TRIP-PCI: PAR1 Pepducin-Based Interventions in Arterial Thrombosis

TRIP-PCI：基于 PAR1 Pepducin 的动脉血栓形成干预措施

• 批准号: 8211892
• 负责人: ATHAN KULIOPULOS
• 金额: $ 215.98万
• 依托单位: TUFTS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-06-01 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8211892
• 关键词: Acute; Adverse effects; Agonist; Animal Model; Animals; Atherosclerosis; Award; Baltimore; Binding; Blood Clot; Blood Platelets; Blood Vessels; Blood coagulation; Blood flow; Blood specimen; Boston; Cardiology; Cardiovascular system; Cause of Death; Cavia; Cell Communication; Cessation of life; Chemistry; Clinical Trials; Coagulants; Coagulation Process; Collagen; Complex; Coronary; Coronary artery; Coronary heart disease; Data; Death Rate; Disease; Dose; Double-Blind Method; Drug Delivery Systems; Drug Kinetics; Evaluation; Event; F2R gene; Fibrinogen; GTP-Binding Proteins; Grant; Hemorrhage; Hemostatic function; High Prevalence; Human; Incidence; Inflammation; Injury; Instruction; Interstitial Collagenase; Intervention; Kidney; Lead; Life; Mediator of activation protein; Metalloproteases; Monkeys; Mus; Myocardial; Necrosis; PAR-1 Receptor; Papio; Pathology; Pathway interactions; Patients; Peptide Hydrolases; Peptides; Pharmaceutical Preparations; Pharmacodynamics; Pharmacology; Phase; Phase I Clinical Trials; Placebo Control; Plasma; Platelet Activation; Play; Play Therapy; Property; Randomized; Rattus; Reading; Recurrence; Research Design; Research Personnel; Role; Safety; Signal Transduction; Specialist; Staging; Stents; Surface; System; TNFRSF5 gene; Technology; Testing; Therapeutic; Thrombin; Thrombin Receptor; Thrombosis; Thrombus; Toxicology; Translating; Work; acute coronary syndrome; atherogenesis; atherothrombosis; autocrine; base; bivalirudin; clopidogrel; drug development; eptifibatide; experience; good laboratory practice; healthy volunteer; high risk; human GPR4 protein; inflammatory marker; inhibitor/antagonist; meetings; new therapeutic target; nonhuman primate; novel; novel therapeutics; paracrine; percutaneous coronary intervention; phase 1 study; phase 2 study; placebo controlled study; prevent; programs; receptor; small molecule; success; tirofiban; treatment strategy

DESCRIPTION (provided by applicant): 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. 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.

描述（由申请人提供）：急性冠状动脉综合征（ACS）和经皮冠状动脉介入治疗（PCI）期间冠状动脉血栓事件的发生严重依赖于反应性血小板。抗血小板治疗在预防中起着核心作用