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 apixaban (Eliquis, Bristol Myers Squibb/Pfizer) in healthy volunteers.
Andexanet alfa, a US Food and Drug Administration (FDA)-designated breakthrough therapy, was administered as an intravenous (IV) 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.
According to a company release, 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,” says 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.”
The company announced that it 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 (ETP), 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 IV bolus (n=24) or to placebo (n=9). In this part 2 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 randomized in a 3:1 ratio to andexanet alfa administered as a 400mg IV bolus followed by a continuous infusion of 4mg/min for 120 minutes (n=23) or to placebo (n=8).
Results of first part of ANNEXA-A study
Results from the first part of the ANNEXA-A study were presented during an oral session at the American Heart Association (AHA) 2014 Scientific Sessions in Chicago in November 2014. The first part of the study achieved all primary and pre-specified secondary endpoints with statistical significance (p< 0.0001). Andexanet alfa administered as an IV bolus produced rapid and nearly complete reversal of the anticoagulant effect of apixaban. Two to five minutes after completion of a bolus dose of andexanet alfa, the anticoagulant activity of apixaban was reversed by approximately 94% (p<0.0001) compared with placebo as measured by anti-Factor Xa activity. Every subject treated with andexanet alfa had between 90 and 96% reversal of the anticoagulant activity of apixaban. No serious adverse events, thrombotic events, or antibodies to Factor X or Xa were reported following andexanet alfa administration. Mild infusion reaction was reported in three subjects.
About andexanet alfa
Andexanet alfa is a modified human Factor Xa molecule that acts as a decoy to target and sequester with high specificity 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 allowing for the restoration of normal haemostatic processes. Andexanet alfa has the potential to address numerous clinical scenarios where an antidote is needed by allowing for flexible and controlled reversal. This can be short-acting through the administration of an IV bolus or longer-acting with the addition of an extended infusion.
Andexanet alfa is the only compound being studied as a reversal agent for Factor Xa inhibitors that directly and specifically corrects anti-Factor Xa activity — the anticoagulant mechanism of these agents.
Andexanet alfa has been granted orphan drug designation by the FDA for reversing the anticoagulant effect of direct or indirect Factor Xa inhibitors in patients experiencing a serious uncontrolled bleeding event or who require urgent or emergent surgery.