Portola Pharma Issues Results for First Phase 2 Trial Showing Extended Duration Infusion with PRT4445
Portola Pharmaceuticals, Inc. (Nasdaq: PTLA) today announced new interim findings from a Phase 2 proof-of-concept study of its investigational Factor Xa inhibitor antidote, Andexanet alfa, in healthy volunteers who received the Factor Xa inhibitor Eliquis^® (apixaban). Andexanet alfa was administered intravenously as a bolus followed by a continuous infusion for up to two hours. Data from this study showed 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.
"Currently, 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," said John T. Curnutte, M.D., Ph.D., executive vice president of research and development for Portola. "This study shows that the safety and activity seen with Andexanet alfa in previous clinical studies can be extended in duration, demonstrating that the nearly complete anticoagulation reversal can be sustained for the duration of the infusion. This may allow physicians to treat a broader range of patients, such as those with bleeding due to a traumatic injury or those requiring surgery. We plan to initiate pivotal studies in 2014 as part of our pursuit of an expedited approval process to address this unmet need."
These new interim findings demonstrated that two minutes after completion of a 420 mg bolus dose of Andexanet alfa (n=6), the anticoagulant activity of Eliquis was reversed by approximately 92% (p < 0.0001) as measured by anti-Factor Xa activity compared with placebo (n=3). At the end of the two-hour infusion, the anticoagulation activity of Eliquis remained reversed by approximately 91% (p < 0.0001). The safety follow-up for this study is ongoing with no serious adverse events or premature discontinuations of Andexanet alfa reported to date. Safety data for over 65 healthy volunteers dosed with Andexanet alfa across Phase 1 and Phase 2 clinical studies showed no thrombotic events or antibodies against Andexanet alfa, endogenous Factor Xa, or Factor X. One serious adverse event, a case of pneumonia, was seen in the Phase 1 study.
Need for Reversal Agent for Factor Xa Inhibitors
Currently, millions of patients are treated with Factor Xa inhibitors for short-term use or chronic conditions, and the anticoagulant market is expected to continue to grow with the adoption of novel oral anticoagulants. Clinical trial results suggest that, depending on their underlying medical condition, annually between 1% and 4% of these patients will experience uncontrolled bleeding and an additional 1% will require emergency surgery ^i. Currently, there is no antidote or reversal agent approved for use against Factor Xa inhibitors. Leading clinicians have identified, and the United States Food and Drug Administration (FDA) has recognized, the lack of an effective reversal agent for Factor Xa inhibitors as a significant unmet medical need.
Phase 2 Study Design and Results
This randomized, placebo-controlled, double-blind, cohort dose-escalation Phase 2 proof-of-concept study treated 54 healthy volunteers with 5 mg of Eliquis twice a day on days 1 through 6 and then randomized them in a 6:3 ratio to intravenous (IV) Andexanet alfa in six different cohorts. The first three cohorts were a single IV bolus at 90 mg, 210 mg and 420 mg. The last three cohorts were 420 mg IV bolus plus either a 45-minute infusion, a two-hour infusion or a repeat bolus at 45 minutes.
Portola previously announced positive pharmacodynamic and safety data from the three bolus-only dose cohorts. Those data demonstrated a dose-related reversal of the anticoagulant activity of Eliquis. Two minutes after administration of 420 mg Andexanet alfa (n=6), the anticoagulant activity of Eliquis decreased by greater than 95% as measured by anti-Factor Xa activity compared with placebo (n=3). The reversal of anti-Factor Xa activity correlated with a reduction in the level of free, unbound Eliquis in the plasma consistent with the mechanism of action of Andexanet alfa. The data were previously presented in an oral session at the XXIV Congress of the International Society on Thrombosis and Haemostasis in Amsterdam in July 2013.
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