--Data Extend the Potential for Andexanet as an Antidote Beyond
Oral Factor Xa Inhibitors to Injectible Low Molecular Weight Heparin--
SOUTH SAN FRANCISCO, Calif., June 11, 2014 (GLOBE NEWSWIRE) -- Portola Pharmaceuticals (Nasdaq:PTLA) today announced that a Phase 2 proof-of-concept study in healthy volunteers demonstrated that andexanet alfa, a potential first-in-class Factor Xa inhibitor antidote, immediately reversed the anticoagulation activity of enoxaparin, a low molecular weight heparin and standard of care in venous thromboembolism prevention. Andexanet alfa was well tolerated with no serious adverse events reported. Detailed data will be presented during both oral and poster sessions at the 60th Scientific and Standardization Committee (SSC) Meeting of the International Society on Thrombosis and Haemostasis (ISTH), which is taking place from June 23-26 in Milwaukee, Wis. Portola is developing andexanet alfa, an FDA-designated breakthrough therapy, to reverse the anticoagulation activity of Factor Xa inhibitor-treated patients who are experiencing a major bleeding episode or who require emergency surgery.
"These Phase 2 data with enoxaparin are the first to demonstrate that andexanet alfa, in addition to reversing the anticoagulation activity of oral Factor Xa inhibitors, can reverse a low molecular weight heparin, thereby expanding the potential use of andexanet to enoxaparin-treated patients. There is an established threshold at which the anticoagulation activity of enoxaparin is considered clinically reversed, and andexanet hit this target," said John T. Curnutte, M.D., Ph.D., executive vice president of research and development for Portola. "Novel oral Factor Xa inhibitors and enoxaparin are a mainstay in thrombosis prevention and treatment based on their demonstrated efficacy and safety profile. In some cases, however, patients require reversal of anticoagulation because of a major bleed or need for urgent surgery. Recent patient data showed that, over one year, there were more than 75,000 visits to U.S. hospitals by patients with a bleeding event on Factor Xa inhibitors. This number will only increase as adoption of these important agents continues to grow. To address the urgent unmet need for a universal antidote, we are working closely with the FDA to bring andexanet alfa to market as quickly as possible."
In the randomized, double-blind, placebo-controlled, dose-escalation, Phase 2 proof-of-concept study, 27 healthy volunteers were administered enoxaparin 40 mg subcutaneously once daily for six days and then randomized in a 2:1 ratio to andexanet alfa administered as an IV bolus (210 mg or 420 mg) or to placebo. Enoxaparin is an indirect inhibitor of Factor Xa, and results showed that anti-Factor Xa activity was reduced within two minutes to a level below the established enoxaparin therapeutic anticoagulation threshold. Inhibition of thrombin generation was also restored to normal baseline levels immediately following completion of the bolus dose. The reversal of anti-Factor Xa activity was maintained for two to three hours after the single bolus administration as was the normalization of thrombin generation. Andexanet alfa was well tolerated with no thrombotic events or serious adverse events reported. No antibodies to andexanet alfa, Factor Xa or Factor X were observed.
The andexanet alfa abstract is now publically available at www.isth.org. Details of the presentations follow.
Abstract Title: Reversal of Enoxaparin-Induced Anticoagulation in Healthy Subjects by Andexanet Alfa (PRT064445), an Antidote for Direct and Indirect FXA Inhibitors -- A Phase 2 Randomized, Double-Blind, Placebo-Controlled Trial (abstract #COA01)
Presenting Author: Mark Crowther, M.D., M.Sc., associate chair, Department of Medicine, McMaster University, Hamilton, Ontario
Poster Presentation Date, Time and Location: Monday, June 23, at 6:15 p.m. CDT through the duration of the meeting in Wisconsin Center Ballroom A-C
Oral Presentation Date, Time and Location: Wednesday, June 25 at 8:05 a.m. CDT in Room 203 C-E
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. 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, an FDA-designated breakthrough therapy, is a first-in-class recombinant, modified Factor Xa molecule. It is 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. Andexanet alfa has the potential to address numerous clinical scenarios by allowing for flexible and controlled reversal, which can be short-acting through the administration of an IV bolus or longer-acting with the addition of an extended infusion.
About the Andexanet Alfa Clinical Development Program
Portola is evaluating andexanet alfa in Phase 3 studies with Bristol-Myers Squibb Company (BMS) and Pfizer Inc.'s Eliquis® (apixaban) and Bayer HealthCare and Janssen's XARELTO® (rivaroxaban). These randomized, double-blind, placebo-controlled studies are designed to evaluate the safety and efficacy of andexanet alfa in reversing Eliquis- or XARELTO®-induced anticoagulation rapidly after an IV bolus and sustaining that effect through a continuous infusion.
Results from three separate Phase 2 proof-of concept studies with Eliquis, XARELTO® 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 100 healthy volunteers, with no thrombotic events or antibodies to Factor Xa or Factor X observed.
A Phase 2 proof-of-concept study with Daiichi Sankyo's Factor Xa inhibitor edoxaban is ongoing, and a Phase 2 proof-of-concept study with Portola's Factor Xa inhibitor betrixaban is planned.
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 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 first-in-class 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 worldwide.
Portola's second product candidate in the area of thrombosis, andexanet alfa, 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 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.
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 1/2 proof-of-concept study 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.
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. 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; our 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 our most recent filings with the Securities and Exchange Commission, including our Annual Report on Form 10-K and our Quarterly Report on Form 10-Q for the first quarter of 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).
i Source: Truven MARKETSCAN® Commercial, Medicare Supplemental and Medicaid Database (12 months ending June 2013).