NEJM reports on Phase 3 ANNEXA studies of andexanet alfa

SOUTH SAN FRANCISCO, Calif.—Portola Pharmaceuticals announced that the results of its Phase 3 ANNEXA (Andexanet Alfa a Novel Antidote to the Anticoagulant Effects of FXa Inhibitors) studies were published online recently by The New England Journal of Medicine. ANNEXA-R and ANNEXA-A evaluated the safety and efficacy of andexanet alfa, an investigational reversal agent, which was designated a breakthrough therapy by the U.S. Food and Drug Administration (FDA) for reversing the anticoagulant activity of the Factor Xa inhibitors rivaroxaban and apixaban in healthy volunteers. Results showed that both ANNEXA part one (bolus only) and part two (bolus plus continuous infusion) met all primary and secondary efficacy endpoints, including the measurement of reversal anti-Xa activity for both rivaroxaban and apixaban.

“The published Phase 3 ANNEXA studies show that andexanet alfa produces immediate, dose-dependent and well-tolerated reversal of anti-Factor Xa activity,” says Dr. John T. Curnutte, executive vice president of research and development for Portola. “The reversal can be either temporary through the administration of an intravenous bolus (Part 1 of the trials) or sustained by the addition of an extended infusion (Part 2 of the trials). In clinical practice, for example, patients with a severe visible bleed such as a prolonged major nosebleed or laceration may require short-acting reversal of their anticoagulant, while those who need emergency surgery may require long-acting reversal. Andexanet alfa is able to address both scenarios.”

In part one, andexanet alfa given as an intravenous 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. In Part 2, andexanet alfa administered as an IV bolus followed by a continuous two-hour infusion sustained that reversal for the duration of the infusion, reducing anticoagulant activity. Andexanet alfa was well tolerated, with no serious or severe adverse events, no thrombotic events and no antibodies to Factor X or Xa observed.

Full results of part two of ANNEXA-R also were presented during a late-breaking clinical trial session at the American Heart Association’s (AHA) Scientific Sessions 2015 in Orlando, Fla.

Commensurate with the increase in use of Factor Xa inhibitors, the number of hospital admissions due to bleeding associated with these agents continues to grow. Currently, there is no FDA-approved reversal agent for Factor Xa inhibitors for patients using such agents. Portola is developing andexanet alfa, a recombinant protein specifically designed to reverse the anticoagulant activity of Factor Xa inhibitors, as a universal reversal agent for patients anticoagulated with an oral or injectable Factor Xa inhibitor who experience a serious uncontrolled bleeding event or who require urgent or emergency surgery.

“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 is important because it means that andexanet alfa, by allowing for flexible and controlled reversal, could address different clinical scenarios in which a reversal agent is needed,” said Curnutte. “These positive ANNEXA study results suggest that andexanet alfa, if approved, could become the first universal reversal agent for Factor Xa inhibitors and could also become the new standard of care for managing serious uncontrolled bleeding in patients treated with these novel anticoagulants.”

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 hemostatic processes. 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.

Portola is currently evaluating andexanet alfa in ANNEXA-4, a Phase 4 single-arm, open label confirmatory study in patients receiving apixaban, rivaroxaban, edoxaban or enoxaparin (a low molecular weight heparin and indirect Factor Xa inhibitor) who present with an acute major bleed. Data from a small number of patients from ANNEXA-4, as well as data from ANNEXA-A and ANNEXA-R, will serve as the clinical basis for the Biologics License Application (BLA). A rolling submission of the BLA has been initiated under accelerated approval and the submission package is expected to be complete by the end of this year.

Portola Pharmaceuticals is a biopharmaceutical company developing product candidates that could significantly advance the fields of thrombosis and other hematologic diseases. The company is advancing its three wholly owned programs using novel biomarker and genetic approaches that may increase the likelihood of clinical, regulatory and commercial success of its potentially life-saving therapies. These programs include betrixaban, an oral, once-daily Factor Xa inhibitor being evaluated in the APEX Phase 3 study for prophylaxis of venous thromboembolism; andexanet alfa, a recombinant protein designed to reverse the anticoagulant effect in patients treated with an oral or injectable Factor Xa inhibitor; and cerdulatinib, a Syk/JAK inhibitor in development to treat hematologic cancers. Portola’s partnered program is focused on developing selective Syk inhibitors for inflammatory conditions.