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Portola Pharmaceuticals
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.
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