Andexanet alfa for reversal of factor Xa inhibitors induced-anticoagulation in nonclinical and clinical studies

摘要

Anticoagulants are widely used for the prevention and treatment of thrombosis but have the liability of bleeding due to over-anticoagulation. Traditional anticoagulants have an antidote for their reversal, such as vitamin K for reversal of warfarin and protamine for reversal of heparin. Although the newer classes of inhibitors targeting coagulation factor Xa (fXa) (direct fXa inhibitors and ATⅢ-dependent low molecular weight heparin (LMWH) and fondaparinux) have become the mainstay in thrombosis prevention and treatment, unlike heparin and warfarin, the newer anticoagulants lack an effective antidote to reverse the anticoagulant effects in case of urgent medical intervention or bleeding. Andexanet alfa (andexanet), an FDA-designated breakthrough therapy and orphan drug status currently in late stage clinical development, is a specific antidote for all fXa inhibitors. Andexanet is a recombinant modified human fXa that lacks the coagulation activity of native fXa but retains high binding affinity to all fXa inhibitors, thus sequestering the inhibitors and allowing for the restoration of normal hemostasis. Andexanet is expressed in Chinese hamster ovary (CHO) cells directly as a functional protein (not as a zymogen) and purified from harvested cell culture fluid without additional activation steps necessary for conversion of native fX to fXa. Nonclinical studies have demonstrated that andexanet binds to direct fXa inhibitors (rivaroxaban, apixaban, edoxaban, betrixaban) with high affinity (Kd = 0.5 ～1.5 nM). It dose-dependently and completely reversed the anticoagulant activity of these inhibitors in buffered system with purified fXa as well as in human plasma as measured by anti-fXa activity and thrombin generation. In animal models of bleeding and blood loss (rats and rabbits), andexanet reduced anticoagulation-induced increase in blood loss by direct fXa inhibitors, such as rivaroxaban and edoxaban. Similarly, andexanet was also effective in reversal of ATⅢ-dependent fXa inhibitors (enoxaparin, fondaparinux) in both in vitro and in vivo animal models. Andexanet was well-tolerated in preclinical toxicology studies (rats and monkeys) and Phase 1 single ascending dose study in healthy volunteers. In Phase 2 studies in young healthy subjects, andexanet dose-dependently and significantly reversed pharmacodynamics markers of anticoagulation (anti-fXa, inhibition of thrombin generation) for all fXa inhibitors studied (apixaban, rivaroxaban, edoxaban and enoxaparin), and reduced the unbound inhibitor plasma concentrations for all direct fXa inhibitors. In Phase 3 randomized, double-blind, placebo controlled studies, older volunteers age 50 -70 were dosed with apixaban (5 mg twice daily) or rivaroxaban (20 mg daily) to steady state. Andexanet reversed the anticoagulant activity of apixaban and rivaroxaban within minutes following the Ⅳ bolus of andexanet and the reversal was maintained over the duration of infusion for 2 hours and was well tolerated. The studies met the primary and all secondary endpoints with high statistical significance. In conclusion, andexanet is a specific, rapidly-acting antidote being developed for urgent reversal of fXa inhibitor anticoagulant activity. The ongoing Phase 3b/4 study is evaluating the efficacy and safety of andexanet in patients with fXa inhibitor-associated acute major bleeding.