Date: 2015-06-22
Type of information: Presentation of results at a congress
phase: 3
Announcement: presentation of results at the International Society on Thrombosis and Haemostasis (ISTH) 2015 Congress in Toronto
Company: Pfizer (USA - NY) BMS (USA - NY) Portola Pharmaceuticals (USA - CA)
Product: andexanet alfa and Eliquis® (apixaban)
Action
mechanism: protein. Andexanet alfa, an FDA-designated breakthrough therapy, is a first-in-class recombinant, modified Factor Xa molecule. It is being developed as an antidote 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. antithrombotic. 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 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.
Disease: reversion of the anticoagulant activity of Eliquis®
Therapeutic area: Cardiovascular diseases - Hematological diseases
Country:
Trial
details: The randomized, double-blind, placebo-controlled Phase 3 ANNEXA-A study is evaluating the safety and efficacy of andexanet alfa in reversing Eliquis-induced anticoagulation in older healthy volunteers ages 50-75. Efficacy is being evaluated using biomarker endpoints, including anti-Factor Xa levels as the primary endpoint. Secondary endpoints include levels of plasma unbound (free fraction) of Eliquis® and thrombin generation levels.
In the first part of the ANNEXA-A study, reported here, 33 healthy volunteers (ages 50-73) were given Eliquis® 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).
Latest
news: * On June 22, 2015, Portola Pharmaceuticals, BMS and Pfizer 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 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. 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. ANNEXA-A Study Part 2 Results: 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. * On November 17, 2014, Portola Pharmaceuticals, Bristol-Myers Squibb and Pfizer announced results from the first part of the Phase 3 ANNEXA™-A (Andexanet Alfa a Novel Antidote to the Anticoagulant Effects of fXA Inhibitors – Apixaban) studies. Andexanet alfa produced rapid and nearly complete reversal (by approximately 94 percent, p value <0.0001) of the anticoagulant effect of Eliquis® (apixaban) in healthy volunteers ages 50-75. The full data set will be presented in an oral presentation during the “Clinical Science: Special Reports” session at the American Heart Association (AHA) 2014 Scientific Sessions in Chicago, IL. This first part of the Phase 3 ANNEXA-A trial achieved all of its primary and secondary endpoints with statistical significance (p value <0.0001). The trial included 33 subjects, with 24 randomized to andexanet alfa and nine to placebo. In the study, two to five minutes after completion of a bolus dose of andexanet alfa, the anticoagulant activity of Eliquis® was reversed by approximately 94 percent (p value <0.0001) compared with placebo as measured by anti-Factor Xa activity. Every subject treated with andexanet alfa had between 90 and 96 percent reversal of the anticoagulant activity of Eliquis. The reversal of anti-Factor Xa activity correlated with a significant reduction in the level of free, unbound Eliquis in the plasma, consistent with the mechanism of action of andexanet alfa. Additionally, andexanet alfa restored thrombin generation to baseline normal levels (prior to Eliquis therapy). In this study, no serious adverse events, thrombotic events, or antibodies to Factor X or Xa were reported following andexanet alfa administration. Mild infusion reaction was reported in three subjects. Portola is evaluating andexanet alfa in 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, such as anti-Factor Xa activity, to demonstrate efficacy. These studies are designed to support the Company’s BLA filing for Accelerated Approval. As part of the Accelerated Approval process, a Phase 3b/4 confirmatory patient study evaluating clinical outcomes with andexanet alfa is planned and will be initiated prior to the BLA filing.
Results from four separate Phase 2 proof-of concept studies in healthy volunteers demonstrated that andexanet alfa immediately reversed the anticoagulation activity of four different Factor Xa inhibitors and that the reversal could be sustained. Andexanet alfa has been shown to be well tolerated in Phase 1 and 2 clinical studies, which have included more than 100 healthy volunteers, with no thrombotic events or antibodies to Factor Xa or Factor X observed.
