PAR4 (Protease-Activated Receptor 4) Antagonism with BMS-986120 Inhibits Human Ex Vivo Thrombus Formation

Wilson, Simon J., Ismat, Fraz A., Wang, Zhaoqing, Cerra, Michael, Narayan, Hafid, Raftis, Jennifer, Gray, Timothy J., Connell, Shea, Garonzik, Samira, Ma, Xuewen, Yang, Jing and Newby, David E. (2018) PAR4 (Protease-Activated Receptor 4) Antagonism with BMS-986120 Inhibits Human Ex Vivo Thrombus Formation. Arteriosclerosis, Thrombosis, and Vascular Biology, 38 (2). pp. 448-456. ISSN 1079-5642

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Abstract

Objective-BMS-986120 is a novel first-in-class oral PAR4 (protease-Activated receptor 4) antagonist with potent and selective antiplatelet effects. We sought to determine for the first time, the effect of BMS-986120 on human ex vivo thrombus formation. Approach and Results-Forty healthy volunteers completed a phase 1 parallel-group PROBE trial (Prospective Randomized Open-Label Blinded End Point). Ex vivo platelet activation, platelet aggregation, and thrombus formation were measured at 0, 2, and 24 hours after (1) oral BMS-986120 (60 mg) or (2) oral aspirin (600 mg) followed at 18 hours with oral aspirin (600 mg) and oral clopidogrel (600 mg). BMS-986120 demonstrated highly selective and reversible inhibition of PAR4 agonist peptide (100 μM)-stimulated P-selectin expression, platelet-monocyte aggregates, and platelet aggregation (P<0.001 for all). Compared with pretreatment, total thrombus area (μm2/mm) at high shear was reduced by 29.2% (95% confidence interval, 18.3%-38.7%; P<0.001) at 2 hours and by 21.4% (9.3%-32.0%; P=0.002) at 24 hours. Reductions in thrombus formation were driven by a decrease in platelet-rich thrombus deposition: 34.8% (19.3%-47.3%; P<0.001) at 2 hours and 23.3% (5.1%-38.0%; P=0.016) at 24 hours. In contrast to aspirin alone, or in combination with clopidogrel, BMS-986120 had no effect on thrombus formation at low shear (P=nonsignificant). BMS-986120 administration was not associated with an increase in coagulation times or serious adverse events. Conclusions-BMS-986120 is a highly selective and reversible oral PAR4 antagonist that substantially reduces platelet-rich thrombus formation under conditions of high shear stress. Our results suggest PAR4 antagonism has major potential as a therapeutic antiplatelet strategy. Clinical Trial Registration-URL: http://www.clinicaltrials.gov. Unique identifier: NCT02439190.

Item Type: Article
Uncontrolled Keywords: antiplatelet,human,novel,protease-activated receptor 4,thrombosis,cardiology and cardiovascular medicine ,/dk/atira/pure/subjectarea/asjc/2700/2705
Faculty \ School: Faculty of Medicine and Health Sciences > Norwich Medical School
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Depositing User: LivePure Connector
Date Deposited: 15 Jan 2019 14:30
Last Modified: 18 Jul 2020 23:33
URI: https://ueaeprints.uea.ac.uk/id/eprint/69578
DOI: 10.1161/ATVBAHA.117.310104

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