BACKGROUND: Milvexian (BMS-986177/JNJ-70033093) is an orally bioavailable factor 
XIa (FXIa) inhibitor currently in phase 2 clinical trials.
OBJECTIVES: To evaluate in vitro properties and in vivo characteristics of 
milvexian.
METHODS: In vitro properties of milvexian were evaluated with coagulation and 
enzyme assays, and in vivo profiles were characterized with rabbit models of 
electrolytic-induced carotid arterial thrombosis and cuticle bleeding time (BT).
RESULTS: Milvexian is an active-site, reversible inhibitor of human and rabbit 
FXIa (Ki 0.11 and 0.38 nM, respectively). Milvexian increased activated partial 
thromboplastin time (APTT) without changing prothrombin time and potently 
prolonged plasma APTT in humans and rabbits. Milvexian did not alter platelet 
aggregation to ADP, arachidonic acid, or collagen. Milvexian was evaluated for 
in vivo prevention and treatment of thrombosis. For prevention, milvexian 
0.063 + 0.04, 0.25 + 0.17, and 1 + 0.67 mg/kg+mg/kg/h preserved 32 ± 6*, 
54 ± 10*, and 76 ± 5%* of carotid blood flow (CBF) and reduced thrombus weight 
by 15 ± 10*, 45 ± 2*, and 70 ± 4%*, respectively (*p < .05; n = 6/dose). For 
treatment, thrombosis was initiated for 15 min and CBF decreased to 40% of 
control. Seventy-five minutes after milvexian administration, CBF averaged 
1 ± 0.3, 39 ± 10, and 66 ± 2%* in groups treated with vehicle and milvexian 
0.25 + 0.17 and 1 + 0.67 mg/kg+mg/kg/h, respectively (*p < .05 vs. vehicle; 
n = 6/group). The combination of milvexian 1 + 0.67 mg/kg+mg/kg/h and aspirin 
4 mg/kg/h intravenous did not increase BT versus aspirin monotherapy.
CONCLUSIONS: Milvexian is an effective antithrombotic agent with limited impact 
on hemostasis, even when combined with aspirin in rabbits. This study supports 
inhibition of FXIa with milvexian as a promising antithrombotic therapy with a 
wide therapeutic window.