Abstract Number: PB0179
Meeting: ISTH 2020 Congress
Background: FXIa inhibition is a promising drug target with the potential for an improved therapeutic index over the currently approved oral anticoagulants. BMS-986177/JNJ-70033093 (BMS-177/JNJ-3093) is a novel small molecular inhibitor of FXIa currently in Phase II clinical trials.
Aims: The current study characterized the antithrombotic efficacy of BMS-177/JNJ-3093 in a rabbit arterial-venous (AV)- shunt model of venous thrombosis and compared it to the FXa inhibitor apixaban and the direct thrombin inhibitor dabigatran.
Methods: The AV-shunt model of thrombosis was conducted in anesthetized rabbits where a shunt was placed between the femoral artery and femoral vein for 40 mins. A thread placed in the shunt served as the thrombogenic surface. Vehicle or drugs were administered as i.v. bolus plus infusion. Thrombus weights were served as the primary efficacy end-point. Blood was collected to measure activated partial thromboplastin time (aPTT), prothrombin time (PT), thrombin time (TT), and drug levels.
Results: BMS-177/JNJ-3093 significantly reduced thrombus weight in the rabbit AV-shunt model of thrombosis, with 34.3 ± 7.9, 51.6 ± 6.8 (p< 0.01, n=5) and 66.9 ± 4.8 % (p< 0.001, n=6) inhibition vs. vehicle, respectively, at 0.52 + 0.06, 1.70 + 0.06 and 5.47 + 0.53 µM BMS-177/JNJ-3093 plasma levels, with 50% inhibition of thrombus weight (ED50) at 1.60 ± 0.05 µM. Ex vivo clotting data supported a dose-dependent prolongation of aPTT (with 1.54-, 2.23- and 3.12-fold increases respectively from the baseline), but no changes in PT and TT. Dose-dependent inhibition in thrombus weight was also demonstrated for both apixaban and dabigatran, with ED50 at 0.11 ± 0.02 µM and 0.20 ± 0.02 µM, respectively.
Conclusions: These results demonstrate that BMS-177/JNJ-3093 is an effective antithrombotic agent for the prevention of venous thrombosis supporting the clinical testing in a Phase II total knee arthroplasty study.
To cite this abstract in AMA style:Wang X, Li Q, Du F, Shukla N, Nawrocki A, Chintala M. Antithrombotic Effects of a Novel Small Molecular Fxia Inhibitor BMS-986177/JNJ-70033093 in a Rabbit AV-Shunt Model of Thrombosis [abstract]. Res Pract Thromb Haemost. 2020; 4 (Suppl 1). https://abstracts.isth.org/abstract/antithrombotic-effects-of-a-novel-small-molecular-fxia-inhibitor-bms-986177-jnj-70033093-in-a-rabbit-av-shunt-model-of-thrombosis/. Accessed January 23, 2022.
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