Key result
Milvexian dose-dependently reduced thrombus weights by up to 66.9% compared to vehicle in a rabbit arteriovenous shunt model of venous thrombosis.
Why the study?
Factor XIa inhibition is a promising mechanism to improve the therapeutic index over current anticoagulants, prompting characterization of the novel FXIa inhibitor milvexian.
Does milvexian reduce thrombus weight in a rabbit arteriovenous shunt model of venous thrombosis?
Does milvexian reduce thrombus weight in a rabbit arteriovenous shunt model of venous thrombosis?
Effect estimate: 66.9% reduction
p-value: p=<0.001
In a rabbit AV shunt model, the FXIa inhibitor milvexian dose-dependently reduced venous thrombus weight and prolonged aPTT without affecting PT or TT, supporting its antithrombotic efficacy.
Supports advancing FXIa inhibitors toward human trials; leaves open clinical efficacy and safety.
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.
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Li et al. (2023) studied Venous thrombosis. Milvexian vs. Vehicle was evaluated on Thrombus weight (66.9% reduction, p=<0.001). Milvexian dose-dependently reduced thrombus weights by up to 66.9% compared to vehicle in a rabbit arteriovenous shunt model of venous thrombosis.
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