SOUTH SAN FRANCISCO, Calif., March 2, 2015 (GLOBE NEWSWIRE) -- Portola Pharmaceuticals (Nasdaq:PTLA) today announced full 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) in healthy volunteers. Results showed the first part of this registration-enabling study met all primary and secondary endpoints with high statistical significance (p<0.0001 compared with placebo). Andexanet alfa administered as an intravenous (IV) bolus produced rapid and significant reversal of the anticoagulant effect of XARELTO® as measured by anti-Factor Xa activity (>90 percent reduction of mean anti-Factor Xa activity within five minutes of the end of administration). Additionally, there was a significant reduction in the level of free (unbound) XARELTO® in the plasma, and thrombin generation was rapidly restored to within the normal baseline range following administration of andexanet alfa. In the study, andexanet alfa was well tolerated. There were no serious or severe adverse events, no thrombotic events, and no antibodies to Factor X or Xa observed.
Andexanet alfa, a U.S. Food and Drug Administration (FDA)-designated breakthrough therapy, is a recombinant protein specifically designed to reverse the anticoagulant activity 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.
"Given the rapid and near-complete reversal of the anticoagulant effect of XARELTO® demonstrated in the Phase 3 ANNEXA-R study and of apixaban in the Phase 3 ANNEXA-A study, we believe that andexanet alfa has the potential to become the first approved universal antidote for Factor Xa inhibitors and the standard of care to manage bleeding associated with these novel anticoagulants," said John T. Curnutte, M.D., Ph.D., executive vice president, research and development for Portola. "Andexanet alfa is the only Factor Xa inhibitor antidote in development shown to directly and significantly impact definitive markers of coagulation, such as anti-Factor Xa levels, in clinical studies. We plan to submit these data as part of our Biologics License Application to the FDA by the end of this year. With andexanet alfa and betrixaban, our investigational Factor Xa inhibitor, we are building a robust thrombosis franchise of potentially life-saving medicines that could benefit millions of patients worldwide."
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 free unbound XARELTO® and endogenous thrombin potential (ETP), a measure of thrombin generation.
In the first part of the ANNEXA-R study, 41 healthy volunteers were given XARELTO® 20 mg once daily for four days to steady state. They were then randomized in a 2:1 ratio to receive at Cmax either andexanet alfa administered as an 800 mg IV bolus (n=27) or placebo (n=14).
Results showed that, for the primary endpoint, andexanet alfa reduced the anti-Factor Xa activity of rivaroxaban from baseline to nadir by >90 percent, a highly significant difference (p<0.0001). For the secondary endpoints:
- Significantly more andexanet alfa subjects (26 of 27) than placebo subjects (0) had a 90 percent or greater reduction in anti-Factor Xa activity from baseline to nadir (p<0.0001).
- The free (unbound) XARELTO® concentration from baseline to nadir was reduced significantly by andexanet alfa compared with placebo (p<0.0001).
- ETP significantly increased from baseline to peak in andexanet alfa subjects compared with placebo subjects (p<0.0001).
- 26 of 27 andexanet alfa subjects returned to the normal range of thrombin generation within 10 minutes of the end of the bolus administration.
In the study, andexanet alfa was well tolerated. There were no serious or severe adverse events, no thrombotic events, and no antibodies to Factor X or Xa were observed.
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.
The abstract of the study results was posted today and can be accessed at http://www.abstractsonline.com/pp8/#!/3658. The data will be presented 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."
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 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 the Andexanet Alfa Clinical Development Program
Portola is evaluating andexanet alfa in two 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, including anti-Factor Xa inhibitor units, to demonstrate efficacy. The Company reported statistically significant results from the first part of the Phase 3 ANNEXA-A study, which evaluated andexanet alfa administered as a single 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.
ANNEXA-4, a Phase 4 single-arm confirmatory study in patients receiving apixaban, rivaroxaban, edoxaban or enoxaparin (a low molecular weight heparin and indirect Factor Xa inhibitor) who present with an acute major bleed, is also ongoing. Data from the ANNEXA-A and ANNEXA-R studies, as well as data from a small number of patients from ANNEXA-4, will serve as the clinical basis of a Biologics License Application (BLA), which Portola plans to submit under an Accelerated Approval pathway.
Results from four separate Phase 2 proof-of concept studies with apixaban, rivaroxaban, edoxaban and enoxaparin 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.
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, a U.S. Food and Drug Administration (FDA)-designated breakthrough therapy, is a recombinant protein designed to reverse the anticoagulant activity 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 – 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 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, clinical trial cost, design and timing, the potential indications, efficacy, safety and activity of andexanet alfa, and the potential market and indications for our 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).