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Portola Pharmaceuticals Announces First Phase 2 Results Demonstrating Extended Duration Infusion With Andexanet Alfa (PRT4445*) Provides Prolonged Reversal of Anticoagulation Activity of Factor Xa Inhibitor Eliquis(R)
"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
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
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
About Andexanet Alfa (PRT4445*)
Andexanet alfa is a novel recombinant, modified Factor Xa molecule that has the potential to be the first universal antidote to reverse the effects of Factor Xa inhibitors in patients who suffer an uncontrolled bleeding episode, trauma, or require emergency surgery. Andexanet alfa is similar to native Factor Xa, but has been modified to restrict its biological activity, such as its ability to cleave thrombin, an enzyme involved in the clotting cascade. Andexanet alfa acts as a Factor Xa decoy that binds and sequesters direct Factor Xa inhibitors in the blood. Once bound to Andexanet alfa, the Factor Xa inhibitors are unable to bind to and inhibit native Factor Xa. The native Factor Xa should then be available to participate in the coagulation process and restore hemostasis.
Portola has entered into collaboration agreements with each of the pharmaceutical companies that have Factor Xa inhibitors on the market or in clinical development, including
Statements contained in this press release regarding matters that are not historical facts are "forward-looking statements" within the meaning of the Private Securities Litigation Reform Act of 1995. Because such statements are subject to risks and uncertainties, actual results may differ materially from those expressed or implied by such forward-looking statements. Such statements include, but are not limited to, statements regarding Andexanet alfa's potential efficacy, safety, duration of activity and potential to reverse the effects of all Factor Xa inhibitors, the potential for physicians to treat a broader range of patients, our plans for future clinical studies and pursuit of an expedited approval process for Andexanet alfa and anticipated growth in the market for anticoagulants. Risks that contribute to the uncertain nature of the forward-looking statements include: the accuracy of Portola's estimates regarding its ability to initiate and/or complete its clinical studies; the success of Portola's clinical studies and the demonstrated efficacy of Portola's product candidates thereunder; regulatory developments in
*PRT4445 has a proposed International Nonproprietary Name (pINN) of Andexanet alfa.
i Rivaroxaban ROCKET (3.6% TIMI Major); Apixaban ARISTOTLE (2.1% ISTH Major, 0.96 TIMI Major); Levi, Blood. 2008;111:4471-4476; Circulation. 2012;126:343-348.