A specific antidote for reversal of anticoagulation by direct and indirect inhibitors of coagulation factor Xa

Abstract

Inhibitors of coagulation factor Xa (fXa) have emerged as a new class of antithrombotics but lack effective antidotes for patients experiencing serious bleeding. We designed and expressed a modified form of fXa as an antidote for fXa inhibitors. This recombinant protein (r-Antidote, PRT064445) is catalytically inactive and lacks the membrane-binding γ-carboxyglutamic acid domain of native fXa but retains the ability of native fXa to bind direct fXa inhibitors as well as low molecular weight heparin-activated antithrombin III (ATIII). r-Antidote dose-dependently reversed the inhibition of fXa by direct fXa inhibitors and corrected the prolongation of ex vivo clotting times by such inhibitors. In rabbits treated with the direct fXa inhibitor rivaroxaban, r-Antidote restored hemostasis in a liver laceration model. The effect of r-Antidote was mediated by reducing plasma anti-fXa activity and the non-protein bound fraction of the fXa inhibitor in plasma. In rats, r-Antidote administration dose-dependently and completely corrected increases in blood loss resulting from ATIII-dependent anticoagulation by enoxaparin or fondaparinux. r-Antidote has the potential to be used as a universal antidote for a broad range of fXa inhibitors.

Managing target-specific oral anticoagulant associated bleeding including an update on pharmacological reversal agents

“…Andexanet alfa (Portola Pharmaceuticals, San Francisco, USA) is a recombinant factor Xa derivative which lacks catalytic and membrane binding activity currently undergoing clinical development for specific reversal of factor Xa inhibitor anticoagulant effect [35]. It dose-dependently corrected abnormal anti-Xa activity due to rivaroxaban, apixaban, betrixaban and edoxaban in vitro [35,36].…”

“…It dose-dependently corrected abnormal anti-Xa activity due to rivaroxaban, apixaban, betrixaban and edoxaban in vitro [35,36]. When administered to rats treated with rivaroxaban, apixaban and betrixaban, andexanet corrected the INR [35].…”

“…It dose-dependently corrected abnormal anti-Xa activity due to rivaroxaban, apixaban, betrixaban and edoxaban in vitro [35,36]. When administered to rats treated with rivaroxaban, apixaban and betrixaban, andexanet corrected the INR [35]. In rivaroxaban-treated rabbits, andexanet corrected coagulation assays and reduced blood loss following liver laceration [35].…”

“…When administered to rats treated with rivaroxaban, apixaban and betrixaban, andexanet corrected the INR [35]. In rivaroxaban-treated rabbits, andexanet corrected coagulation assays and reduced blood loss following liver laceration [35]. Results of a phase II study showed that andexanet dose-dependently decreased anti-Xa activity and reduced plasma concentrations of free apixaban compared to placebo in healthy volunteers receiving apixaban [37].…”

Selecting antithrombotic therapy for patients with atrial fibrillation

“…58 PRT06445 (andexanet alfa), a recombinant protein antidote specific for factor Xa inhibitors, has entered clinical studies, with a phase 2 trial reporting high reversing capability for apixaban. 59 …”