Background: Venous thromboembolism is a leading cause of death and disability worldwide. Targeting factor XI (FXI) may prevent thrombosis without increasing bleeding risk. Milvexian (formerly referred to as BMS-986177/JNJ-70033093) is an orally-bioavailable, small molecule that inhibits FXIa with high affinity and selectivity. In preclinical models, milvexian has shown antithrombotic activity while preserving hemostasis, and in healthy humans appears safe and well-tolerated.

Aims: Characterize the pharmacodynamic effect of milvexian on plasma clot formation and stability in vitro.

Methods: Clot formation in normal pooled plasma and in plasmas from 5 healthy individuals was initiated in the presence of tissue factor, phospholipids, CaCl₂, and varying concentrations of milvexian or buffer. Fibrinolysis experiments included tissue plasminogen activator. Reactions were monitored by turbidity. Descriptive parameters were calculated and analyzed to yield concentrations exhibiting half-maximal effects.

Results: Milvexian delayed the onset of clot formation and time to the turbidity plateau or peak, and reduced the rate of clot formation in a dose-dependent manner. Milvexian also reduced the final clot turbidity in clot formation assays and the area under the curve in fibrinolysis assays, suggesting reduced fibrin incorporation into the clots. Milvexian also shortened the clot lysis time, indicating decreased resistance of clots to fibrinolysis. Effects were seen within dose ranges achieved following oral administration in humans, demonstrating pharmacodynamic effects at pharmacologically-relevant concentrations. For most parameters, half-maximal effects on clot formation and stability were achieved between 3-4 µg/mL milvexian. Anticoagulant effects were observed at levels below functional thresholds previously associated with bleeding risk in FXI-deficient patients.

Conclusions: Milvexian delays the time to clot formation, decreases fibrin incorporation into the clot, and reduces the resistance of clots to fibrinolysis. These findings reveal the mechanism of action for a FXIa active-site inhibitor and generate hypotheses for how to achieve antithrombotic activity without increasing bleeding risk.

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ISTH Congress Abstracts - https://abstracts.isth.org/abstract/factor-xia-inhibitor-milvexian-bms-986177-jnj-70033093-suppresses-plasma-clot-formation-and-reduces-resistance-to-fibrinolysis-in-vitro/