Abstract 18771: Protease-Activated Receptor Type 4 (PAR-4) Antagonism With BMS-986120 Selectively Inhibits Human Thrombus Formation Under Conditions of High Shear Stress
Introduction: Despite current anti-platelet agents, many individuals continue to experience recurrent ischaemic events. BMS-986120 is a novel anti-platelet agent that antagonises protease-activated receptor type 4 (PAR-4) and may have a more favourable anti-thrombotic and bleeding profile.
Hypothesis: BMS-986120 will reduce human thrombus formation in an ex vivo (Badimon) perfusion model.
Methods: Forty (40) healthy volunteers completed a phase 1 parallel group (n=20 per group) prospective randomized open-label blinded endpoint trial. Ex vivo platelet aggregation, platelet activation and thrombus formation were measured at 0 h (pre-treatment), 2 h and 24 h after (a) oral BMS-986120 (60 mg), or (b) oral aspirin (600 mg) with a second oral dose of aspirin (600 mg) and oral clopidogrel (600 mg) at 18 h.
Results: BMS-986120 demonstrated selective and reversible inhibition of PAR-4 agonist peptide (AP) stimulated platelet aggregation, P-selectin expression and platelet-monocyte binding (Figure 1A-F). Compared to pre-treatment, BMS-986120 reduced thrombus formation at high shear by 28.1% at 2 h (change in thrombus area (Δ) 6256 [3561-8951] μm2, p<0.0001) and by 22.0% at 24 h (Δ 4889 [914-8864] μm2, p=0.013) but had no effect at low shear (p=0.55; Figure 1G). Aspirin reduced thrombus formation by 32.4% (Δ 7496 [1349-13634] μm2, p=0.014) at high shear, 16.1% (Δ 4143 [828-7458] μm2, p=0.012) at low shear, and 34.2% (Δ 7920 [2507-13332] μm2, p=0.003) at high shear in combination with clopidogrel (Figure 1H).
Conclusion: BMS-986120 selectively inhibits PAR-4 AP induced platelet activation and aggregation, and reduces human thrombus formation under high shear stress only. This profile suggests BMS-986120 has the potential to inhibit arterial thrombosis under pathological conditions while avoiding interfering with haemostatic plug formation.
Author Disclosures: S.J. Wilson: None. F.A. Ismat: Employment; Significant; Bristol Myers Squibb. H. Narayan: None. J. Raftis: None. T.J. Gray: None. M. Cerra: Employment; Significant; Bristol Myers Squibb. Z. Wang: Employment; Significant; Bristol Myers Squibb. X. Ma: Employment; Significant; Bristol Myers Squibb. J. Yang: Employment; Significant; Bristol Myers Squibb. D.E. Newby: Research Grant; Significant; British Heart Foundation.
- © 2016 by American Heart Association, Inc.