Initial results from a phase 2 proof-of-concept study of Andexanet alfa, investigational factor Xa inhibitor antidote, in healthy volunteers who were administered the factor Xa inhibitor Rivaroxaban ( Xarelto ) were presented.
Results from the first two dosing cohorts of the study demonstrated that Andexanet alfa is able to dose-dependently reverse the anticoagulant effects of Rivaroxaban. In addition, no serious adverse events were reported.
Andexanet alfa is being developed as a potential first-in-class, universal antidote for patients who experience an uncontrolled bleeding episode or who require emergency surgery while being anticoagulated with afFactor Xa inhibitor.
This randomized, placebo-controlled, double-blind, cohort dose-escalation phase 2 proof-of-concept study treated healthy volunteers with an oral dose of Rivaroxaban at 20 mg qd for 6 days and then randomized them in a 6:3 ratio to Andexanet alfa in different dosing cohorts. The first two cohorts received a single IV bolus of Andexanet alfa at 210 mg or 420 mg, respectively. Within two minutes following completion of the 210 mg and 420 mg bolus of Andexanet alfa, anti-factor Xa activity decreased dose-dependently by 20% and 53%, respectively.
Rivaroxaban-induced inhibition of thrombin generation and prolongation of both prothrombin time and activated clotting time were also rapidly reversed by Andexanet alfa in a dose-dependent manner. Interim safety data showed that Andexanet alfa was well tolerated, with no thrombotic events, or serious or severe adverse events reported.
Currently, millions of patients are treated with factor Xa inhibitors for short-term use or chronic conditions in the G7 countries, and the anticoagulant market is expected to continue to grow with the adoption of novel oral anticoagulants. Clinical trial results suggest that, depending on their underlying medical condition, annually between 1 and 4% of these patients will experience major bleeding and an additional 1% will require emergency surgery. Based on these data and projected use of factor Xa inhibitors, the Portola Pharmaceuticals estimates there could be approximately 500,000 hospital visits each year by patients who would benefit from an antidote by the year 2020. Currently, there is no antidote or reversal agent approved for use against factor Xa inhibitors. ( Xagena )
Source: Portola Pharmaceuticals, 2013