Abstract Number: PB0121
Meeting: ISTH 2020 Congress
Background: Factor XIa (FXIa) is a promising antithrombotic target. BMS-986177/JNJ-70033093 (BMS-177) is an orally-bioavailable, reversible and direct inhibitor of human and rabbit FXIa with Ki of 0.11, and 0.38 nM, respectively.
Aims: The antithrombotic and bleeding time (BT) effects of BMS-177 were characterized in rabbits.
Methods: Efficacy of BMS-177 was evaluated in the prevention- and treatment-mode in the rabbit model of electrically-mediated-carotid-arterial-thrombosis. In the prevention-mode, BMS-177 or vehicle was administered as IV bolus plus infusion from 30 min before thrombosis initiation until the end of the experiment. In the treatment-mode, growth of thrombus was initiated first for 15 min before administration of BMS-177 or vehicle. Carotid blood flow (CBF) and thrombus weight reduction (TWR) were used as markers of efficacy. In addition, effects of BMS-177 alone and in combination of aspirin on hemostasis were assessed in a provoked cuticle BT model.
Results: In the prevention-mode, BMS-177 given at 0.063+0.04, 0.25+0.17 and 1+0.67 mg/kg+mg/kg/h produced a preservation of CBF by 32±6*, 54±10* and 76±6* and TWR by 15±10*, 45±2* and 70±4%*, respectively (*P< 0.05, n=6 per dose). In the treatment-mode, after initiation of thrombosis for 15 min, CBF was gradually decreased to 40% of control levels. BMS-177 was then administered to arrest growth of preexisting thrombus. CBF at 90 min averaged 1±0.3, 39±10 and 66±2%* in the groups treated with vehicle and with BMS-177 (mg/kg±mg/kg/h) at 0.25+0.17 and 1+0.67, respectively (*P < 0.05 vs. vehicle, n=6 per group). BMS-177 increased ex vivo activated partial thromboplastin time without changing prothrombin time. The combination of BMS-177 at 1+0.67 mg/kg+mg/kg/h and aspirin at 4 mg/kg/h IV resulted in no additional increases in BT (vs. monotherapy options).
Conclusions: BMS-177 is an effective antithrombotic agent with limited impact on hemostasis even when combined with aspirin in rabbits. BMS-177 is currently in Phase 2 clinical trials.
To cite this abstract in AMA style:Wong P, Crain E, Dilger A, Wexler R, Ewing W, Gordon D, Luettgen J. Small-Molecule Factor XIa Inhibitor, BMS-986177/JNJ-70033093, Prevents and Treats Arterial Thrombosis in Rabbits at Doses that Preserve Hemostasis [abstract]. Res Pract Thromb Haemost. 2020; 4 (Suppl 1). https://abstracts.isth.org/abstract/small-molecule-factor-xia-inhibitor-bms-986177-jnj-70033093-prevents-and-treats-arterial-thrombosis-in-rabbits-at-doses-that-preserve-hemostasis/. Accessed November 30, 2021.
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