An investigational antidote to factor Xa inhibitors has proven succesful in reversing the effects of apixaban and rivaroxaban in a pair of phase 3 studies of healthy
volunteers.
In the ANNEXA-R and ANNEXA-A studies, researchers evaluated the safety and efficacy of the antidote, andexanet alfa, in volunteers receiving rivaroxaban and apixaban, respectively.
In both studies, andexanet alfa met all efficacy endpoints.
There were no serious or severe adverse events and no thrombotic events in either study.
“The findings of [these studies] are an advance towards resolving major bleeding complications effectively within minutes,” said Deborah Siegal, MD, of McMaster University in Hamilton, Ontario, Canada.
Dr Siegal and her colleagues reported the findings in NEJM. The studies were funded by Portola Pharmaceuticals, the company developing andexanet alfa.
The randomized, double-blind, placebo-controlled ANNEXA-R and ANNEXA-A studies were conducted to evaluate the safety and efficacy of andexanet alfa in reversing the anticoagulant effect of rivaroxaban and apixaban, respectively, in healthy volunteers ages 50 to 68.
The primary endpoint was reduction in anti-factor Xa levels. Secondary endpoints included reduction in plasma levels of unbound rivaroxaban or apixaban and restoration of the endogenous thrombin potential, a measure of thrombin generation.
ANNEXA-R efficacy
In part 1 of this study, 41 healthy volunteers received rivaroxaban at 20 mg once daily for 4 days. They were then randomized in a 2:1 ratio to receive either andexanet alfa administered as an 800 mg intravenous (IV) bolus (n=27) or placebo (n=14).
Within 2 to 5 minutes of bolus completion, andexanet alfa significantly reduced the anti-factor Xa activity of rivaroxaban compared with placebo—92% and 18%, respectively (P<0.001).
And andexanet alfa significantly reduced the level of unbound rivaroxaban in the plasma compared with placebo—23.4 ng/mL and 4.2 ng/mL, respectively (P<0.001).
Thrombin generation was fully restored in 96% of subjects who received andexanet alfa and 7% of placebo-treated subjects (P<0.001).
In part 2 of the study, 39 healthy volunteers received rivaroxaban at 20 mg once daily for 4 days. They were then randomized in a 2:1 ratio to receive either andexanet alfa administered as an 800 mg IV bolus followed by a continuous infusion of 8 mg/min for 120 minutes (n=26) or placebo (n=13).
Andexanet alfa significantly reduced anti-factor Xa activity compared with placebo—97% and 45%, respectively (P<0.001). And reversal persisted in andexanet alfa-treated subjects for 1 to 2 hours after the infusion was complete.
The reduction in unbound rivaroxaban was sustained with the bolus plus infusion, which significantly reduced the mean plasma concentration of unbound rivaroxaban compared with placebo—30.3 ng/mL and 12.1 ng/mL, respectively (P<0.001).
Thrombin generation was fully restored in 100% of subjects who received andexanet alfa and 0% of placebo-treated subjects (P<0.001).
ANNEXA-A efficacy
In part 1 of this study, 33 subjects received apixaban at 5 mg twice daily for 3.5 days. They were then randomized in a 3:1 ratio to receive either andexanet alfa administered as a 400 mg IV bolus (n=24) or placebo (n=9).
Within 2 to 5 minutes of bolus completion, andexanet alfa reduced the anti-factor Xa activity of apixaban compared with placebo—94% and 21%, respectively (P<0.001).
Andexanet alfa significantly reduced the level of unbound apixaban in the plasma compared with placebo—9.3 ng/mL and 1.9 ng/mL, respectively (P<0.001).
Thrombin generation was fully restored in 100% of subjects who received andexanet alfa and 11% of placebo-treated subjects (P<0.001).
In part 2, 31 healthy volunteers received apixaban at 5 mg twice daily for 4 days. They were then randomized in a 3:1 ratio to receive either andexanet alfa administered as a 400 mg IV bolus followed by a continuous infusion of 4 mg/min for 120 minutes (n=24) or placebo (n=8).
Andexanet alfa significantly reduced anti-factor Xa activity compared with placebo—92% and 33%, respectively (P<0.001). And reversal persisted in andexanet alfa-treated subjects for 1 to 2 hours after the infusion was complete.
The reduction in unbound apixaban was sustained with the bolus plus infusion, which significantly reduced the mean plasma concentration of unbound apixaban compared with placebo—6.5 ng/mL and 3.0 ng/mL, respectively (P<0.001).
Thrombin generation was fully restored in 100% of subjects who received andexanet alfa and 25% of placebo-treated subjects (P<0.001).
ANNEXA safety results
There were no serious or severe adverse events and no thrombotic events in either study. All adverse events related to andexanet alfa were considered mild.
Among subjects who received andexanet alfa in the ANNEXA-A study, there were 4 cases of gastrointestinal disorders—2 cases of constipation and 2 cases of dysgeusia. There were 3 cases in which subjects felt hot after administration of the drug, 4 cases of flushing, and 1 case of urticaria.
Among subjects who received andexanet alfa in the ANNEXA-R study, there were 2 cases of flushing and 1 case of urticaria.
Among subjects who received placebo in either study, there was 1 case of flushing.
One subject with a history of hives developed erythematous hives after receiving andexanet alfa. The infusion was stopped after 35 minutes, the subject received a single dose of diphenhydramine, and the hives resolved.
None of the subjects developed antibodies to factor X or factor Xa, and there were no neutralizing antibodies against andexanet alfa.
However, 1 subject who received placebo (2%) and 17 subjects who received andexanet alfa (17%) had non-neutralizing antibodies against andexanet alfa. Two of the subjects had non-neutralizing antibodies before andexanet alfa administration.
The antibodies tended to appear within 15 to 30 days of andexanet administration, and the titers were generally low (at or below 1:640). The exception was 1 subject who had a titer of 1:2560.
About andexanet alfa
Andexanet alfa is a modified human factor Xa molecule that acts as a decoy to target and sequester 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.
Portola Pharmaceuticals is currently evaluating andexanet alfa in ANNEXA-4, a phase 4, single-arm, confirmatory study in patients receiving apixaban, rivaroxaban, edoxaban, or enoxaparin who present with an acute major bleed.
Data from a small number of patients from ANNEXA-4, as well as data from ANNEXA-A and ANNEXA-R, will serve as the clinical basis for the biologics license application to the US Food and Drug Administration.
A rolling submission of the application has been initiated under accelerated approval, and the submission package is expected to be complete by the end of this year. The Food and Drug Administration has already granted andexanet alfa orphan drug designation and breakthrough therapy designation.
