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(由申请人提供)：急性冠脉综合征(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 支架血栓和复发性ML在这组高危患者中的应用。蛋白酶激活受体-1(PAI)在冠状动脉介入治疗和急性冠脉综合征中被认为是调节凝血酶诱导的血小板活化的一个新的治疗靶点。除了经典的凝血酶激活PARI外，我们最近发现了一种新的凝血机制，它是由基质金属蛋白酶-1(MMP1)驱动的。我们发现，当血小板与血管壁的胶原蛋白接触后，基质金属蛋白酶-1以自分泌的方式激活PAII。针对这种金属蛋白酶受体系统的药物可以为动脉粥样硬化性血栓性疾病和急性冠脉综合征患者的治疗提供一种新的方法。为了在不干扰凝血酶正常止血功能的情况下阻断凝血酶和基质金属蛋白酶-1的激活，我们将使用PZ-128，一种一流的PAI细胞内抑制剂。我们开发了我们的新的‘Pepducin’技术，作为一种新的双重治疗策略，可以同时抑制凝血酶-PARI和MMP1-PAR1导致的冠状动脉介入治疗患者的动脉血栓形成。Pepducins是脂化的多肽，它特异性地靶向于其同源受体的细胞质表面，并干扰内部定位的G蛋白的信号传递。在这次翻译之旅的第一阶段 计划中，我们成功地配制、合成和纯化了50g GMP量的PZ-128。PZ-128非常稳定，在良好的实验室操作规范(GLP)下，已经在非人类灵长类动物和其他动物身上进行了广泛的安全性和耐受性测试，并有能力阻止同种依赖的血小板激活和动脉血栓形成。PZ-128安全、耐受性好，具有良好的药代动力学(PK)和药效学(PD)特性。在TRIP计划第二阶段的第一年，我们将在34名健康志愿者中进行第一个人类阶段研究，以证明PZ-128的安全性、耐受性和PD抗血小板作用。在2-5年，我们将在800名经皮冠状动脉介入治疗(凝血酶受体抑制肽(TRIP)-PCI)患者中进行一项多中心随机、双盲、安慰剂对照、递增剂量的II期研究，我们有经验的介入心脏病学临床试验的同事：巴尔的摩的Gurbel博士、波士顿的Kimmelstiel博士和辛辛那提的Kereiake博士。终点将是安全性和对长达6个月的缺血事件的评估(MACE：死亡。急性血运重建)、心肌坏死标志物和冠状动脉血流的血管造影评估、血浆MMPI、凝血酶(TAT)和血小板功能。相关性(见说明)：在美国心脏病协会提供的最新数据中，冠心病仍然是美国死亡的唯一主要原因。鉴于动脉粥样硬化血栓形成的高患病率、高ML和死亡率以及不良反应(出血和其他安全问题)的发生率，对新疗法的需求仍然很高，PZ-128就是例证，这种疗法可以在不过度影响止血的情况下靶向激活血小板。