SOUTH SAN FRANCISCO, Calif., March 19, 2014 (GLOBE NEWSWIRE) -- Portola Pharmaceuticals (Nasdaq:PTLA) today announced that it has initiated a Phase 3 study of andexanet alfa, the company's investigational Factor Xa inhibitor reversal agent. The study will evaluate the safety and efficacy of andexanet alfa with Bristol-Myers Squibb Company (NYSE: BMY) and Pfizer Inc.'s (NYSE: PFE) Factor Xa inhibitor Eliquis® (apixaban). Portola is developing andexanet alfa, an FDA-designated breakthrough therapy, as a potential first-in-class antidote to reverse the anticoagulation activity of Factor Xa inhibitor-treated patients who are suffering a major bleeding episode or who require emergency surgery. The Company is pursuing an Accelerated Approval pathway for andexanet alfa, which is the only agent that has demonstrated reversal of the anticoagulation activity of Factor Xa inhibitors as measured by biomarkers, including anti-Factor Xa activity, in human studies.
"The initiation of our first Phase 3 study for andexanet alfa represents a significant milestone in the clinical development of this innovative drug to address the important unmet medical need for a Factor Xa inhibitor antidote," said John C. Curnutte, M.D., Ph.D., executive vice president, research and development at Portola. "We are strategically focused on using biomarker and genetic approaches in our clinical development programs to identify the patients who will most likely benefit from our products and potentially accelerate their approval. For this Phase 3 study, we are using biomarker endpoints that have been agreed to with the FDA to support potential Accelerated Approval for the reversal of Factor Xa inhibitor anticoagulation. We expect to report initial data from the first part of the study, in which andexanet alfa is administered as a bolus infusion, in the fourth quarter of this year, followed by bolus-plus-continuous infusion data from the second part of the study in early 2015."
Phase 3 Study Design
The randomized, double-blind, placebo-controlled Phase 3 study is designed to evaluate the efficacy of andexanet alfa in reversing Eliquis-induced anticoagulation rapidly after an IV bolus and sustaining that effect through a continuous infusion. The study will evaluate the efficacy of andexanet alfa in older healthy volunteers (ages 50-75 years) as demonstrated by biomarker endpoints, including anti-Factor Xa levels, plasma free fraction of the anticoagulant and thrombin generation. In the first part of the study, approximately 32 healthy volunteers will be given Eliquis 5 mg twice daily and then randomized in a 3:1 ratio to andexanet alfa administered as a 400 mg IV bolus or to placebo. In the second part of the study, approximately 32 healthy volunteers will be randomized in a 3:1 ratio to andexanet alfa administered as a 400 mg IV bolus followed by a continuous infusion of 480 mg at 4 mg/min for 120 minutes or to placebo. Study participants will be followed for up to 43 days to assess safety.
About the Need for a Factor Xa Inhibitor Reversal Agent
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. Clinical trial results suggest 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, depending on the patient's underlying medical condition. Development of an agent specifically designed to reverse the 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 first-in-class recombinant, modified Factor Xa molecule being developed as a direct reversal agent for patients receiving a Factor Xa inhibitor who suffer a major bleeding episode or who may require emergency surgery. Andexanet alfa acts as a Factor Xa decoy that targets and sequesters with high specificity both direct and indirect 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.
Results from two Phase 2 proof-of concept studies demonstrated that andexanet alfa immediately reversed the anti-Factor Xa activity of Eliquis and XARELTO® (rivaroxaban) in healthy volunteers. Andexanet alfa provided temporary reversal through the administration of an IV bolus infusion or sustained reversal with the addition of an extended infusion. In clinical practice, patients with bleeding due to a traumatic injury may require short-acting reversal of their anticoagulant, while those who need emergency surgery may require long-acting reversal. Andexanet alfa has the potential to address numerous clinical scenarios by allowing for flexible and controlled reversal. Andexanet alfa has been shown to be well tolerated in clinical studies, which have included more than 90 volunteers, with no thrombotic events, serious adverse events or antibodies to Factor Xa or Factor X observed.
Additional Phase 2 proof-of-concept studies with the direct Factor Xa inhibitors betrixaban and Savaysa™ (edoxaban) and the indirect Factor Xa inhibitor enoxaparin are either planned or ongoing.
Earlier this year, Portola and BMS/Pfizer entered into a Phase 3 collaboration that included an upfront payment and provides additional milestone payments that cover the clinical costs of the Phase 3 study. Portola retains 100 percent worldwide decision-making and commercialization rights to andexanet alfa. Portola and Bayer HealthCare and Janssen Pharmaceuticals Inc. have a similar Phase 3 collaboration and expect to begin a Phase 3 study of andexanet alfa with XARELTO in the first half of 2014.
About Portola Pharmaceuticals, Inc.
Portola Pharmaceuticals is a biopharmaceutical company developing product candidates that have the potential to represent significant advances in the fields of thrombosis and hematology. 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 first-in-class therapies.
Portola's lead compound, betrixaban, is an oral, once-daily Factor Xa inhibitor 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 properties may be particularly suited to potentially demonstrate efficacy without significantly increasing bleeding in this patient population. Currently, there is no anticoagulant approved for extended-duration VTE prophylaxis in acute medically ill patients.
Portola's second lead development candidate, andexanet alfa, has the potential to be a first-in-class reversal agent to reverse the effects of Factor Xa inhibitors in patients who suffer a major bleeding episode or who require emergency surgery. Portola has entered into clinical collaboration agreements with all of the manufacturers of direct Factor Xa inhibitors, including Bristol-Myers Squibb and Pfizer (Eliquis® [apixaban]), Bayer HealthCare and Janssen Pharmaceuticals (XARELTO® [rivaroxaban]), and Daiichi Sankyo (SavaysaTM [edoxaban]), while retaining all decision-making and commercial rights to andexanet alfa. Andexanet alfa has been designated as a Breakthrough Therapy by the U.S. Food and Drug Administration.
Cerdulatinib* (PRT2070) and PRT2607
Portola's third wholly-owned product candidate, cerdulatinib (PRT2070), 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 studied in patients with 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. 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 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 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 efficacy, safety and activity of andexanet alfa, betrixaban and cerdulatinib. 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; 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 2013 Annual Report on Form 10-K filed with the Securities and Exchange Commission on March 3, 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.
*Cerdulatinib is a proposed International Nonproprietary Name (pINN).