Novel α2-Antiplasmin Inactivation for Lysis of Intravascular Thrombi (NAIL-IT) Trial

新型 α2-抗纤溶酶灭活用于溶解血管内血栓 (NAIL-IT) 试验

基本信息

批准号：
10255174
负责人：
Sun Yong Jeong
金额：
$ 140.9万
依托单位：
TRANSLATIONAL SCIENCES, INC.
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-05 至 2023-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10255174
关键词：
Acute Acute myocardial infarction Address Affect Alteplase American Anticoagulation Antiplasmin Blood Blood coagulation Blood flow Brain Brain Infarction Brain hemorrhage COVID-19 patient COVID-19 treatment Cardiovascular Diseases Cessation of life Chronic Clinical Clinical Data Clinical Trials Coagulation Process Critical Illness Cyclic GMP Cytolysis Dangerousness Data Death Rate Development Dose Double-Blind Method Embolism Face Fibrin fragment D Fibrinolysis Guidelines Heart Heart failure Hemorrhage Hospitals Hour Human Ischemic Stroke Lead Leg Lung Monoclonal Antibodies Patient-Focused Outcomes Patients Pharmacology Phase II Clinical Trials Placebos Plasminogen Activator Pulmonary Embolism Pulmonary Thromboembolism Pulmonary artery structure Recurrence Research Research Personnel Risk Safety Serious Adverse Event Shock Stroke Structure of parenchyma of lung Sudden Death Symptoms Testing Therapeutic Therapeutic Embolization Thrombosis Thrombus Time Translational Research Travel United States National Institutes of Health Veins Venous Venous Thrombosis Ventricular blood pressure reduction chronic thromboembolic pulmonary hypertension disability improved improved outcome in vivo inhibitor/antagonist innovation limb ischemia male manufacturing process nonhuman primate novel novel therapeutics phase I trial phase II trial phase III trial pre-clinical pressure prevent reduce symptoms stability testing standard of care therapeutic evaluation thrombotic thrombotic complications venous thromboembolism volunteer

项目摘要

Each year venous thromboembolism affects up to 2 million Americans and 24 million people worldwide. Patients with venous thromboembolism have blood clots in the legs (venous thrombosis) that may travel to the lungs (pulmonary embolism). Pulmonary embolism (PE) is a leading cause of hospital deaths. Pulmonary emboli may acutely obstruct blood flow, causing right heart failure, circulatory collapse and death within hours or days. Over a longer period of time, persistent pulmonary emboli may cause serious, disabling complications such as chronic thromboembolic pulmonary hypertension and right heart failure For more than 85 years, anticoagulation has been standard therapy for PE. Anticoagulation does not dissolve thrombi and is an inadequate treatment for massive PE. However, treatment with a thrombus- dissolving agent, such as recombinant tissue plasminogen activator (r-tPA), dissolves pulmonary emboli to improve heart pressures, reduce clot burden, increase the ability of the lung tissue to oxygenate the blood and decrease post-thrombotic symptoms better than standard anticoagulation therapy. Nevertheless, r-tPA-like agents cause severe or fatal hemorrhage and the benefit of r-tPA therapy exceeds the risk of bleeding only in patients that face imminent death from massive PE. For the vast majority of patients, r-tPA therapy is not safe, even in those patients with intermediate-risk PE, which may have 30-day death rates as high as 10%.To save lives, reduce recurrent thrombosis and decrease long term complications in patients with PE, Translational Sciences (TSI) seeks to develop a therapeutic a2AP-inactivating monoclonal antibody (a2AP-I) as the first new class of safe, thrombus-dissolving agents since plasminogen activator therapy was first used in humans > 60 years ago. This new therapy is targeted to neutralize a2AP, the major inhibitor of thrombus dissolution in vivo. Extensive research from our lab and others has shown that a2AP deficiency, or an a2AP-I removes the brakes on thrombus dissolution by activating endogenous fibrinolysis, causing venous thrombi and pulmonary emboli to dissolve spontaneously without causing bleeding. Even in experimental stroke, where the ischemic brain is a sensitive test of therapeutic risk, a2AP-I therapy enhances thrombus dissolution, reduces brain infarction, decreases brain hemorrhage and saves lives by comparison to r-tPA. An a2AP-I has extraordinary potential for improving the treatment of PE. On the basis of pre-clinical data, we project that by comparison to current therapy, treatment with TS23 could significantly reduce right heart failure, improve survival, decrease recurrent thrombosis and prevent long-term disability in patients with pulmonary embolism. TSI currently holds an IND for Phase II trial of TS23 in PE and now brings together leading investigators for an efficient trial to assess the safety and efficacy of TS23 in patients with intermediate-risk pulmonary embolism.

每年静脉血栓栓塞影响多达 200 万美国人和全世界 2400 万人。静脉血栓栓塞患者腿部有血栓（静脉血栓），这些血栓可能会流向肺部（肺栓塞）。肺栓塞（PE）是医院死亡的主要原因。肺部栓子可能会严重阻碍血流，导致右心衰竭、循环衰竭，并在数小时内死亡或几天。在较长时间内，持续性肺栓塞可能会导致严重的致残并发症例如慢性血栓栓塞性肺动脉高压和右心衰竭 85 年多来，抗凝一直是肺栓塞的标准治疗方法。抗凝不溶解血栓，对于大量 PE 来说是不充分的治疗。然而，血栓治疗溶解剂，例如重组组织纤溶酶原激活剂（r-tPA），可溶解肺栓塞改善心脏压力，减少血栓负荷，增加肺组织给血液充氧的能力，比标准抗凝治疗更好地减少血栓后症状。尽管如此，r-tPA 样药物会导致严重或致命的出血，而 r-tPA 治疗的益处仅在以下情况下超过出血风险：因大规模PE而面临迫在眉睫的死亡的患者。对于绝大多数患者来说，r-tPA 治疗并不安全，即使是那些中危PE患者，其30天死亡率也可能高达10%。生命，减少复发性血栓形成并减少 PE 患者的长期并发症，转化 Sciences (TSI) 寻求开发一种治疗性 a2AP 失活单克隆抗体 (a2AP-I)，作为第一个新的自纤溶酶原激活剂疗法首次用于人类 > 60 以来，一类安全的血栓溶解剂几年前。这种新疗法的目标是中和a2AP，a2AP是体内血栓溶解的主要抑制剂。我们实验室和其他实验室的广泛研究表明，a2AP 缺陷或 a2AP-I 会消除刹车通过激活内源性纤溶作用来溶解血栓，引起静脉血栓和肺栓塞自然溶解，不引起出血。即使在实验性中风中，缺血性大脑也是治疗风险的敏感测试，a2AP-I疗法增强血栓溶解，减少脑梗塞，与 r-tPA 相比，可减少脑出血并挽救生命。 a2AP-I 具有非凡的潜力改善PE的治疗。根据临床前数据，我们通过与当前的比较来预测治疗，TS23 治疗可以显着减少右心衰竭，提高生存率，减少复发血栓形成并预防肺栓塞患者的长期残疾。 TSI 目前持有 IND TS23 在 PE 中的 II 期试验，现在汇集了领先的研究人员进行有效的试验来评估 TS23 在中危肺栓塞患者中的安全性和有效性。