Milvexian, an orally bioavailable, small‐molecule, reversible, direct inhibitor of factor XIa: In vitro studies and in vivo evaluation in experimental thrombosis in rabbits

Wong, Pancras C.; Crain, Earl J.; Bozarth, Jeffrey M.; Wu, Yiming; Dilger, Andrew K.; Wexler, Ruth R.; Ewing, William R.; Gordon, David; Luettgen, Joseph M.

doi:10.1111/jth.15588

Cited by 40 publications

(44 citation statements)

References 27 publications

(64 reference statements)

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“…While the described general pharmacological profile of asundexian is consistent with those of other agents targeting FXIa, including milvexian, 23 osocimab, 7,18,24 abelacimab, 25 and the antisense oligonucleotide IONIS FXI‐R x , which blocks the hepatic synthesis of FXI, 19 important differences exist in their route of administration, onset of action, and duration of effect. Asundexian and milvexian can be administered orally, whereas osocimab, abelacimab, and IONIS FXI‐R x need to be administered subcutaneously or intravenously.…”

Section: Discussionsupporting

confidence: 53%

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

Heitmeier

Visser

Tersteegen

et al. 2022

Journal of Thrombosis and Haemostasis

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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.

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Section: Discussionsupporting

confidence: 53%

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

Heitmeier

Visser

Tersteegen

et al. 2022

Journal of Thrombosis and Haemostasis

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“…This results in a FXI deficiency‐like state, in the sense that the amount of FXI available for activation in plasma is reduced. Milvexian, a macrocyclic small‐molecule inhibitor, engages the FXIa catalytic active site, where it competes for binding with natural substrates such as FIX 33,34 . Information for the TKA trials using these drugs is presented in Table 2.…”

Section: Drug Name Drug Description Mechanism Of Action Administratio...mentioning

confidence: 99%

“…Milvexian, a macrocyclic small-molecule inhibitor, engages the FXIa catalytic active site, where it competes for binding with natural substrates such as FIX. 33,34 Information for the TKA trials using these drugs is presented in Table 2. We need to be cautious when comparing results across these trials, which were conducted GAILANI and adjudicators for analyzing imaging studies.…”

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confidence: 99%

Factor XI as a target for preventing venous thromboembolism

Gailani

2022

Journal of Thrombosis and Haemostasis

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“…In [1], the typesetter did not include Figure 3C. The missing Figure 3C and the caption text are given below.…”

Section: Figurementioning

confidence: 99%

Erratum

2022

Journal of Thrombosis and Haemostasis

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Milvexian, an orally bioavailable, small‐molecule, reversible, direct inhibitor of factor XIa: In vitro studies and in vivo evaluation in experimental thrombosis in rabbits

Abstract: This is an open access article under the terms of the Creat ive Commo ns Attri butio n-NonCo mmerc ial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

Cited by 40 publications

References 27 publications

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

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

Factor XI as a target for preventing venous thromboembolism

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