Portola Pharmaceuticals Initiates Phase 4 Study to Support Accelerated Approval of Andexanet Alfa -- Its Breakthrough-Designated Factor Xa Inhibitor Antidote
SOUTH SAN FRANCISCO, Calif., Jan 12, 2015 (GLOBE NEWSWIRE via COMTEX) --
Portola Pharmaceuticals PTLA, +0.14% today announced the initiation of a single-arm Phase 4 study to support the approval of andexanet alfa by the U.S. Food and Drug Administration (FDA) under an Accelerated Approval pathway. Portola is developing this FDA-designated breakthrough therapy as a universal antidote for patients receiving a Factor Xa inhibitor anticoagulant who suffer a major bleeding episode or who may require emergency surgery.
"We collaborated closely with the FDA on a Phase 4 study design. The combination of data from our two Phase 3 studies and data from a small number of patients in this Phase 4 study will serve as the clinical basis of a Biologics License Application [BLA], which we plan to submit at the end of 2015 for approval of andexanet alfa under an Accelerated Approval pathway," said John T. Curnutte, M.D., Ph.D., executive vice president, research and development for Portola. "We're pleased with our progress in developing what could be the first universal Factor Xa inhibitor antidote approved to help physicians meet the growing unmet medical need of managing the severe bleeding associated with these new and important oral anticoagulants. We are developing andexanet alfa to meet the criteria required by the agency and physicians to become the standard of care universal reversal agent for Factor Xa inhibitors."
Design of Phase 4 Study
The open-label, single-arm, Phase 4 study is being conducted in patients receiving apixaban, rivaroxaban or enoxaparin (a low molecular weight heparin) who present with an acute major bleed. Acute major bleeding includes life-threatening bleeding, bleeding associated with very low blood counts, or bleeding that occurs in a critical area such as the brain or surrounding the heart. The trial excludes bleeding due to major trauma and large blood vessel rupture. Patients will receive andexanet alfa as an intravenous (IV) bolus followed immediately by a continuous infusion. The study is evaluating andexanet alfa's ability to decrease anti-Factor Xa activity and restore hemostasis in patients. Safety endpoints include overall 45 day safety, including an evaluation of thrombotic activity and antibody development. The study will be conducted at over 50 sites in North America and Europe.
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 data(i) confirm earlier clinical trial results showing that, while most novel anticoagulants have lower bleeding rates than warfarin, serious bleeding (annually, between 1-4 percent) could still occur. 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 unique in that it is the only reversal agent in development that has been demonstrated 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 levels (free fraction). This comprehensive reversal has been demonstrated with andexanet alfa in all of our clinical studies conducted to date using the Factor Xa inhibitors -- apixaban, rivaroxaban, edoxaban and enoxaparin.
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 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. A Phase 4 confirmatory study is also ongoing, of which data from a small number of patients will be submitted with the BLA.
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.
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 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.
For more information, visit www.portola.com and follow the Company on Twitter @Portola_Pharma.
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, timing of clinical study results, future regulatory filings and pursuit of an Accelerated Approval process for andexanet alfa, anticipated growth in the market for anticoagulants, and the potential efficacy, safety and activity of Portola's 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 and most recent Quarterly Report on Form 10-Q. 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)