Portola Announces In Vivo Study Results Demonstrating Andexanet Alfa Significantly Reduced Bleeding and Reversed Anticoagulation Activity of Rivaroxaban While Four-Factor Prothrombin Complex Concentrate Did Not
SOUTH SAN FRANCISCO, Calif., June 24, 2015 (GLOBE NEWSWIRE) -- Portola Pharmaceuticals (Nasdaq:PTLA) today announced results of a study demonstrating that andexanet alfa significantly reduced bleeding in a validated animal model of bleeding using the Factor Xa inhibitor rivaroxaban as the anticoagulant. The reduction in blood loss correlated with reversal of the anticoagulant effects of rivaroxaban as measured by anti-Factor Xa activity, a definitive pharmacodynamic measurement of the anticoagulant activity of Factor Xa inhibitors. In contrast, the four-factor prothrombin complex concentrate (PCC) Kcentra® did not impact bleeding or the anti-Factor Xa coagulation biomarker in the study. The results were presented today in an oral session at the International Society on Thrombosis and Haemostasis (ISTH) 2015 Congress in Toronto.
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. Portola is currently evaluating the antidote in two randomized, placebo-controlled Phase 3 ANNEXA™ registration studies with apixaban and rivaroxaban and in a Phase 4 confirmatory study in patients receiving apixaban, rivaroxaban or enoxaparin who present with an acute major bleed.
"The finding that andexanet alfa significantly reduced blood loss in an animal model of rivaroxaban bleeding while the PCC showed no reversal activity or improvement in bleeding is consistent with other animal model data from studies conducted by Portola and other labs," said John T. Curnutte, M.D., Ph.D., executive vice president, research and development, for Portola. "These results distinguish andexanet alfa as the only agent that acts as a Factor Xa inhibitor antidote by binding directly to Factor Xa inhibitors."
Dr. Curnutte added, "Four-factor PCCs are U.S. Food and Drug Administration-approved to reverse the effects of vitamin K antagonists but are not approved to reverse the anticoagulant effects of Factor Xa inhibitors, and no known label-enabling studies are ongoing. Additionally, the FDA and the European Medicines Agency do not view four-factor PCCs as a standard of care therapy in our ongoing Phase 4 study of andexanet alfa in anticoagulated patients who present with an acute major bleed."
Study Design and Results
The study compared the activity of andexanet alfa to the four-factor PCC in reversing rivaroxaban anticoagulation in an animal model of bleeding, as assessed by blood loss and pharmacodynamic markers of coagulation. Results showed that andexanet alfa significantly reduced blood loss to a level similar to that seen in animals not administered rivaroxaban. Andexanet alfa also significantly and rapidly decreased anti-Factor Xa activity, as well as unbound rivaroxaban, and corrected the prothrombin time. In contrast, therapeutic doses of the PCC had no effect on the rate of blood loss, or on any of the pharmacodynamic markers of coagulation, or on plasma rivaroxaban levels.
| Oral Presentation Details | |
| Abstract Title: | Andexanet alfa but not four-factor prothrombin complex concentrate reverses rivaroxaban-induced anticoagulation as measured by reduction in blood loss in a rabbit liver laceration model (abstract #OR318) |
| Presenting Author: | Polly Pine, Ph.D., head of pharmacology, Portola Pharmaceuticals |
| Oral Session Title: | NOACs and Reversal |
| Presentation Date, | |
| Time and Location: | Wednesday, June 24, 2:30 p.m. ET, Exhibit Hall G & F |
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. Annually, more than 100,000 U.S. patients are currently impacted and may benefit from an antidote. With the expected increase in adoption of these anticoagulants, Portola projects that this number will increase by the year 2020 to up to 200,000 patients in the United States. Development of a specific antidote designed to reverse the anticoagulant activity of Factor Xa inhibitors may provide an important treatment option for these patients.
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. Reversal activity 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 second part of the study, which evaluated andexanet alfa administered as a bolus plus a continuous infusion to sustain the reversal of anticoagulation activity of apixaban. Portola also reported statistically significant results from the first part of the Phase 3 ANNEXA-R study with Bayer HealthCare and Janssen's direct Factor Xa inhibitor rivaroxaban. The second part of the ANNEXA-R study is ongoing and is evaluating a bolus plus a continuous infusion of andexanet alfa to sustain the reversal of anticoagulation activity of rivaroxaban.
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. A Phase 2 proof-of-concept study with Portola's investigational Factor Xa inhibitor betrixaban is planned.
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. The most common adverse events have been mild infusion reactions.
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 programs are focused on developing selective Syk inhibitors for inflammatory conditions.
Betrixaban
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
Andexanet alfa, an FDA-designated breakthrough therapy, is a recombinant protein designed to reverse the anticoagulant effect 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 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.
Cerdulatinib
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.
Forward-looking Statement
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, the potential indications, efficacy, safety and activity of andexanet alfa, and the potential market and indications for its 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, and Quarterly Report on Form 10-Q, which was filed on May 7, 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).
CONTACT: Investor Contact: Michele Mantynen Portola Pharmaceuticals ir@portola.com Media Contact: Julie Normart W2O Group jnormart@w2ogroup.com 