SOUTH SAN FRANCISCO, Calif., April 8, 2015 (GLOBE NEWSWIRE) -- Portola Pharmaceuticals (Nasdaq:PTLA) today announced positive topline results from the second part of the Phase 3 ANNEXA™-A (Andexanet Alfa a Novel Antidote to the Anticoagulant Effects of FXa Inhibitors – Apixaban) study, which evaluated the safety and efficacy of andexanet alfa, an investigational antidote, with the Factor Xa inhibitor Eliquis (apixaban) in healthy volunteers. Andexanet alfa, a U.S. Food and Drug Administration (FDA)-designated breakthrough therapy, was administered as an intravenous (IV) bolus followed by a continuous two-hour infusion to sustain the reversal of anticoagulation activity. This registration-enabling study achieved all primary and secondary endpoints with high statistical significance. Andexanet alfa produced rapid reversal of the anticoagulant effect of apixaban, as measured by anti-Factor Xa activity, which was sustained for the duration of the infusion. In the study, andexanet alfa was well tolerated, with no serious adverse events, thrombotic events, or antibodies to Factor X or Xa reported. The full data from this second part of the ANNEXA-A study will be presented at an upcoming scientific meeting.
"Andexanet alfa has now demonstrated its ability to rapidly and significantly reverse the anticoagulant effect of apixaban administered as a bolus only or bolus plus continuous infusion in ANNEXA-A Parts 1 and 2. These important findings show that andexanet alfa has the potential to treat a broad group of patients who require an antidote, including those requiring longer-duration reversal and those in which only short-duration reversal is necessary to address the patient's needs. Importantly, in all cases, andexanet alfa's short half-life allows patients to be re-anticoagulated as needed," said John T. Curnutte, M.D., Ph.D., executive vice president, research and development for Portola. "Andexanet alfa distinguishes itself as the only Factor Xa inhibitor antidote in development shown to bind to oral FXa inhibitors and have a significant impact on three critical biomarkers: anti-Factor Xa activity, thrombin generation and free fraction of the anticoagulant. Both the FDA and European Medicines Agency have agreed that the reduction of anti-Factor Xa activity is an acceptable primary endpoint for Accelerated Approval (Expedited or Conditional Approval in the EU) with supporting secondary endpoints, including normalization of thrombin generation and sequestration of the anticoagulant. Given the highly statistically significant efficacy results we have seen in Phase 2 and Phase 3 studies across oral and injectable Factor Xa inhibitors, we believe andexanet alfa has the potential to be a first-in-class antidote for patients taking a Factor Xa anticoagulant who suffer a major bleeding episode or require emergency surgery."
Portola plans to submit data from the ANNEXA-A (apixaban) and ANNEXA-R (rivaroxaban) studies, and initial data from a Phase 4 study, as part of its Biologics License Application to the FDA under an Accelerated Approval pathway by the end of 2015.
ANNEXA-A Study Design
The randomized, double-blind, placebo-controlled Phase 3 ANNEXA-A study evaluated the safety and efficacy of andexanet alfa in reversing apixaban-induced anticoagulation in older healthy volunteers ages 50-75 years. Efficacy was evaluated using biomarker endpoints, with anti-Factor Xa levels as the primary endpoint. Secondary endpoints included plasma levels of free unbound apixaban and endogenous thrombin potential (ETP), a measure of thrombin generation.
In the first part of the study, which was previously presented, 33 healthy volunteers were given apixaban 5 mg twice daily for four days and then randomized in a 3:1 ratio to andexanet alfa administered as a 400 mg IV bolus (n=24) or to placebo (n=9). Today, Portola announced topline results from the second part of the study, in which 31 healthy volunteers were given apixaban 5 mg twice daily for four days and then randomized in a 3:1 ratio to andexanet alfa administered as a 400 mg IV bolus followed by a continuous infusion of 4 mg/min for 120 minutes (n=23) or to placebo (n=8).
Results of First Part of ANNEXA-A Study
Results from the first part of the ANNEXA-A study were presented during an oral session at the American Heart Association (AHA) 2014 Scientific Sessions in Chicago in November 2014. The first part of the study achieved all primary and pre-specified secondary endpoints with statistical significance (p< 0.0001). Andexanet alfa administered as an IV bolus produced rapid and nearly complete reversal of the anticoagulant effect of apixaban. Two to five minutes after completion of a bolus dose of andexanet alfa, the anticoagulant activity of apixaban was reversed by approximately 94 percent (p< 0.0001) compared with placebo as measured by anti-Factor Xa activity. Every subject treated with andexanet alfa had between 90 and 96 percent reversal of the anticoagulant activity of apixaban. No serious adverse events, thrombotic events, or antibodies to Factor X or Xa were reported following andexanet alfa administration. Mild infusion reaction was reported in three subjects.
Addressing the Absence of a Factor Xa Inhibitor Antidote
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. Recent patient datai confirm earlier clinical trial results showing that, annually, between 1 to 4 percent of patients treated with Factor Xa inhibitors may experience major bleeding and an additional 1 percent may require emergency surgery. Development of a specific antidote designed to reverse the anticoagulant activity of Factor Xa inhibitors may provide an important treatment option for patients who experience a major bleeding event or require emergency surgery.
About Andexanet Alfa
Andexanet alfa is a modified human Factor Xa molecule that acts as a decoy to target and sequester with high specificity both oral and injectable Factor Xa inhibitors in the blood. Once bound, the Factor Xa inhibitors are unable to bind to and inhibit native Factor Xa, thus allowing for the restoration of normal hemostatic processes. Andexanet alfa has the potential to address numerous clinical scenarios where an antidote is needed by allowing for flexible and controlled reversal. This can be short-acting through the administration of an IV bolus or longer-acting with the addition of an extended infusion.
Andexanet alfa is the only compound being studied as a reversal agent for Factor Xa inhibitors that directly and specifically corrects anti-Factor Xa activity -- the anticoagulant mechanism of these agents.
Andexanet alfa has been granted orphan drug designation by the FDA for reversing the anticoagulant effect of direct or indirect Factor Xa inhibitors in patients experiencing a serious uncontrolled bleeding event or who require urgent or emergent surgery.
About Portola Pharmaceuticals, Inc.
Portola Pharmaceuticals is a biopharmaceutical company developing product candidates that could significantly advance the fields of thrombosis and other hematologic diseases. The Company is advancing its three wholly-owned programs using novel biomarker and genetic approaches that may increase the likelihood of clinical, regulatory and commercial success of its potentially life-saving therapies. Portola's partnered program is focused on developing selective Syk inhibitors for inflammatory conditions.
Portola's wholly-owned, oral, once-daily Factor Xa inhibitor betrixaban is being evaluated in the only biomarker-based Phase 3 study for hospital-to-home prophylaxis of venous thromboembolism (VTE) in acute medically ill patients. Betrixaban's distinct properties may have the potential to allow the agent to demonstrate efficacy without the significant increase in the rate of major bleeding that was seen in this patient population with other Factor Xa inhibitors. If approved, betrixaban could be the first anticoagulant for both hospital and post-discharge VTE prophylaxis and the standard of care in this large market of more than 20 million patients in the G7 countries alone.
Andexanet alfa, an FDA-designated breakthrough therapy, is a recombinant protein designed to reverse the anticoagulant effect in patients treated with an oral or injectable Factor Xa inhibitor. Andexanet alfa has the potential to be a first-in-class antidote for anticoagulated patients who suffer a major bleeding episode or require emergency surgery. Portola has entered into Phase 3 clinical collaboration agreements with all of the manufacturers of direct Factor Xa inhibitors while retaining all commercial rights to andexanet alfa. The Company is currently evaluating andexanet alfa in the Phase 3 and Phase 4 ANNEXA™ (Andexanet Alfa a Novel Antidote to the Anticoagulant Effects of FXa Inhibitors) registration studies.
Portola's product candidate in the area of hematologic cancer, cerdulatinib, is an orally available molecule that uniquely inhibits two validated tumor proliferation pathways – spleen tyrosine kinase (Syk) and janus kinase (JAK). It is currently being evaluated in a Phase 1/2a proof-of-concept study in patients with B cell leukemias or lymphomas with a focus on genetically-defined subtypes, as well as in patients who have failed therapy due to relapse or acquired mutations.
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: Portola's plans for future clinical studies and pursuit of an Accelerated Approval process for andexanet alfa, anticipated growth in the market for anticoagulants, the potential indications, efficacy, safety and activity of andexanet alfa, and the potential market and indications for its other product candidates. 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 trials; the success of Portola's clinical trials and the demonstrated efficacy of Portola's product candidates thereunder; the accuracy of Portola's estimates regarding its expenses and capital requirements; Portola's ability to manufacture andexanet alfa; regulatory developments in the United States and foreign countries; Portola's ability to obtain and maintain intellectual property protection for its product candidates; and the loss of 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, including its Annual Report on Form 10-K, which was filed on March 2, 2015. 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.
i Source: Truven MARKETSCAN® Commercial, Medicare Supplemental and Medicaid Database (12 months ending March 2014).