The occurrence of coronary artery thrombotic events during acute coronary syndrome (ACS) and percutaneous coronary interventions (PCI) are critically dependent on reactive platelets. Antiplatelet therapy plays a central role in preventing stent thrombosis and recurrent Ml in this high risk group of patients. Protease-activated receptor-1 (PARI) has emerged as a new therapeutic target to regulate thrombin induced platelet activation during PCI and ACS. In addition to classical PARI activation by thrombin, we recently identified a novel blood clotting mechanism that is driven by matrix metalloprotease-1 (MMP-1). We found that MMP-1 activates PARI in an autocrine manner after platelets are exposed to collagen from the blood vessel wall. Drugs targeting this metalloprotease-receptor system could offer a new way to treat patients with atherothrombotic disease and ACS. To block both thrombin and MMP-1 activation of platelets without interfering with the normal hemostatic functions of thrombin, we will use PZ-128, a first-in-class intracellular inhibitor of PARI. We hav developed our novel 'Pepducin'technology as a new dual treatment strategy to suppress both thrombin-PARI and MMP1-PAR1 driven arterial thrombosis in PCI patients. Pepducins are lipidated peptides which specifically target the cytoplasmic surface of their cognate receptor and interrupt signaling to internally-located G proteins. In the first stage of this translational TRIP program, we successfully formulated, synthesized and purified 50 g GMP quantities of PZ-128. PZ-128 is extremely stable and has been extensively tested under Good Laboratory Practices (GLP) in non-human primates and other animals for safety and tolerability, and for ability to block PARI-dependent platelet activation and arterial thrombosis. PZ-128 is safe and well tolerated and has highly favorable pharmacokinetic (PK) and pharmacodynamic (PD) properties. In year 1 of this second stage of the TRIP program, we will conduct a first-in-human Phase I study to demonstrate the safety, tolerability, and PD antiplatelet effect of PZ-128 in 34 healthy volunteers. In years 2-5, we will conduct a multi-center randomized, double-blind, placebo-controlled, ascending dose, Phase II study in 800 PCI patients (Thrombin Receptor Inhibitory Pepducin (TRIP)-PCI) with our experienced interventional cardiology clinical trial colleagues: Dr. Gurbel in Baltimore, Dr. Kimmelstiel in Boston, and Dr. Kereiakes in Cincinnati. Endpoints will be safety and assessment of ischemic events up to 6 months (MACE: death. Ml, urgent revascularization), markers of myocardial necrosis and angiographic evaluation of coronary blood flow, plasma proMMPI, thrombin (TAT) and platelet function.

Public Health Relevance

(See Instructions): In the most recent data provided by the AHA, coronary heart disease remains the single leading cause of death in the US. Given the high prevalence of atherothrombosis, high Ml and death rates, and incidence of adverse effects (bleeding and other safety issues), there remains a high unmet need for new therapeutics as exemplified by PZ-128, that can target activation of platelets without unduly impacting hemostasis.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Specialized Center (P50)
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Special Emphasis Panel (ZHL1-CSR-H (F1))
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Kindzelski, Andrei L
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Tufts University
United States
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Austin, Karyn M; Nguyen, Nga; Javid, Golrokh et al. (2013) Noncanonical matrix metalloprotease-1-protease-activated receptor-1 signaling triggers vascular smooth muscle cell dedifferentiation and arterial stenosis. J Biol Chem 288:23105-15
Austin, Karyn M; Covic, Lidija; Kuliopulos, Athan (2013) Matrix metalloproteases and PAR1 activation. Blood 121:431-9