SOUTH SAN FRANCISCO, Calif., Oct. 14, 2013 (GLOBE NEWSWIRE) -- 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.
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 Bristol-Myers Squibb and Pfizer, Bayer HealthCare and Janssen Pharmaceuticals, and Daiichi Sankyo, while retaining all rights to the program. The company is conducting a series of Phase 2 proof-of-concept studies to evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of Andexanet alfa after dosing of a direct or indirect Factor Xa inhibitor in healthy volunteers. The direct and indirect Factor Xa inhibitors include Eliquis® (apixaban), XARELTO® (rivaroxaban), Lovenox® (enoxaparin), Lixiana® (edoxaban) and Portola's investigational oral Factor Xa inhibitor, Betrixaban.
About Portola Pharmaceuticals, Inc.
Portola Pharmaceuticals is a biopharmaceutical company focused on the development and commercialization of novel therapeutics in the areas of thrombosis, other hematologic disorders and inflammation. Portola's wholly-owned lead compound, Betrixaban, is a novel, oral, once-daily Factor Xa inhibitor in Phase 3 development for extended-duration prophylaxis of a form of thrombosis known as venous thromboembolism (VTE) in acute medically ill patients. Currently, there is no anticoagulant approved for extended-duration VTE prophylaxis in this population. Portola's second lead development candidate, Andexanet alfa (PRT4445*), 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 or trauma, or who require emergency surgery. Portola retains full, worldwide commercial rights to Andexanet alfa. Portola's third product candidate, PRT2070, is an orally available kinase inhibitor that uniquely inhibits two validated tumor proliferation pathways -- spleen tyrosine kinase (Syk) and janus kinase (JAK). It is currently being studied in patients with genetically-defined hematologic cancers, as well as for patients who have failed therapy due to relapse or acquired mutations. Portola's fourth program is partnered with Biogen Idec and is focused on the development of PRT2607, a selective Syk inhibitor. For more information, visit www.portola.com.
Forward-looking statements
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 the United States and foreign countries; and Portola's ability to attract and retain key scientific or management personnel. These and other risks and uncertainties are described more fully in Portola's most recent filings with the Securities and Exchange Commission. All forward-looking statements contained in this press release speak only as of the date on which they were made. Portola undertakes no obligation to update such statements to reflect events that occur or circumstances that exist after the date on which they were made.
*PRT4445 has a proposed International Nonproprietary Name (pINN) of Andexanet alfa.
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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.