Portola Pharmaceuticals has reported interim results from a Phase II proof-of-concept study of its investigational Factor Xa inhibitor antidote, Andexanet alfa (PRT4445), in volunteers who received the Factor Xa inhibitor Eliquis (apixaban).
The PRT4445 was given intravenously as a bolus followed by a continuous infusion for up to two hours.
Results of the trial demonstrated a rapid and nearly complete reversal of the anticoagulation effect of Eliquis measured at two minutes following completion of the bolus, which was sustained during infusion for up to two hours.
Portola executive vice-president of research and development John Curnutte said at present there are no approved agents for reversing or stopping the anticoagulant effect of novel Factor Xa inhibitors.
"We believe that as the use of Factor Xa inhibitors extends to millions of patients, a reversal agent for the estimated hundreds of thousands of patients who will experience a significant acute bleed or who will require urgent surgery will be important," Curnutte said.
According to the study, safety and activity seen with Andexanet alfa in previous clinical trials can be extended in duration, showing that the nearly complete anticoagulation reversal can be sustained for the duration of the infusion that will enable physicians to treat a range of patients with bleeding due to a traumatic injury or those requiring surgery.
The new interim findings showed that compared with placebo the anticoagulant activity of Eliquis was reversed by about 92% as measured by anti-Factor Xa activity two minutes after completion of a 420mg bolus dose of Andexanet alfa.
The anticoagulation activity of Eliquis remained reversed by about 91% at the end of the two-hour infusion.
The data secured from over 65 healthy volunteers dosed with Andexanet alfa in the Phase I and Phase II clinical trials showed no thrombotic events or antibodies against Andexanet alfa, endogenous Factor Xa, or Factor X.
In the randomised, placebo-controlled, double-blind, cohort dose-escalation Phase II proof-of-concept trial, about 54 healthy volunteers were treated with 5mg of Eliquis twice a day on days one through six, and then randomised them in a 6:3 ratio to intravenous (IV) Andexanet alfa in six different cohorts.
The company said that the first three cohorts were a single IV bolus at 90mg, 210mg and 420mg, while the last three cohorts were 420mg IV bolus plus either a 45-minute infusion, a two-hour infusion or a repeat bolus at 45 minutes.
The company has also collaborated with pharmaceutical firms that have Factor Xa inhibitors on the market or in clinical development, including Bristol-Myers Squibb and Pfizer, Bayer HealthCare and Janssen Pharmaceuticals, and Daiichi Sankyo, while retaining all rights to the programme.
Eliquis (apixaban), Xarelto (rivaroxaban), Lovenox (enoxaparin), Lixiana (edoxaban) and Portola’s investigational oral Factor Xa inhibitor, Betrixaban are some of the direct and indirect Factor Xa inhibitors.
The company plans to start pivotal studies in 2014 as part of its pursuit of an expedited approval process to address the unmet need.
Portola expects to develop Andexanet alfa as a universal antidote to help manage or reverse the bleeding complications in patients expected to be treated with Factor Xa inhibitors or low-molecular weight heparin.