US-based biopharmaceutical firm Portola Pharmaceuticals has released additional results of a Phase II proof-of-concept trial of its investigational Factor Xa inhibitor antidote ‘andexanet alfa (PRT4445)’, in healthy volunteers who were administered the Factor Xa inhibitor Xarelto (rivaroxaban).
In the randomised, placebo-controlled, double-blind, cohort dose-escalation Phase II trial, healthy volunteers were given an oral dose of Xarelto at 20mg once daily for six days and then randomised 36 volunteers in a 6:3 ratio to andexanet alfa in four different dosing cohorts.
The trial demonstrated andexanet alfa’s ability to immediately reverse the anticoagulation activity of Xarelto (rivaroxaban) through the administration of a short intravenous bolus.
The results also showed that the reversal can be prolonged if needed by a continuous infusion and andexanet alfa was well tolerated, with no serious adverse events reported in the trial.
Andexanet alfa is being developed as universal antidote for patients who experience an uncontrolled bleeding episode or who need emergency surgery while being anticoagulated with a Factor Xa inhibitor.
By 2020, the company expects that the number of patients presenting to the hospital who could benefit from an antidote may approach 500,000 in the US, Japan and the five largest EU countries alone.
The US Food and Drug Administration (FDA) had granted breakthrough therapy status for andexanet alfa in November 2013.
Portola executive vice-president of R&D John Curnutte said the company has 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," Curnutte said.
"Importantly, we believe andexanet alfa’s highly specific mechanism of action may minimise complications that can be associated with agents that have off-target activity."
The company has presented the data on additional cohorts evaluating higher doses of andexanet in healthy volunteers treated with Xarelto at the 55th American Society of Hematology (ASH) Annual Meeting in New Orleans.
The safety data showed that andexanet alfa was well-tolerated, with no thrombotic events, or serious or severe adverse events reported.