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

• 批准号: 10443870
• 负责人: Sun Yong Jeong
• 金额: $ 140.87万
• 依托单位: TRANSLATIONAL SCIENCES, INC.
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-05 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10443870
• 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; Hemorrhage; Hospitals; Hour; Human; Ischemic Stroke; Lead; Leg; Lung; Monoclonal Antibodies; Patient-Focused Outcomes; Patients; Persons; Pharmacology; Phase II Clinical Trials; Placebo Control; Plasminogen Activator; Pulmonary Embolism; Pulmonary Thromboembolism; Pulmonary artery structure; Recurrence; Research; Research Personnel; Right ventricular strain; 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; 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; right ventricular failure; stability testing; standard of care; therapeutic evaluation; thrombotic; thrombotic complications; venous thromboembolism; volunteer

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.

静脉血栓栓塞每年影响多达200万美国人和2400万人。 静脉血栓栓塞患者腿部有血块（静脉血栓形成），可能会移动到腿部。 肺（肺栓塞）。肺栓塞（PE）是医院死亡的主要原因。肺 栓子可能会严重阻塞血流，导致右心衰竭、循环衰竭和数小时内死亡 或者几天在较长的一段时间内，持续的肺栓塞可能会导致严重的，致残的并发症 如慢性血栓栓塞性肺动脉高压和右心衰竭 85年来，抗凝一直是PE的标准治疗。抗凝剂不 溶解血栓，不足以治疗大量PE。不过，血栓治疗 溶解剂，如重组组织纤溶酶原激活剂（r-tPA），溶解肺栓塞， 改善心脏压力，减少血块负担，增加肺组织吸收血液的能力， 减少血栓后症状优于标准抗凝治疗。然而，r-tPA样 药物引起严重或致命性出血，r-tPA治疗的获益仅在以下情况下超过出血风险： 因为大量肺栓塞而面临死亡的病人对于绝大多数患者，r-tPA治疗并不安全， 即使是那些中度风险PE患者，其30天死亡率可能高达10%。 减少PE患者的复发性血栓形成和长期并发症， TSI公司寻求开发一种治疗性α 2 AP失活单克隆抗体（α 2 AP-I），作为第一个新的 自纤溶酶原激活剂治疗首次用于人类以来，安全的血栓溶解剂类别> 60 年前这种新疗法的目标是中和体内血栓溶解的主要抑制剂a2 AP。 我们实验室和其他机构的广泛研究表明，a2 AP缺陷或a2 AP-I消除了制动器， 通过激活内源性纤维蛋白溶解作用，导致静脉血栓和肺栓塞， 自然溶解而不引起出血即使在实验性中风中，缺血的大脑是一个 治疗风险的敏感性测试，α 2 AP-1治疗增强血栓溶解，减少脑梗塞， 与r-tPA相比，可减少脑出血并挽救生命。a2 AP-I具有非凡的潜力， 改善PE的治疗。根据临床前数据，我们预测，与目前的 TS 23治疗可明显减少右心衰竭，提高生存率，减少复发， 血栓形成和预防肺栓塞患者长期残疾。TSI目前持有IND TS 23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，以评估 TS 23在中危肺栓塞患者中的安全性和有效性。