Andexanet alfa for the reversal of anticoagulant activity in patients treated with direct and indirect factor Xa inhibitors

Abstract

Andexanet alfa is a recombinant factor Xa decoy molecule that inhibits direct and indirect factor Xa inhibitors to allow the normal coagulation process to resume. Its development arises in a space where novel oral anticoagulants are receiving expanded indications yet their use is limited by the lack of an effective reversal agent. Areas covered: This article reviews the biochemical properties, mechanism of action and the preclinical and clinical trials on andexanet alfa. It additionally aims to provide expert commentary and future perspectives on the efficacy, safety and challenges facing andexanet alfa as a universal antidote for direct and indirect factor Xa inhibitors. Expert commentary: Andexanet alfa shows promise to become a highly effective, novel antidote for factor Xa anticoagulation. Its biochemical profile and mechanism of action are immediately more attractive than other drugs on the market and under development due to its inert nature within the normal coagulation cascade, with minimal intrinsic procoagulant or anticoagulant properties. The anticoagulant antidote space will continue to develop as more specific and universal options become available for reversal of the effect of DOACs. Preliminary results of a pivotal phase 3b/4 trial demonstrate a favorable efficacy and safety profile in patients with acute hemorrhage.

Andexanet alfa in the treatment of acute major bleeding related to apixaban and rivaroxaban: a profile of its use in the USA

“…Andexanet alfa [coagulation factor Xa (recombinant), inactivated-zhzo; Andexxa ® ] is a first-in-class recombinant modified factor Xa protein that has been developed with the goal of becoming an agent to reverse anticoagulant effects of direct and indirect factor Xa inhibitors [ 7 ]. This review focuses on the use of intravenously administered andexanet alfa as a specific reversal agent for apixaban and rivaroxaban as approved in the USA [ 8 ].…”

“…Andexanet alfa is a genetically modified variant of human factor Xa protein that acts as a decoy and competes with endogenous factor Xa to bind factor Xa inhibitors [ 7 , 9 ]. The affinity of andexanet alfa for factor Xa inhibitors is thought to be similar to that seen with endogenous factor Xa; however, it is not catalytically active, and is not capable of assembling into the prothombinase complex [ 9 ].…”

Novel Oral Anticoagulants, A Subject in Continuing Debate

“…of antidote . (20,21) Clinical studies confirm the efficacy of novel o r a l a n t i c o a g u l a n t s . …”

Reversing factor Xa inhibitors – clinical utility of andexanet alfa

“…However, ~12% of subjects had low-titer, nonneutralizing antibodies to andexanet alfa. 23 Within 2 minutes of administration, andexanet alfa demonstrated a dose-dependent reversal of the anticoagulant effects of all FXa inhibitors, including reduction in anti-FXa activity and restoration of thrombin generation and clotting times. Also, following the initial IV bolus with continuous infusion of andexanet resulted in a sustained reduction of anti-FXa activity, which returned to placebo levels ~2 hours after stopping the infusion.…”

“…During a series of Phase II clinical trials, healthy adults from ages 18 to 45 years were enrolled in randomized, double-blind, placebo-controlled experiments to assess andexanet’s safety and efficacy. 19 , 21 – 23 On days 1–6, the subjects were initially treated to achieve steady state with an FXa inhibitor, which could be apixaban, rivaroxaban, betrixaban, edoxaban, or enoxaparin. Then, on day 6, they received one of the six different dose regimens of andexanet alfa or matched placebo.…”