New interim findings from a phase 2 proof-of-concept study of an investigational factor Xa inhibitor antidote, Andexanet alfa, in healthy volunteers who received the factor Xa inhibitor Apixaban ( Eliquis ), were presented. Andexanet alfa was administered intravenously as a bolus followed by a continuous infusion for up to two hours. Data from this study showed a rapid and nearly complete reversal of the anticoagulation effect of Apixaban measured at two minutes following completion of the bolus, which was sustained during infusion for up to two hours.
Currently, there are no approved agents for reversing or stopping the anticoagulant effect of novel factor Xa inhibitors. This study has shown that the safety and activity seen with Andexanet alfa in previous clinical studies can be extended in duration, demonstrating that the nearly complete anticoagulation reversal can be sustained for the duration of the infusion. This may allow physicians to treat a broader range of patients, such as those with bleeding due to a traumatic injury or those requiring surgery.
These new interim findings have demonstrated that two minutes after completion of a 420 mg bolus dose of Andexanet alfa ( n=6 ), the anticoagulant activity of Eliquis was reversed by approximately 92% ( p less than 0.0001 ) as measured by anti-factor Xa activity compared with placebo ( n=3 ). At the end of the two-hour infusion, the anticoagulation activity of Apixaban remained reversed by approximately 91% ( p less than 0.0001 ). The safety follow-up for this study is ongoing with no serious adverse events or premature discontinuations of Andexanet alfa reported to date. Safety data for over 65 healthy volunteers dosed with Andexanet alfa across phase 1 and phase 2 clinical studies showed no thrombotic events or antibodies against Andexanet alfa, endogenous factor Xa, or factor X. One serious adverse event, a case of pneumonia, was seen in the phase 1 study.
Clinical trial results suggest that, depending on their underlying medical condition, annually between 1% and 4% of these patients will experience uncontrolled bleeding and an additional 1% will require emergency surgery.
This randomized, placebo-controlled, double-blind, cohort dose-escalation phase 2 proof-of-concept study treated 54 healthy volunteers with 5 mg of Apixaban twice a day on days 1 through 6 and then randomized them in a 6:3 ratio to intravenous ( IV ) Andexanet alfa in six different cohorts. The first three cohorts were a single IV bolus at 90 mg, 210 mg and 420 mg. The last three cohorts were 420 mg IV bolus plus either a 45-minute infusion, a two-hour infusion or a repeat bolus at 45 minutes.
Portola Pharmaceuticals previously announced positive pharmacodynamic and safety data from the three bolus-only dose cohorts. Those data demonstrated a dose-related reversal of the anticoagulant activity of Apixaban. Two minutes after administration of 420 mg Andexanet alfa ( n=6 ), the anticoagulant activity of Apixaban decreased by greater than 95% as measured by anti-factor Xa activity compared with placebo ( n=3 ). The reversal of anti-factor Xa activity correlated with a reduction in the level of free, unbound Apixaban in the plasma consistent with the mechanism of action of Andexanet alfa.
Andexanet alfa is a novel recombinant, modified factor Xa molecule that has the potential to be the first universal antidote to reverse the effects of factor Xa inhibitors in patients who suffer an uncontrolled bleeding episode, trauma, or require emergency surgery. Andexanet alfa is similar to native factor Xa, but has been modified to restrict its biological activity, such as its ability to cleave thrombin, an enzyme involved in the clotting cascade. Andexanet alfa acts as a factor Xa decoy that binds and sequesters direct factor Xa inhibitors in the blood. Once bound to Andexanet alfa, the factor Xa inhibitors are unable to bind to and inhibit native factor Xa. The native factor Xa should then be available to participate in the coagulation process and restore hemostasis. ( Xagena )
Source: Portola Pharmaceuticals, 2013