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: 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
• 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

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（由申请方提供）：急性冠状动脉综合征（ACS）和经皮冠状动脉介入治疗（PCI）期间冠状动脉血栓形成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血小板减少性紫癜中起着重要作用。 支架内血栓形成和MI复发。 蛋白酶激活受体-1（PARI）已成为PCI和ACS中调节凝血酶诱导的血小板活化的新的治疗靶点。除了经典的PARI激活凝血酶，我们最近确定了一种新的凝血机制，是由基质金属蛋白酶-1（MMP-1）。我们发现，MMP-1激活PARI自分泌的方式后，血小板暴露于血管壁的胶原蛋白。针对这种金属蛋白酶-受体系统的药物可能为治疗动脉粥样硬化血栓形成疾病和ACS患者提供一种新的方法。为了阻断凝血酶和MMP-1对血小板的激活而不干扰凝血酶的正常止血功能，我们将使用PZ-128，一种一流的PARI细胞内抑制剂。我们已经开发了我们的新的“Pepducin”技术作为一种新的双重治疗策略，以抑制PCI患者中凝血酶-PAR 1和MMP 1-PAR 1驱动的动脉血栓形成。 肽蛋白是脂化肽，其特异性靶向其同源受体的细胞质表面并中断向内部定位的G蛋白的信号传导。在这个翻译TRIP的第一阶段， 计划中，我们成功配制、合成和纯化了50 g GMP量的PZ-128。PZ-128非常稳定，并且已经根据非人灵长类动物和其他动物的药物非临床研究质量管理规范（GLP）进行了广泛的安全性和耐受性测试，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，具有非常有利的药代动力学（PK）和药效学（PD）特性。在TRIP项目第二阶段的第一年，我们将进行一项首次人体I期研究，以证明PZ-128在34名健康志愿者中的安全性、耐受性和PD抗血小板作用。在第2-5年，我们将与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博士和辛辛那提的Kereiakes博士）在800例PCI患者中开展一项多中心、随机、双盲、安慰剂对照、剂量递增的II期研究（凝血酶受体抑制性肽蛋白（TRIP）-PCI）。终点将是安全性和长达6个月的缺血性事件评估（MACE：死亡。MI，紧急血运重建）、心肌坏死标志物和冠状动脉血流的血管造影评估、血浆proMMPI、凝血酶（达特）和血小板功能。相关性（见说明）：在AHA提供的最新数据中，冠心病仍然是美国唯一的主要死亡原因。考虑到动脉粥样硬化血栓形成的高患病率、高MI和死亡率以及不良反应（出血和其他安全性问题）的发生率，对于新的治疗剂（如PZ-128所例示的，其可以靶向血小板活化而不过度影响止血）仍然存在高度未满足的需求。