longer-duration reversal and those in which only short-duration reversal is necessary to address the patient’s needs. Importantly, in all cases, andexanet alfa’s short half-life allows patients to be re-anticoagulated as needed,” said John T Curnutte, executive vice president, research and development for Portola. “Andexanet alfa distinguishes itself as the only Factor Xa inhibitor antidote in development shown to bind to oral FXa inhibitors and have a significant impact on three critical biomarkers: anti-Factor Xa activity, thrombin generation and free fraction of the anticoagulant. Both the FDA and European Medicines Agency have agreed that the reduction of anti-Factor Xa activity is an acceptable primary endpoint for accelerated approval (expedited or conditional approval in the EU) with supporting secondary endpoints, including normalisation of thrombin generation and sequestration of the anticoagulant. Given the highly statistically significant efficacy results we have seen in phase 2 and phase 3 studies across oral and injectable Factor Xa inhibitors, we believe andexanet alfa has the potential to be a first-in-class antidote for patients taking a Factor Xa anticoagulant who suffer a major bleeding episode or require emergency surgery.”
Portola plans to submit data from the ANNEXA-A (apixaban) and ANNEXA-R (rivaroxaban) studies, and initial data from a phase 4 study, as part of its Biologics License Application to the FDA under an accelerated approval pathway by the end of 2015.
ANNEXA-A study design
The randomised, double-blind, placebo-controlled phase 3 ANNEXA-A study evaluated the safety and efficacy of andexanet alfa in reversing apixaban-induced anticoagulation in older healthy volunteers ages 50–75 years. Efficacy was evaluated using biomarker endpoints, with anti-Factor Xa levels as the primary endpoint. Secondary endpoints included plasma levels of free unbound apixaban and endogenous thrombin potential, a measure of thrombin generation.
In the first part of the study, which was previously presented, 33 healthy volunteers were given apixaban 5mg twice daily for four days and then randomised in a 3:1 ratio to andexanet alfa administered as a 400mg intravenous bolus (n=24) or to placebo (n=9). Today, Portola announced topline results from the second part of the study, in which 31 healthy volunteers were given apixaban 5mg twice daily for four days and then randomsised in a 3:1 ratio to andexanet alfa administered as a 400 mg intravenous bolus followed by a continuous infusion of 4 mg/min for 120 minutes (n=23) or to placebo (n=8).