Abstract 5603: Oral Dosing of PRT060128, a Novel Direct-acting, Reversible P2Y 12 Antagonist Overcomes High Platelet Reactivity in Patients Non-responsive to Clopidogrel Therapy

Abstract

Introduction: The ADP receptor P2Y 12 plays a central role in platelet function. Clopidogrel therapy is associated with various limitations including irreversible inhibition, a delayed antiplatelet effect, wide response variability, and non-responsiveness that has been linked to adverse ischemic event occurrence. We report the first pharmacodynamic study of a single oral dose of PRT060128 (PRT128), a novel, direct-acting reversible P2Y 12 inhibitor in patients with high platelet reactivity while on maintenance dose clopidogrel therapy(75mg/d) and aspirin. Methods: Previously stented patients (n=27) on maintenance aspirin and clopidogrel therapy were screened for high platelet reactivity (HPR) defined as upper tertile 5μ M ADP-induced aggregation (>43%) based on prior studies conducted at our Center; 7/27 had HPR and were treated with a single oral dose (60 mg) of PRT128. Platelet function was assessed at baseline, 4 hours, 6 hours, and 24 hours post-dosing by light transmittance aggregometry (LTA) stimulated by 5μ M, 20 μ M ADP, and 4μ g/ml collagen; Thrombelastography PlateletMapping (MA ADP ), Accumetrics P2Y12 assay (PRU), platelet reactivity ratio (%) by vasodilator stimulated phosphoprotein phosphorylation (VASP), and Perfusion Chamber Assay (PCA). Results: Results shown in the Table represent means ± standard deviation for the 7 patients at each time point. Conclusion: Based on results using multiple pharmacodynamic assays, PRT060128 is a potent rapid-acting inhibitor of P2Y 12 that overcomes high platelet reactivity in patients non-responsive to clopidogrel therapy. The pharmacodynamic properties of this novel P2Y 12 antagonist warrant future large scale investigations to determine clinical efficacy.