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Portola Pharmaceuticals Initiates Phase 3 Study of Andexanet Alfa, Potential First-in-Class Factor Xa Inhibitor Reversal Agent, Under Accelerated Approval Pathway
"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
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
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
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
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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
*Cerdulatinib is a proposed International Nonproprietary Name (pINN).