An antidote for Factor Xa inhibitors

SOUTH SAN FRANCISCO, Calif.—Portola Pharmaceuticals has entered into a second clinical collaboration agreement with Daiichi Sankyo to study andexanet alfa, Portola’s investigational Factor Xa inhibitor antidote, in Phase 3 registration studies with Daiichi Sankyo’s Factor Xa inhibitor edoxaban. Portola’s original collaboration agreement with Daiichi Sankyo, announced in June 2013, covered the conduct of a Phase 2 proof-of-concept study, for which results are anticipated later this year. The Phase 3 edoxaban studies, known as ANNEXA- E (Andexanet Alfa a Novel Antidote to the Anticoagulant Effects of fXA Inhibitors - Edoxaban), are expected to start in 2015. Daiichi will provide clinical and regulatory guidance, but Portola is responsible for the conduct of the studies, a Portola spokesperson tells DDNews.

Under this non-exclusive collaboration agreement, Portola will receive an upfront payment and is eligible to receive additional development and regulatory milestone payments. Portola retains full worldwide commercial rights to andexanet alfa, for which Portola is pursuing an accelerated approval pathway.

“We have now established Phase 3 clinical collaboration agreements with all of the manufacturers of Factor Xa inhibitors. This, combined with the FDA’s designation of andexanet alfa as a breakthrough therapy, underscores the significant need for an antidote for the millions of patients currently being treated with these novel anticoagulants,” said Portola CEO William Lis. “We are pursuing an accelerated approval pathway for andexanet alfa in order to bring this novel therapy to market as quickly as possible for the benefit of patients.”

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 confirm earlier clinical trial results showing that, while most novel anticoagulants have lower bleeding rates than warfarin, serious bleeding (annually, 1 to 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.

Andexanet alfa, a U.S. Food and Drug Administration-designated breakthrough therapy, is a first-in-class recombinant, modified Factor Xa molecule. Factor Xa inhibitors work by binding native Factor Xa and interfering with the body’s normal coagulation process, Portola explains. Andexanet mimics native Factor Xa and binds to Factor Xa inhibitors, acting as a decoy. Given the mechanism of action and the data available to date, andexanet alfa has the potential to be a universal antidote for both direct and indirect Factor Xa inhibitors, including apixaban, rivaroxaban, enoxaparin, edoxaban and betrixaban. It is being developed as a direct reversal agent for patients receiving a Factor Xa inhibitor. Andexanet alfa 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, 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.

Portola is evaluating andexanet alfa in Phase 3 studies with Bristol-Myers Squibb Co. 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. All of the Phase 3 collaboration agreements were structured similarly—Portola receives an upfront payment and is eligible to receive additional development and regulatory milestone payments. Portola is responsible for conducting each study and retains full, worldwide commercial rights to andexanet alfa.

Results from three separate Phase 2 proof-of-concept studies with Eliquis, XARELTO and Lovenox (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.

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 for its potentially life-saving therapies.

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.