SOUTH SAN FRANCISCO, Calif., PRINCETON, N.J. and NEW YORK—Portola Pharmaceuticals, Bristol-Myers Squibb Company and Pfizer Inc. have announced full results from the second part of the Phase 3 ANNEXA-A (Andexanet Alfa a Novel Antidote to the anticoagulant effects of FXa Inhibitors—Apixaban) study. This registration-enabling study evaluated the safety and efficacy of andexanet alfa, an investigational antidote and U.S. Food and Drug Administration (FDA)-designated breakthrough therapy, administered as an intravenous (IV) bolus followed by a continuous two-hour infusion to sustain the reversal of anticoagulation activity of the Factor Xa inhibitor Eliquis (apixaban) in healthy volunteers ages 50-75 years.
This second part of the study achieved all primary and pre-specified secondary endpoints with high statistical significance. Andexanet alfa produced rapid reversal of the anticoagulant effect of Eliquis, as measured by anti-Factor Xa activity, which was sustained for the duration of the infusion. Andexanet alfa significantly reduced the level of free unbound Eliquis in the plasma and restored thrombin generation to normal. Andexanet alfa was well tolerated, with no serious adverse events, thrombotic events, or antibodies to Factor X or Xa reported. Mild infusion reactions were reported in six subjects: four in the andexanet arm and two in the placebo arm. No subjects discontinued the study due to an adverse event. The full data set was presented in a Late-Breaking Clinical Trial oral session at the International Society on Thrombosis and Haemostasis (ISTH) 2015 Congress in Toronto.
"These Phase 3 findings demonstrate that andexanet alfa can rapidly reverse anticoagulant activity for a short or sustained period of time and that anticoagulant activity can be reinitiated following discontinuation of the infusion. This is significant given different clinical needs for shorter-duration or longer-duration reversal," said John T. Curnutte, M.D., Ph.D., executive vice president, research and development, for Portola. "Importantly, our trial endpoints are based on the accepted pharmacodynamic measurements of anticoagulant activity agreed to with regulatory authorities and serve as the basis for our accelerated approval pathway. The results to date across our Phase 2 and Phase 3 andexanet alfa studies with both oral and injectable Factor Xa inhibitors suggest that andexanet alfa is the only investigational reversal agent to clinically show meaningful reversal of Factor Xa anticoagulant activity. There is an increasing number of patients on Factor Xa inhibitors who may need their anticoagulant reversed because they are bleeding or require surgery."
"Bristol-Myers Squibb and Pfizer are committed to continuing to deliver innovative therapies to patients and are pleased with the positive results of both parts of the ANNEXA-A study," said Rory O'Connor, M.D., senior vice president and head of Global Medical Affairs, Global Innovative Pharmaceuticals Business, Pfizer Inc. "Patients often take anticoagulants to treat or reduce the risk of life-threatening blood clots from forming. In patients who experience a major bleeding event or require emergency surgery, there is a need to stop the blood thinning effects of an anticoagulant. In this study, andexanet alfa was shown to rapidly reverse the anticoagulant effects of Eliquis."
"We are proud to share in the presentation of this ANNEXA-A Part 2 study data," said Douglas Manion, M.D., head of specialty development, Bristol-Myers Squibb. "As we saw in Part 1, these results demonstrate that andexanet alfa could prove to be an effective reversal agent for Eliquis." Portola plans to submit data from the ANNEXA-A (apixaban) and ANNEXA-R (rivaroxaban) studies, and initial data from a Phase 4 study, as part of its Biologics License Application (BLA) to the FDA under an Accelerated Approval pathway by the end of 2015.
The randomized, double-blind, placebo-controlled Phase 3 ANNEXA-A study evaluated the safety and efficacy of andexanet alfa in reversing apixaban-induced anticoagulation in older healthy volunteers ages 50-75 years. Efficacy was evaluated using biomarker endpoints, with anti-Factor Xa levels as the primary endpoint. Secondary endpoints included plasma levels of free unbound apixaban and endogenous thrombin potential (ETP), a measure of thrombin generation.
In ANNEXA-A Part 1, 33 healthy volunteers were given apixaban 5 mg twice daily for four days and then randomized in a 3:1 ratio to andexanet alfa administered as a 400 mg IV bolus (n=24) or to placebo (n=9). In the second part of the study, 31 healthy volunteers were given apixaban 5 mg twice daily for four days and then randomized in a 3:1 ratio to andexanet alfa administered as a 400 mg IV bolus followed by a continuous infusion of 4 mg/min for 120 minutes (n=23) or to placebo (n=8). Results showed that, following the administration of a bolus of andexanet alfa, the anticoagulant activity of apixaban, as measured by anti-Factor Xa activity, was reversed by 93.5 percent (p<0.0001). Following completion of the two-hour continuous infusion of andexanet alfa, the anticoagulant activity of apixaban remained significantly reversed, by 92.7 percent (p<0.0001). These two endpoints demonstrate that andexanet alfa infusion was able to keep anti-Factor Xa levels flat from the end of the bolus (93.5 percent) to the end of the two-hour infusion (92.7 percent).
Additional secondary endpoints showed reversal of at least 80 percent of anti-Factor Xa activity occurred in all 23 subjects who received andexanet alfa (p<0.0001). Plasma levels of free unbound apixaban were significantly reduced with andexanet alfa (p=0.0002). Thrombin generation at peak (end of infusion) was restored to the normal range in 23 out of 23 (100 percent) andexanet alfa recipients. Thrombin generation above the lower limit of normal occurred in all 23 subjects who received andexanet alfa (p<0.0001). No serious adverse events, thrombotic events, or antibodies to Factor X or Xa were reported following andexanet alfa administration. Mild infusion reactions were reported in six subjects. No subjects discontinued the study due to an adverse event.
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, annually, between 1 to 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. 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. This 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.
Eliquis (apixaban) is an oral selective Factor Xa inhibitor. By inhibiting Factor Xa, a key blood-clotting protein, Eliquis decreases thrombin generation and blood clot formation. Eliquis is approved for multiple indications in the U.S. based on efficacy and safety data, including results from seven Phase 3 clinical trials. Eliquis is a prescription medicine indicated to reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation; for the prophylaxis of deep vein thrombosis (DVT), which may lead to pulmonary embolism (PE), in patients who have undergone hip or knee replacement surgery; for the treatment of DVT and PE; and to reduce the risk of recurrent DVT and PE following initial therapy.