Factor XI Inhibitors for Prevention and Treatment of Venous Thromboembolism: A Review on the Rationale and Update on Current Evidence

Abstract

Although anticoagulation therapy has evolved from non-specific drugs (i.e., heparins and vitamin K antagonists) to agents that directly target specific coagulation factors (i.e., direct oral anticoagulants, argatroban, fondaparinux), thrombosis remains a leading cause of death worldwide. Direct oral anticoagulants (i.e., factor IIa- and factor Xa-inhibitors) now dominate clinical practice because of their favorable pharmacological profile and ease of use, particularly in venous thromboembolism (VTE) treatment and stroke prevention in atrial fibrillation. However, despite having a better safety profile than vitamin K antagonists, their bleeding risk is not insignificant. This is true for all currently available anticoagulants, and a high bleeding risk is considered a contraindication to anticoagulation. As a result, ongoing research focuses on developing future anticoagulants with an improved safety profile. Several promising approaches to reduce the bleeding risk involve targeting the intrinsic (or contact activation) pathway of coagulation, with the ultimate goal of preventing thrombosis without impairing hemostasis. Based on epidemiological data on hereditary factor deficiencies and preclinical studies factor XI (FXI) emerged as the most promising candidate target. In this review, we highlight unmet clinical needs of anticoagulation therapy, outlay the rationale and evidence for inhibiting FXI, discuss FXI inhibitors in current clinical trials, conduct an exploratory meta-analysis on their efficacy and safety, and provide an outlook on the potential clinical application of these novel anticoagulants.

Factor XI inhibitors: what should clinicians know

“…There have been several orally bioavailable small molecule inhibitors of FXI, which have undergone at least Phase 1 trials including ONO-7684, SHR2285, milevexian (BMS-986177) and asundexian (BAY 2433334) [5]. Milevexian and asundexian are each potent and reversible active site inhibitors of FXIa with low renal clearance, and half-lives of approximately 12 h and 17 h, respectively, suitable for once to twice daily dosing [16]. Additionally, EP-7041 and BMS-962212 are parenterally administered FXI inhibitors with very rapid onset of action in addition to rapid offset/short half-life, which makes them potentially intriguing candidates for patients requiring anticoagulation in acute settings [5].…”

Pathophysiological mechanisms of thrombosis in acute and long COVID-19

“…The most advanced FXII inhibitors are fully human or humanized monoclonal antibodies (including 3F7). Another potential therapeutic target is FXI, and FXI inhibitors include IONIS416858, bay1213790, MAA868, etc ( 184 , 185 ). High doses of IONIS416858 (an ASO targeting FXI) used to treat venous thrombosis outperformed enoxaparin without increased bleeding risk.…”

What Is the Future of Factor XI Inhibitors?

“…Exploratory meta-analyses using postoperative venous thromboembolism and clinically relevant bleeding (the composite of major and clinically relevant nonmajor bleeding) for the efficacy and safety analysis, respectively, reported a 40% to 50% reduction in venous thromboembolism with FXI inhibition compared with enoxaparin and a 59% reduction in bleeding. 2 Once proof-of-concept was shown, attention shifted from thromboprophylaxis to indications with greater unmet needs. In separate, phase 2 studies, fesomersen and osocimab were compared with placebo in patients with end-stage kidney disease undergoing hemodialysis, a population at high risk for atherothrombotic complica-tions and bleeding.…”

“…Exploratory meta-analyses using postoperative venous thromboembolism and clinically relevant bleeding (the composite of major and clinically relevant nonmajor bleeding) for the efficacy and safety analysis, respectively, reported a 40% to 50% reduction in venous thromboembolism with FXI inhibition compared with enoxaparin and a 59% reduction in bleeding. 2…”