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: 8694084
• 负责人: ATHAN KULIOPULOS
• 金额: $ 201.39万
• 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/8694084
• 关键词: Acute; Adverse effects; Agonist; Animal Model; Animals; Atherosclerosis; Award; Baltimore; Binding; 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

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 这一高危患者群体中的支架内血栓形成和复发性 Ml。 蛋白酶激活受体-1 (PARI) 已成为调节 PCI 和 ACS 期间凝血酶诱导的血小板活化的新治疗靶点。除了凝血酶激活经典的 PARI 之外，我们最近还发现了一种由基质金属蛋白酶 1 (MMP-1) 驱动的新型凝血机制。我们发现，血小板暴露于血管壁胶原蛋白后，MMP-1 以自分泌方式激活 PARI。针对这种金属蛋白酶受体系统的药物可以为治疗动脉粥样硬化血栓性疾病和 ACS 患者提供一种新方法。为了阻断血小板的凝血酶和 MMP-1 激活而不干扰凝血酶的正常止血功能，我们将使用 PZ-128，这是一种一流的 PARI 细胞内抑制剂。我们开发了新型“Pepducin”技术，作为一种新的双重治疗策略，可抑制 PCI 患者中凝血酶-PARI 和 MMP1-PAR1 驱动的动脉血栓形成。 Pepducins 是脂化肽，特异性靶向其同源受体的细胞质表面并中断内部 G 蛋白的信号传导。在这次转化之旅的第一阶段 计划中，我们成功配制、合成并纯化了 50 g GMP 量的 PZ-128。 PZ-128 极其稳定，并已根据良好实验室规范 (GLP) 在非人类灵长类动物和其他动物中进行了广泛测试，以确保其安全性和耐受性，以及阻断 PARI 依赖性血小板活化和动脉血栓形成的能力。 PZ-128 安全且耐受性良好，并具有非常有利的药代动力学 (PK) 和药效 (PD) 特性。在 TRIP 计划第二阶段的第一年，我们将进行一项首次人体 I 期研究，以在 34 名健康志愿者中证明 PZ-128 的安全性、耐受性和 PD 抗血小板作用。在第 2-5 年，我们将与我们经验丰富的介入心脏病学临床试验同事：巴尔的摩的 Gurbel 博士、波士顿的 Kimmelstiel 博士和波士顿的 Kereiakes 博士，对 800 名 PCI 患者进行多中心随机、双盲、安慰剂对照、剂量递增的 II 期研究（凝血酶受体抑制性 Pepducin (TRIP)-PCI）。 辛辛那提。终点将是安全性和长达6个月的缺血事件的评估（MACE：死亡。M1、紧急血运重建）、心肌坏死标志物以及冠状动脉血流、血浆proMMPI、凝血酶（TAT）和血小板功能的血管造影评估。相关性（参见说明）：根据美国心脏协会提供的最新数据，冠心病仍然是美国唯一的主要死亡原因。鉴于动脉粥样硬化血栓形成的高患病率、高 M1 和死亡率以及不良反应（出血和其他安全问题）的发生率，对以 PZ-128 为代表的新疗法的需求仍然很高，未得到满足，该疗法可以靶向激活血小板而不过度影响止血。