SOUTH SAN FRANCISCO, Calif., Jan. 9, 2015 (GLOBE NEWSWIRE) -- Portola Pharmaceuticals (Nasdaq:PTLA) today announced topline results from the first part of the Phase 3 ANNEXA™-R (Andexanet Alfa a Novel Antidote to the Anticoagulant Effects of FXa Inhibitors – Rivaroxaban) study, which is evaluating the safety and efficacy of andexanet alfa with the Factor Xa inhibitor XARELTO® (rivaroxaban). Results showed that the study met its primary endpoint with high statistical significance. Andexanet alfa administered as an intravenous (IV) bolus significantly and immediately reversed the steady-state anticoagulation activity of XARELTO® and was well tolerated. The Company expects to present the full data set at the American College of Cardiology's (ACC) 64th Annual Scientific Session in San Diego on Monday, March 16 at 11:30 a.m. PT in an oral session titled "Highlighted Original Research: Acute Coronary Syndromes and the Year in Review." The second part of the ANNEXA-R study, which is evaluating a bolus plus a continuous infusion of andexanet alfa to sustain reversal, is ongoing.
Portola is developing andexanet alfa, a U.S. Food and Drug Administration (FDA)-designated breakthrough therapy, as a universal antidote for patients treated with oral and injectable Factor Xa inhibitors who are experiencing a major bleeding episode or who require emergency surgery. Andexanet alfa has been studied in more than 140 volunteers in clinical studies.
"The statistically significant Phase 3 ANNEXA-R study data, together with results presented previously with apixaban, provide compelling evidence that this groundbreaking agent could serve as a universal antidote for Factor Xa inhibitor anticoagulants," said John T. Curnutte, M.D., Ph.D., executive vice president, research and development for Portola. "Andexanet alfa is unique among the other reversal agents in development in that it has been the only agent to immediately and significantly reverse all of the key pharmacodynamic measurements of coagulation that have been agreed to with the FDA for accelerated approval. These include anti-Factor Xa levels, thrombin generation and unbound anticoagulant (free fraction). This has been demonstrated with all of the Factor Xa inhibitors studied to date – apixaban, rivaroxaban, edoxaban and enoxaparin."
ANNEXA-R Study Design and Results
The randomized, double-blind, placebo-controlled Phase 3 ANNEXA-R study is evaluating the safety and efficacy of andexanet alfa in reversing XARELTO® -induced anticoagulation in healthy volunteers ages 50-75 years. Efficacy is being evaluated using biomarker endpoints, with anti-Factor Xa levels as the primary endpoint. Secondary endpoints include plasma levels of plasma unbound (free fraction) of XARELTO® and thrombin generation levels.
In the first part of the ANNEXA-R study, reported today, 41 healthy volunteers were given XARELTO® 20 mg once daily for four days and then randomized in a 2:1 ratio to receive at Cmax either andexanet alfa administered as an 800 mg IV bolus (n=27) or to placebo (n=14). The study achieved its primary endpoint with high statistical significance. Results showed that andexanet alfa significantly and immediately reversed the anticoagulation activity of XARELTO®. Andexanet alfa was shown to be well tolerated.
In the second part of the ANNEXA-R study, approximately 40 healthy volunteers will be given XARELTO® 20 mg once daily for four days and will then be randomized in a 2:1 ratio to receive either andexanet alfa administered as an 800 mg IV bolus followed by a continuous infusion of 8 mg/min for 120 minutes or to placebo. Data from this part of the study are expected in mid-2015.
About the Need for 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 1-4 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 acts as a Factor Xa decoy that targets and sequesters 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.
About the Andexanet Alfa Clinical Development Program
Portola is evaluating andexanet alfa in randomized, placebo-controlled Phase 3 ANNEXA™ (Andexanet Alfa a Novel Antidote to the Anticoagulant Effects of fXA Inhibitors) registration studies using pharmacodynamic endpoints agreed to with the FDA, such as anti-Factor Xa inhibitor units, to demonstrate efficacy.
Portola reported statistically significant results from the first part of the Phase 3 ANNEXA-A study, which evaluated andexanet alfa administered as a single intravenous (IV) bolus dose with Bristol-Myers Squibb Company and Pfizer Inc.'s direct Factor Xa inhibitor apixaban, and from the first part of the Phase 3 ANNEXA-R study with Bayer HealthCare and Janssen's direct Factor Xa inhibitor rivaroxaban. The second parts of the ANNEXA-A and ANNEXA-R studies are ongoing and are evaluating a bolus plus a continuous infusion of andexanet alfa to sustain the reversal of anticoagulation activity.
These studies are designed to support the Company's BLA filing for Accelerated Approval. As part of the Accelerated Approval process, a Phase 4 confirmatory patient study evaluating clinical outcomes with andexanet alfa is planned.
Results from four separate Phase 2 proof-of concept studies with apixaban, rivaroxaban, edoxaban and enoxaparin, a low molecular weight heparin and indirect Factor Xa inhibitor, in healthy volunteers demonstrated that andexanet alfa immediately reversed the anticoagulation activity of each Factor Xa inhibitor and that the reversal could be sustained. Andexanet alfa has been shown to be well tolerated in clinical studies, which have included more than 140 healthy volunteers. No thrombotic events or antibodies to Factor Xa or Factor X have been observed.
A Phase 2 proof-of-concept study with Portola's investigational Factor Xa inhibitor betrixaban is planned.
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, a recombinant modified human Factor Xa molecule, has the potential to be a first-in-class antidote to reverse the effects of Factor Xa inhibitors in patients who suffer a major bleeding episode or who require emergency surgery. Andexanet alfa has been designated as a breakthrough therapy by the U.S. Food and Drug Administration. Portola has entered into Phase 3 clinical collaboration agreements with all of the manufacturers of direct Factor Xa inhibitors – Bristol-Myers Squibb and Pfizer (Eliquis [apixaban]), Bayer HealthCare and Janssen Pharmaceuticals (XARELTO® [rivaroxaban]), and Daiichi Sankyo (edoxaban) – while retaining all commercial rights to andexanet alfa. The Company is currently evaluating andexanet alfa in the Phase 3 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, clinical trial cost, design and timing, and the potential indications, efficacy, safety and activity of andexanet alfa. 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 and most recent Quarterly Report on Form 10-Q for the third quarter of 2014, which was filed on November 4, 2014. 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).