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CC BY 4.0 · TH Open 2023; 07(02): e97-e104
DOI: 10.1055/a-2061-3311
Original Article

Antithrombotic Effects of the Novel Small-Molecule Factor XIa Inhibitor Milvexian in a Rabbit Arteriovenous Shunt Model of Venous Thrombosis

Xinkang Wang 
1   Cardiovascular & Metabolism Therapeutic Area, Janssen Research & Development, LLC, Spring House, Pennsylvania, United States
,
Qiu Li
1   Cardiovascular & Metabolism Therapeutic Area, Janssen Research & Development, LLC, Spring House, Pennsylvania, United States
,
Fuyong Du
1   Cardiovascular & Metabolism Therapeutic Area, Janssen Research & Development, LLC, Spring House, Pennsylvania, United States
,
Neetu Shukla
2   Formulation, Janssen Research & Development, LLC, Spring House, Pennsylvania, United States
,
Andrea R. Nawrocki
1   Cardiovascular & Metabolism Therapeutic Area, Janssen Research & Development, LLC, Spring House, Pennsylvania, United States
,
Madhu Chintala
1   Cardiovascular & Metabolism Therapeutic Area, Janssen Research & Development, LLC, Spring House, Pennsylvania, United States
› Institutsangaben Funding This study was supported by Bristol Myers Squibb and Janssen Research & Development, LLC. Editorial support was provided by Michael Henretty of Lumanity Communications Inc. and was funded by Bristol Myers Squibb and Janssen Global Services, LLC.
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Abstract

Background Factor XIa (FXIa) is an emerging therapeutic target, and FXIa inhibition is a promising mechanism to improve therapeutic index over current anticoagulants. Milvexian (BMS-986177/JNJ-70033093) is an oral small-molecule FXIa inhibitor.

Objective Milvexian's antithrombotic efficacy was characterized in a rabbit arteriovenous (AV) shunt model of venous thrombosis and compared with the factor Xa inhibitor apixaban and the direct thrombin inhibitor dabigatran.

Methods The AV shunt model of thrombosis was conducted in anesthetized rabbits. Vehicle or drugs were administered as intravenous bolus plus a continuous infusion. Thrombus weight was the primary efficacy endpoint. Ex vivo activated partial thromboplastin time (aPTT), prothrombin time (PT), and thrombin time (TT) were measured as the pharmacodynamic responses.

Results Milvexian dose dependently reduced thrombus weights by 34.3 ± 7.9, 51.6 ± 6.8 (p < 0.01; n = 5), and 66.9 ± 4.8% (p < 0.001; n = 6) versus vehicle at 0.25 + 0.17, 1.0 + 0.67, and 4.0 ± 2.68 mg/kg bolus + mg/kg/h infusion, respectively. Ex vivo clotting data supported a dose-dependent prolongation of aPTT (with 1.54-, 2.23-, and 3.12-fold increases from baseline upon the AV shunt start), but no changes in PT and TT. Dose-dependent inhibition in thrombus weight and clotting assays was also demonstrated for both apixaban and dabigatran as the references for the model validation.

Conclusion Results demonstrate that milvexian is an effective anticoagulant for prevention of venous thrombosis in the rabbit model, which supports the utility of milvexian in venous thrombosis, as seen in the phase 2 clinical study.

Keywords

anticoagulants - factor XI - thrombosis - models - animal - pharmacology

Authorship Details

Xinkang Wang contributed to the study design and execution, as well as drafted the manuscript. Qiu Li contributed the in-life study and data analysis. Fuyong Du contributed to the in-life study, ex vivo assays, and data analysis. Neetu Shukla provided the formulation support. Andrea R. Nawrocki contributed to the study design and manuscript revision. Madhu Chintala contributed to the study design, data interpretation, and manuscript revision. All the authors reviewed and approved the final manuscript for submission.




Publikationsverlauf

Eingereicht: 02. November 2022

Angenommen: 20. März 2023

Accepted Manuscript online:
23. März 2023

Artikel online veröffentlicht:
24. April 2023

© 2023. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/)

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 

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