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

基本信息

批准号：
8475397
负责人：
ATHAN KULIOPULOS
金额：
$ 205.58万
依托单位：
TUFTS MEDICAL CENTER
依托单位国家：
美国
项目类别：
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/8475397
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 Kinetics Drug Targeting 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

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 Kinetics Drug Targeting 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

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项目摘要

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）和经皮冠状动脉干预措施（PCI）期间冠状动脉血栓形成事件（PCI）的出现是严重取决于反应性血小板。抗血小板疗法在防止在这一高风险患者组中，支架血栓形成和复发ML。蛋白酶激活的受体1（PARI）已成为一种新的治疗靶标，用于调节PCI和ACS期间凝血酶诱导的血小板激活。除了凝血酶的经典pari激活外，我们最近还确定了一种由基质金属蛋白酶1（MMP-1）驱动的新型血液凝血机制。我们发现，在血小板暴露于血管壁上胶原蛋白后，MMP-1以自分泌方式激活Pari。针对金属蛋白酶受体系统的药物可以提供一种治疗动脉粥样硬化疾病和ACS患者的新方法。为了阻止血小板的凝血酶和MMP-1激活，而不会干扰凝血酶的正常止血功能，我们将使用PZ-128（PZ-128），这是PARI的第一类抑制剂。我们将新颖的“遍布蛋白”技术开发为一种新的双重治疗策略，以抑制PCI患者的凝血酶PARI和MMP1-PAR1驱动的动脉血栓形成。腹膜蛋白是脂质的肽，这些肽特异性地靶向其同源受体的细胞质表面，并在内部分离的G蛋白中中断信号传导。在这次翻译之旅的第一阶段程序，我们成功制定，合成和纯化了50 g GMP的PZ-128。 PZ-128非常稳定，并且在非人类灵长类动物和其他动物的良好实验室实践（GLP）下进行了广泛的测试，以确保安全性和耐受性，并具有阻止Pari依赖性血小板激活和动脉血栓形成的能力。 PZ-128是安全且耐受性良好的，具有高度有利的药代动力学（PK）和药效学（PD）特性。在旅行计划的第二阶段的第一年中，我们将进行第一阶段的第一阶段研究，以证明PZ-128在34名健康志愿者中的安全性，耐受性和PD抗血小板效应。在2 - 5年中，我们将对800名PCI患者（凝血酶受体抑制性遍布性遍布pepducin（Trip）-PCI）进行多个中心的随机，双盲，上升剂量，II期研究，并通过我们经验丰富的介入心脏心脏病学临床试验同事：Kimmelstiel博士和Kimmelstiel博士，Bosteiel博士在Baltimore博士中辛辛那提。终点将是长达6个月的缺血事件的安全性和评估（MACE：死亡。ML，紧急血运重建），心肌坏死的标志和冠状动脉血流，血浆Prommpi，凝血酶，凝血酶（TAT）和血小板功能的血管造影评估。相关性（请参阅说明）：在AHA提供的最新数据中，冠状动脉疾病仍然是美国的唯一主要死亡原因。鉴于动脉粥样硬化，高ML和死亡率的高流行以及不良反应的发生率（出血和其他安全问题），PZ-128的例证新疗法仍然很高的未满足需要，可以靶向血浆而不会产生不适当地影响止痛的血浆。