Determination of the Potential Clinical Benefits of Small Molecule Factor XIa Inhibitors in Arterial Thrombosis

Abstract

Anticoagulants are the mainstay for the prevention and treatment of thrombosis. However, bleeding complications remain a primary concern. Recent advances in understanding the contribution of activated factor XI (FXIa) in arterial thrombosis with a limited impact on hemostasis have led to the development of several FXIa-targeting modalities. Injectable agents including monoclonal antibodies and antisense oligonucleotides against FXIa have been primarily studied in venous thrombosis. The orally active small molecules that specifically inhibit the active site of FXIa are currently being investigated for their antithrombotic activity in both arteries and veins. This review focuses on a discussion of the potential clinical benefits of small molecule FXIa inhibitors, mainly asundexian and milvexian, in arterial thrombosis based on their pharmacological profiles and the compelling results of phase 2 clinical studies. The preclinical and epidemiological basis for the impact of FXIa in hemostasis and arterial thrombosis is also addressed. In recent clinical study results, asundexian appears to reduce ischemic events in patients with myocardial infarction and minor-to-moderate stroke, whereas milvexian possibly provides benefits in patients with minor stroke or high-risk transient ischemic attack (TIA). In addition, asundexian and milvexian had a minor impact on hemostasis even in combination with dual-antiplatelet therapy. Other orally active FXIa inhibitors also produce antithrombotic activity in vivo with low bleeding risk. Therefore, FXIa inhibitors might represent a new class of direct-acting oral anticoagulants (DOACs) for the treatment of thrombosis, although the explicit clinical positions of asundexian and milvexian in patients with ischemic stroke, high-risk TIA, and coronary artery disease require confirmation from the outcomes of ongoing phase 3 trials.

Distinct pleiotropic effects of direct oral anticoagulants on cultured endothelial cells: a comprehensive review

“…The most promising class of compounds is FXIa inhibitors, which target the coagulation cascade upstream of the currently existing DOACs. Some of these compounds, such as asundexian and milvexian, are currently in phase 3 clinical trials, and there is evidence that they can inhibit thrombosis while preserving hemostasis ( Schumacher et al, 2010 ; Muscente and De Caterina, 2023 ; Wichaiyo et al, 2023 ). Emerging preclinical evidence suggests that FXIa inhibitors may exert pleiotropic effects, such as anti-inflammatory and anti-atherogenic ( Ngo et al, 2021 ).…”

Factor XI Inhibitors: A New Horizon in Anticoagulation Therapy

“…In animal models, factor XI inhibition has shown a significant reduction in thrombus growth rate, overall mass, and thrombo-occlusion in arterial thrombosis settings [ 36 ]. The benefits are attributed to the crosstalk between coagulation and platelets, with the common pathway (amplified by factor XI) playing a crucial role in platelet stimulation and thrombus formation [ 37 ]. Preclinical evidence also indicates various other benefits of targeting factor XI for preventing arterial thrombosis, including reduced infarct size, lower inflammation, endothelial dysfunction, and reactive oxygen species; diminished thrombus growth and inflammation; and slowed plaque progression and reduced macrophage infiltration in atherosclerotic plaque [ 37 ].…”

Design, Synthesis, and Evaluation of New Hybrid Derivatives of 5,6-Dihydro-4H-pyrrolo[3,2,1-ij]quinolin-2(1H)-one as Potential Dual Inhibitors of Blood Coagulation Factors Xa and XIa

“…At the same time, in recent years there has been increasing interest by the scientific community in the internal pathway of blood coagulation, showing the importance of its contribution to thrombosis [ 19 , 20 , 21 ]. Increasing evidence suggests that factor XIa, which belongs to the intrinsic coagulation activation pathway, is an attractive target [ 21 , 22 , 23 , 24 ]. FXIa is a long-lived factor, which can circulate in the bloodstream for a long time and plays an important role in thrombosis.…”