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Plenary Article

New oral protease-activated receptor 4 antagonist BMS-986120: tolerability, pharmacokinetics, pharmacodynamics, and gene variant effects in humans

ORCID Icon, , , , , , , , , & ORCID Icon show all
Pages 969-978 | Received 15 Mar 2022, Accepted 08 Jun 2022, Published online: 26 Jun 2022

References

  • Coccheri S. Use and misuse of aspirin in primary cardiovascular prevention. Clin Med Insights Cardiol 2017; 11: 1179546817702149. Epub 2017/05/05. doi:10.1177/1179546817702149
  • Eikelboom JW, Hirsh J, Spencer FA, Baglin TP, Weitz JI. Antiplatelet drugs: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest 2012; 141: e89S–e119S. Epub 2012/02/15. doi:10.1378/chest.11-2293
  • Whitlock EP, Burda BU, Williams SB, Guirguis-Blake JM, Evans CV. Bleeding risks with aspirin use for primary prevention in adults: a systematic review for the U.S. Preventive Services Task Force. Ann Intern Med 2016; 164: 826–835. Epub 2016/04/12. doi:10.7326/M15-2112
  • Heuberger DM, Schuepbach RA. Protease-activated receptors (PARs): mechanisms of action and potential therapeutic modulators in PAR-driven inflammatory diseases. Thromb J 2019; 17: 4. Epub 2019/04/13. doi:10.1186/s12959-019-0194-8
  • Zontivity® (vorapaxar) [Prescribing information]. 2014. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/204886s000lbl.pdf
  • Morrow DA, Braunwald E, Bonaca MP, Ameriso SF, Dalby AJ, Fish MP, Fox KA, Lipka LJ, Liu X, Nicolau JC, et al. Vorapaxar in the secondary prevention of atherothrombotic events. N Engl J Med 2012; 366: 1404–1413. Epub 2012/03/27. doi:10.1056/NEJMoa1200933
  • Tricoci P, Huang Z, Held C, Moliterno DJ, Armstrong PW, Van de Werf F, White HD, Aylward PE, Wallentin L, Chen E, et al. Thrombin-receptor antagonist vorapaxar in acute coronary syndromes. N Engl J Med 2012; 366: 20–33. Epub 2011/11/15. doi:10.1056/NEJMoa1109719
  • Holinstat M, Voss B, Bilodeau ML, McLaughlin JN, Cleator J, Hamm HE. PAR4, but not PAR1, signals human platelet aggregation via Ca2+ mobilization and synergistic P2Y12 receptor activation. J Biol Chem 2006; 281: 26665–26674. Epub 2006/07/14. doi:10.1074/jbc.M602174200
  • Wong PC, Seiffert D, Bird JE, Watson CA, Bostwick JS, Giancarli M, Allegretto N, Hua J, Harden D, Guay J, et al. Blockade of protease-activated receptor-4 (PAR4) provides robust antithrombotic activity with low bleeding. Sci Transl Med 2017; 9. Epub 2017/01/06. doi:10.1126/scitranslmed.aaf5294
  • Wilson SJ, Ismat FA, Wang Z, Cerra M, Narayan H, Raftis J, Gray TJ, Connell S, Garonzik S, Ma X, et al. PAR4 (protease-activated receptor 4) antagonism with BMS-986120 inhibits human ex vivo thrombus formation. Arterioscler Thromb Vasc Biol 2018; 38: 448–456. Epub 2017/12/23. doi:10.1161/ATVBAHA.117.310104
  • Edelstein LC, Simon LM, Lindsay CR, Kong X, Teruel-Montoya R, Tourdot BE, Chen ES, Ma L, Coughlin S, Nieman M, et al. Common variants in the human platelet PAR4 thrombin receptor alter platelet function and differ by race. Blood 2014; 124: 3450–3458. Epub 2014/10/09. doi:10.1182/blood-2014-04-572479
  • Whitley MJ, Henke DM, Ghazi A, Nieman M, Stoller M, Simon LM, Chen E, Vesci J, Holinstat M, McKenzie SE, et al. The protease-activated receptor 4 Ala120Thr variant alters platelet responsiveness to low-dose thrombin and protease-activated receptor 4 desensitization, and is blocked by non-competitive P2Y12 inhibition. J Thromb Haemost 2018; 16: 2501–2514. Epub 2018/10/23. doi:10.1111/jth.14318
  • Yang J, Mapelli C, Wang Z, Sum CS, Hua J, Lawrence RM, Ni Y, Seiffert DA. An optimized agonist peptide of protease-activated receptor 4 and its use in a validated platelet-aggregation assay. Platelets 2022; 1–8. Epub 2022/03/29. doi:10.1080/09537104.2022.2053091
  • Chen F, Maridakis V, O’Neill EA, Beals C, Radziszewski W, de Lepeleire I, Van Dyck K, Depre M, Bolognese JA, de Hoon J, et al. A randomized clinical trial comparing point-of-care platelet function assays and bleeding time in healthy subjects treated with aspirin or clopidogrel. Platelets 2012; 23: 249–258. Epub 2011/09/17. doi:10.3109/09537104.2011.604806
  • Kraft WK, Gilmartin JH, Chappell DL, Gheyas F, Walker BM, Nagalla S, Naik UP, Horrow JC, Wrishko RE, Zhang S, et al. Effect of vorapaxar alone and in combination with aspirin on bleeding time and platelet aggregation in healthy adult subjects. Clin Transl Sci 2016; 9: 221–227. Epub 2016/06/16. doi:10.1111/cts.12405
  • Xu WF, Andersen H, Whitmore TE, Presnell SR, Yee DP, Ching A, Gilbert T, Davie EW, Foster DC. Cloning and characterization of human protease-activated receptor 4. Proc Natl Acad Sci U S A 1998; 95: 6642–6646. Epub 1998/06/17. doi:10.1073/pnas.95.12.6642
  • Griffin CT, Srinivasan Y, Zheng YW, Huang W, Coughlin SR. A role for thrombin receptor signaling in endothelial cells during embryonic development. Science 2001; 293: 1666–1670. Epub 2001/09/05. doi:10.1126/science.1061259.
  • Awamleh Garcia P, Alonso Martin JJ, Jimenez Hernandez RM, Graupner Abad C, Talavera Calle P, Serrano Antolin J, Cristobal Varela C, Curcio Ruigomez A, Muniz J, Gomez Doblas JJ, et al. Abnormal electrocardiographic findings in the population older than 40 years. Prevalence and clinical significance. Results of the OFRECE study. Rev Esp Cardiol (Engl Ed) 2019; 72: 820–826. Epub 2019/02/19. doi:10.1016/j.rec.2019.01.001
  • De Bacquer D, De Backer G, Kornitzer M. Prevalences of ECG findings in large population based samples of men and women. Heart 2000; 84: 625–633. Epub 2000/11/18. doi:10.1136/heart.84.6.625
  • Edelstein LC, Simon LM, Montoya RT, Holinstat M, Chen ES, Bergeron A, Kong X, Nagalla S, Mohandas N, Cohen DE, et al. Racial differences in human platelet PAR4 reactivity reflect expression of PCTP and miR-376c. Nat Med 2013; 19: 1609–1616. Epub 2013/11/13. doi:10.1038/nm.3385
  • Morikawa Y, Kato H, Kashiwagi H, Nishiura N, Akuta K, Honda S, Kanakura Y, Tomiyama Y. Protease-activated receptor-4 (PAR4) variant influences on platelet reactivity induced by PAR4-activating peptide through altered Ca2+ mobilization and ERK phosphorylation in healthy Japanese subjects. Thromb Res 2018; 162: 44–52. Epub 2018/01/01. doi:10.1016/j.thromres.2017.12.014
  • Downes K, Astle W, McKinney H, Batista J, Kempster C, Garner S, Allegretto N, Ouwehand WH, Yang J. Platelet responsiveness to PAR4 activation in a healthy population and its inhibition by a potent and selective PAR4 antagonist. Eur Heart J 2016; 37(suppl 1): 1017.