Investigational antidote against Factor Xa inhibitor produces safe reversal of anticoagulation
22/06/2015
ISTH 2015 Results of second part of phase 3 ANNEXA-A study demonstrate that andexanet alfa gives rapid and sustained reversal of anticoagulant effect of Factor Xa inhibitor apixaban.
Source:News - June 23, 2015
The 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 were presented yesterday in a Late-Breaking Clinical Trial Oral Session at the International Society on Thrombosis and Haemostasis (ISTH) 2015 Congress. The ANNEXA-A study evaluated the safety and efficacy of andexanet alfa, an investigational antidote, 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 apixaban in healthy volunteers ages 50-75 years. In the United States, andexanet alfa was designated Food and Drug Administration (FDA) breakthrough therapy.
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.
ANNEXA-A was a randomized, double-blind, placebo-controlled Phase 3, in which 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).
This second part of the study achieved all primary and pre-specified secondary endpoints with high statistical significance. Andexanet alfa produced rapid reversal (93.5%, P<0.0001) of the anticoagulant effect of apixaban, as measured by anti-Factor Xa activity, which was sustained for the duration of the infusion (reversal after completion of the 2 hour infusion: 92.7%, P<0.0001). Reversal of at least 80% of the anti-Factor Xa-activity occurred in all 23 subjects receiving andexanet alfa (P<0.0001). Andexanet alfa significantly reduced the level of free unbound apixaban 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.
"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."Press release Portola Pharmaceuticals June 22 2015 (message of Portola Pharmaceuticals, Bristol-Myers Squibb Company and Pfizer Inc)
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.
ANNEXA-A was a randomized, double-blind, placebo-controlled Phase 3, in which 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).
This second part of the study achieved all primary and pre-specified secondary endpoints with high statistical significance. Andexanet alfa produced rapid reversal (93.5%, P<0.0001) of the anticoagulant effect of apixaban, as measured by anti-Factor Xa activity, which was sustained for the duration of the infusion (reversal after completion of the 2 hour infusion: 92.7%, P<0.0001). Reversal of at least 80% of the anti-Factor Xa-activity occurred in all 23 subjects receiving andexanet alfa (P<0.0001). Andexanet alfa significantly reduced the level of free unbound apixaban 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.
"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."Press release Portola Pharmaceuticals June 22 2015 (message of Portola Pharmaceuticals, Bristol-Myers Squibb Company and Pfizer Inc)