Pharmacological profile of asundexian, a novel, orally bioavailable inhibitor of factor XIa

Abstract

Background: Activated coagulation factor XI (FXIa) contributes to the development and propagation of thrombosis but plays only a minor role in hemostasis; therefore, it is an attractive antithrombotic target. Objectives:To evaluate the pharmacology of asundexian (BAY 2433334), a small molecule inhibitor targeting FXIa, in vitro and in various rabbit models. Methods:The effects of asundexian on FXIa activity, selectivity versus other proteases, plasma thrombin generation, and clotting assays were evaluated. Antithrombotic effects were determined in FeCl 2 -and arterio-venous (AV) shunt models. Asundexian was administered intravenously or orally, before or during thrombus formation, and with or without antiplatelet drugs (aspirin and ticagrelor). Potential effects of asundexian on bleeding were evaluated in ear-, gum-, and liver injury models.Results: Asundexian inhibited human FXIa with high potency and selectivity. It reduced FXIa activity, thrombin generation triggered by contact activation or low concentrations of tissue factor, and prolonged activated partial thromboplastin time in human, rabbit, and various other species, but not in rodents. In the FeCl 2 -injury models, asundexian reduced thrombus weight versus control, and in the arterial model when added to aspirin and ticagrelor. In the AV shunt model, asundexian reduced thrombus weight when administered before or during thrombus formation. Asundexian alone or in combination with antiplatelet drugs did not increase bleeding times or blood loss in any of the models studied. Conclusions:Asundexian is a potent oral FXIa inhibitor with antithrombotic efficacy in arterial and venous thrombosis models in prevention and intervention settings, without increasing bleeding.

A Multicenter, Phase 2, Randomized, Placebo-Controlled, Double-Blind, Parallel-Group, Dose-Finding Trial of the Oral Factor XIa Inhibitor Asundexian to Prevent Adverse Cardiovascular Outcomes After Acute Myocardial Infarction

“…conclusion is supported by the results of experimental and animal studies as well as experience in patients with congenital FXI deficiency who appear to be protected against ischemic events but have little or no increased risk of bleeding. 12 The potential for dissociating the risks of thrombosis and bleeding is supported by the results of phase 2 and 3 trials involving the use of antisense oligonucleotides, monoclonal antibodies, and a small molecule that targets FXIa. [13][14][15][16] Asundexian is a highly bioavailable oral direct selective FXIa inhibitor with a terminal half-life of 14 to 17 hours, supporting once-daily dosing.…”

Commentary on “Pharmacological profile of asundexian, a novel, orally bioavailable inhibitor of factor XIa”: Small molecule factor XIa inhibitor asundexian allows for safer anticoagulation

“…Dr. Stefan Heitmeier’s team 12 at Bayer has developed the small molecule inhibitor of human FXIa asundexian. In their current study they thoroughly characterize asundexian anticoagulant activities in human plasma.…”

Factor XI, a potential target for anticoagulation therapy for venous thromboembolism

“…Asundexian is an orally available, direct small molecule that specifically inhibits FXIa and significantly reduces FXIa activity, prolongs the aPTT, decreases the weight of arteriovenous thrombus, and is independent of antiplatelet drugs ( 100 ). The published phase II clinical trial was a double-blind, multicenter study in 753 patients over 45 years of age with atrial fibrillation ( 30 ).…”