Abstract Number: PB0041
Meeting: ISTH 2021 Congress
Background: Factor Xia (FXIa) inhibition is a promising therapeutic approach with the potential for an improved therapeutic index over currently approved oral anticoagulants. However, reversal of anticoagulation will be required in situations of unexpected major bleeding or for emergency surgery.
Aims: Milvexian is a novel small molecule inhibitor of FXIa currently in Phase II clinical trials. This study evaluated the feasibility of non-specific reversal agents and recombinant activated factor VII to reverse the antithrombotic effects of milvexian in a rabbit model of arterial-venous (AV)- shunt thrombosis.
Methods: The AV-shunt model was conducted in anesthetized rabbits. Based on a prior efficacy dose-response study, the milvexian dose of 4.0 mg/kg bolus + 2.68 mg/kg/h infusion was selected and various doses of FEIBA (0, 5, 25, 50 and 200 Units/kg), Kcentra (0, 5, 15, 50 units/kg) or NovoSeven (10, 30, 90 μg/kg), iv, provided 5 min prior to initiation of the AV-shunt were evaluated. Thrombus weights served as the primary efficacy end-point. Blood was collected to measure activated partial thromboplastin time, prothrombin time, thrombin time, and plasma concentration of milvexian.
Results: Milvexian significantly reduced thrombus weight in the rabbit AV-shunt model, with 71.3 ± 5.2 % (p<0.001, n=8) inhibition vs. vehicle. The antithrombotic effect of milvexian in this model was completely abolished by 25 units/kg FEIBA (222% increase vs. vehicle in thrombus weight) or 30 μg/kg NovoSeven (64.3% increase), but only partially reversed by Kcentra (at the highest dose of 50 units/kg, with 58.6% inhibition). Plasma levels of milvexian were not altered in the presence of these non-specific reversal agents.
Conclusions: Our studies demonstrated that either FEIBA or NovoSeven but not Kcentra could effectively reverse the antithrombotic effects of BMS-177/JNJ-3093 in the rabbit AV-shunt model.
To cite this abstract in AMA style:Wang X, Li Q, Du F, Caruso J, Nawrocki A, Chintala M. Reversal of Antithrombotic Effects of FXIa Inhibitor Milvexian (BMS-986177/JNJ-70033093) by Non-specific Agents in a Rabbit AV-shunt Model of Thrombosis [abstract]. Res Pract Thromb Haemost. 2021; 5 (Suppl 2). https://abstracts.isth.org/abstract/reversal-of-antithrombotic-effects-of-fxia-inhibitor-milvexian-bms-986177-jnj-70033093-by-non-specific-agents-in-a-rabbit-av-shunt-model-of-thrombosis/. Accessed May 19, 2022.
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