US-based Portola Pharmaceuticals has started a Phase III trial designed to evaluate the safety and efficacy of its investigational Factor Xa inhibitor reversal agent ‘andexanet alfa’ with Bristol-Myers Squibb (BMS) and Pfizer’s Factor Xa inhibitor Eliquis (apixaban).
The US FDA-designated breakthrough therapy ‘andexanet alfa’ is being developed as a potential first-in-class antidote to reverse the anticoagulation activity of Factor Xa inhibitor-treated patients who are suffering a major bleeding episode or who require immediate surgery.
Portola is pursuing an Accelerated Approval pathway for andexanet alfa, which is the only agent that has showed reversal of the anticoagulation activity of Factor Xa inhibitors as measured by biomarkers, including anti-Factor Xa activity, in human studies.
The randomised, double-blind, placebo-controlled Phase III trial will assess the efficacy of andexanet alfa in older healthy volunteers (ages 50-75 years) as showed by biomarker endpoints, including anti-Factor Xa levels, plasma free fraction of the anticoagulant and thrombin generation.
Portola executive vice president of R&D John Curnutte said the start of the company’s first Phase III trial for andexanet alfa represents a significant milestone in the clinical development of this innovative drug to address the important unmet medical need for a Factor Xa inhibitor antidote.
"We are strategically focused on using biomarker and genetic approaches in our clinical development programmes to identify the patients who will most likely benefit from our products and potentially accelerate their approval," Curnutte said.
In the first part of the trial, about 32 healthy volunteers will be given Eliquis 5mg twice daily and then randomised in a 3:1 ratio to andexanet alfa administered as a 400mg IV bolus or to placebo.
In the second part, around 32 healthy volunteers will be randomised in a 3:1 ratio to andexanet alfa administered as a 400mg IV bolus followed by a continuous infusion of 480mg at 4mg/min for 120 minutes or to placebo.
The trial participants will be followed for up to 43 days to assess safety.
In the trial, the company is using biomarker endpoints that have been agreed to with the FDA to support potential Accelerated Approval for the reversal of Factor Xa inhibitor anticoagulation.
The company expects to report initial data from the first part of the study, in which andexanet alfa is administered as a bolus infusion, in the fourth quarter of this year, followed by bolus-plus-continuous infusion data from the second part of the trial in early 2015.
Results from two Phase II proof-of concept trials showed that andexanet alfa immediately reversed the anti-Factor Xa activity of Eliquis and Xarelto (rivaroxaban) in healthy volunteers.
Earlier in 2014, Portola and BMS/Pfizer have entered into a Phase III collaboration that included an upfront payment and provides additional milestone payments that cover the clinical costs of the Phase III study.
Portola retains 100% worldwide decision-making and commercialisation rights to andexanet alfa.
Bayer HealthCare, Portola, Janssen Pharmaceuticals have a similar Phase III collaboration and expect to start a Phase III trial of andexanet alfa with Xarelto in the first half of 2014.