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Portola Pharmaceuticals Announces New Phase 2 Results Confirming Immediate, Dose-Dependent And Well-Tolerated Reversal Of Anticoagulation Activity Of XARELTO(R) (rivaroxaban) With Andexanet Alfa (PRT4445*), Investigational Factor Xa Inhibitor Reversal Agent
NEW ORLEANS and SOUTH SAN FRANCISCO, Calif., Dec. 9, 2013 (GLOBE NEWSWIRE) -- Portola Pharmaceuticals (Nasdaq:PTLA) today announced additional results of a Phase 2 proof-of-concept study that showed andexanet alfa's ability to immediately reverse the anticoagulation activity of XARELTO
® (rivaroxaban) through the administration of a short intravenous bolus. The data also showed that this reversal can be prolonged if needed by a continuous infusion. Andexanet alfa was well tolerated, with no serious adverse events reported. The data were presented at the 55th American Society of Hematology (ASH) Annual Meeting in New Orleans by lead investigator Mark Crowther, M.D., M.Sc., associate chair, Department of Medicine, McMaster University, Hamilton, Ontario.
Andexanet alfa has the potential to be a first-in-class universal antidote designed to reverse the anticoagulant activity of Factor Xa inhibitors in patients who experience an uncontrolled bleeding episode or who require emergency surgery. By the year 2020, Portola estimates that the number of patients presenting to the hospital who could benefit from an antidote may approach 500,000 in the United States, Japan and the five largest European Union countries alone. In November 2013, andexanet alfa was designated as a breakthrough therapy by the U.S. Food and Drug Administration.
"We have now shown that andexanet alfa produces immediate, dose-dependent and well-tolerated reversal of multiple Factor Xa inhibitors. Andexanet alfa's unique flexibility to provide short-term reversal through the administration of an intravenous bolus or sustained reversal by the addition of an extended infusion is critical in covering the multiple clinical scenarios where a reversal agent is needed," said John T. Curnutte, M.D., Ph.D., executive vice president of research and development for Portola. "Importantly, we believe andexanet alfa's highly specific mechanism of action may minimize complications that can be associated with agents that have off-target activity."
Phase 2 Study Design and Results
The randomized, double-blind, placebo-controlled, cohort dose-escalation Phase 2 proof-of-concept study treated healthy volunteers with an oral dose of XARELTO
® at 20 mg once daily for six days and then randomized 36 volunteers in a 6:3 ratio to andexanet alfa in four different dosing cohorts. The first three cohorts received a single IV bolus of andexanet alfa at 210 mg, 420 mg or 600 mg, respectively. A fourth cohort received a single IV bolus of andexanet alfa at 720 mg followed by a 4 mg/minute infusion for one hour.
Immediately following completion of the 210 mg, 420 mg, 600 mg and 720 mg bolus doses of andexanet alfa, anti-Factor Xa activity decreased dose-dependently by 20 percent, 53 percent, 70 percent and 81 percent, respectively, from the pre-andexanet alfa level and returned to placebo levels approximately two hours after treatment. In parallel, the plasma concentrations of unbound XARELTO
® were decreased by 32 percent, 51 percent, 75 percent and 70 percent respectively, relative to pre-andexanet alfa values. XARELTO
®-induced inhibition of thrombin generation and prolongation of both prothrombin time and activated clotting time approached normal levels with andexanet alfa in a dose-dependent manner.
Safety data showed that andexanet alfa was well tolerated, with no thrombotic events or serious adverse events reported. No antibodies to Factor Xa or Factor X were observed in this or other Phase 2 studies, which have included a total of more than 80 volunteers.