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

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  • Simon J. Wilson
    From the British Heart Foundation Centre for Cardiovascular Science (S.J.W., D.E.N.), Medical Research Council Centre for Inflammation Research (J.R., S.C.), and Edinburgh College of Medicine (T.J.G.), University of Edinburgh, United Kingdom; Bristol Myers Squibb, Princeton, NJ (F.A.I., Z.W., M.C., S.G., X.M., J.Y.); and Royal Infirmary of Edinburgh, United Kingdom (H.N.).
  • Fraz A. Ismat
    From the British Heart Foundation Centre for Cardiovascular Science (S.J.W., D.E.N.), Medical Research Council Centre for Inflammation Research (J.R., S.C.), and Edinburgh College of Medicine (T.J.G.), University of Edinburgh, United Kingdom; Bristol Myers Squibb, Princeton, NJ (F.A.I., Z.W., M.C., S.G., X.M., J.Y.); and Royal Infirmary of Edinburgh, United Kingdom (H.N.).
  • Zhaoqing Wang
    From the British Heart Foundation Centre for Cardiovascular Science (S.J.W., D.E.N.), Medical Research Council Centre for Inflammation Research (J.R., S.C.), and Edinburgh College of Medicine (T.J.G.), University of Edinburgh, United Kingdom; Bristol Myers Squibb, Princeton, NJ (F.A.I., Z.W., M.C., S.G., X.M., J.Y.); and Royal Infirmary of Edinburgh, United Kingdom (H.N.).
  • Michael Cerra
    From the British Heart Foundation Centre for Cardiovascular Science (S.J.W., D.E.N.), Medical Research Council Centre for Inflammation Research (J.R., S.C.), and Edinburgh College of Medicine (T.J.G.), University of Edinburgh, United Kingdom; Bristol Myers Squibb, Princeton, NJ (F.A.I., Z.W., M.C., S.G., X.M., J.Y.); and Royal Infirmary of Edinburgh, United Kingdom (H.N.).
  • Hafid Narayan
    From the British Heart Foundation Centre for Cardiovascular Science (S.J.W., D.E.N.), Medical Research Council Centre for Inflammation Research (J.R., S.C.), and Edinburgh College of Medicine (T.J.G.), University of Edinburgh, United Kingdom; Bristol Myers Squibb, Princeton, NJ (F.A.I., Z.W., M.C., S.G., X.M., J.Y.); and Royal Infirmary of Edinburgh, United Kingdom (H.N.).
  • Jennifer Raftis
    From the British Heart Foundation Centre for Cardiovascular Science (S.J.W., D.E.N.), Medical Research Council Centre for Inflammation Research (J.R., S.C.), and Edinburgh College of Medicine (T.J.G.), University of Edinburgh, United Kingdom; Bristol Myers Squibb, Princeton, NJ (F.A.I., Z.W., M.C., S.G., X.M., J.Y.); and Royal Infirmary of Edinburgh, United Kingdom (H.N.).
  • Timothy J. Gray
    From the British Heart Foundation Centre for Cardiovascular Science (S.J.W., D.E.N.), Medical Research Council Centre for Inflammation Research (J.R., S.C.), and Edinburgh College of Medicine (T.J.G.), University of Edinburgh, United Kingdom; Bristol Myers Squibb, Princeton, NJ (F.A.I., Z.W., M.C., S.G., X.M., J.Y.); and Royal Infirmary of Edinburgh, United Kingdom (H.N.).
  • Shea Connell
    From the British Heart Foundation Centre for Cardiovascular Science (S.J.W., D.E.N.), Medical Research Council Centre for Inflammation Research (J.R., S.C.), and Edinburgh College of Medicine (T.J.G.), University of Edinburgh, United Kingdom; Bristol Myers Squibb, Princeton, NJ (F.A.I., Z.W., M.C., S.G., X.M., J.Y.); and Royal Infirmary of Edinburgh, United Kingdom (H.N.).
  • Samira Garonzik
    From the British Heart Foundation Centre for Cardiovascular Science (S.J.W., D.E.N.), Medical Research Council Centre for Inflammation Research (J.R., S.C.), and Edinburgh College of Medicine (T.J.G.), University of Edinburgh, United Kingdom; Bristol Myers Squibb, Princeton, NJ (F.A.I., Z.W., M.C., S.G., X.M., J.Y.); and Royal Infirmary of Edinburgh, United Kingdom (H.N.).
  • Xuewen Ma
    From the British Heart Foundation Centre for Cardiovascular Science (S.J.W., D.E.N.), Medical Research Council Centre for Inflammation Research (J.R., S.C.), and Edinburgh College of Medicine (T.J.G.), University of Edinburgh, United Kingdom; Bristol Myers Squibb, Princeton, NJ (F.A.I., Z.W., M.C., S.G., X.M., J.Y.); and Royal Infirmary of Edinburgh, United Kingdom (H.N.).
  • Jing Yang
    From the British Heart Foundation Centre for Cardiovascular Science (S.J.W., D.E.N.), Medical Research Council Centre for Inflammation Research (J.R., S.C.), and Edinburgh College of Medicine (T.J.G.), University of Edinburgh, United Kingdom; Bristol Myers Squibb, Princeton, NJ (F.A.I., Z.W., M.C., S.G., X.M., J.Y.); and Royal Infirmary of Edinburgh, United Kingdom (H.N.).
  • David E. Newby
    From the British Heart Foundation Centre for Cardiovascular Science (S.J.W., D.E.N.), Medical Research Council Centre for Inflammation Research (J.R., S.C.), and Edinburgh College of Medicine (T.J.G.), University of Edinburgh, United Kingdom; Bristol Myers Squibb, Princeton, NJ (F.A.I., Z.W., M.C., S.G., X.M., J.Y.); and Royal Infirmary of Edinburgh, United Kingdom (H.N.).

説明

<jats:sec> <jats:title>Objective—</jats:title> <jats:p>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.</jats:p> </jats:sec> <jats:sec> <jats:title>Approach and Results—</jats:title> <jats:p> 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 ( <jats:italic>P</jats:italic> <0.001 for all). Compared with pretreatment, total thrombus area (μm <jats:sup>2</jats:sup> /mm) at high shear was reduced by 29.2% (95% confidence interval, 18.3%–38.7%; <jats:italic>P</jats:italic> <0.001) at 2 hours and by 21.4% (9.3%–32.0%; <jats:italic>P</jats:italic> =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%; <jats:italic>P</jats:italic> <0.001) at 2 hours and 23.3% (5.1%–38.0%; <jats:italic>P</jats:italic> =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 ( <jats:italic>P</jats:italic> =nonsignificant). BMS-986120 administration was not associated with an increase in coagulation times or serious adverse events. </jats:p> </jats:sec> <jats:sec> <jats:title>Conclusions—</jats:title> <jats:p>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.</jats:p> </jats:sec> <jats:sec> <jats:title>Clinical Trial Registration—</jats:title> <jats:p> URL: <jats:ext-link xmlns:xlink="http://www.w3.org/1999/xlink" ext-link-type="uri" xlink:href="http://www.clinicaltrials.gov">http://www.clinicaltrials.gov</jats:ext-link> . Unique identifier: NCT02439190. </jats:p> </jats:sec>

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