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.

每年，静脉血栓栓塞都会影响全球多达200万美国人和2400万人。 静脉血栓栓塞患者的腿部血凝块（静脉血栓形成）可能会传播到 肺（肺栓塞）。肺栓塞（PE）是医院死亡的主要原因。肺 Emboli可能会急剧阻碍血液流动，导致右心力衰竭，循环崩溃和数小时内死亡 或几天。在较长的时间内，持续的肺栓塞可能会导致严重的并发症 例如慢性血栓栓塞性肺动脉高压和正确的心力衰竭 超过85年，抗凝一直是PE的标准疗法。抗凝没有 溶解血栓，是大规模PE的治疗方法不足。但是，用血栓治疗 溶解剂，例如重组组织纤溶酶原激活剂（R-TPA），将肺栓塞溶解至 改善心脏压力，减轻凝块负担，提高肺组织氧合血液的能力和 比标准抗凝治疗更好地降低了栓性后症状。然而，类似R-TPA 药物会导致严重或致命的出血，R-TPA治疗的益处超出了出血的风险 面临大规模PE死亡的患者。对于绝大多数患者，R-TPA疗法是不安全的， 即使在那些患有中等风险PE的患者中，其死亡率可能高达10％。 生命，减少复发性血栓形成并减少PE患者的长期并发症 科学（TSI）试图开发一种治疗性A2AP灭活的单克隆抗体（A2AP-I）作为第一个新的 由于纤溶酶原激活剂疗法首先在人类中使用纤溶酶原激活剂疗法以来的安全性，溶解剂类别 几年前。这种新疗法的目标是中和A2AP，这是体内血栓溶解的主要抑制剂。 我们实验室和其他人的广泛研究表明，A2AP缺陷或A2AP-I删除了刹车 通过激活内源性纤维蛋白溶解，引起静脉血栓和肺栓塞，通过激活血栓溶解 自发溶解而不会引起出血。即使在实验性中风中，缺血性大脑也是 对治疗风险的敏感测试，A2AP-I治疗可增强血栓溶解，减少脑梗塞， 与R-TPA相比，减少脑出血并挽救生命。 A2AP-I具有极大的潜力 改善PE的处理。根据临床前数据，我们预测，与当前相比 治疗，用TS23治疗可以显着减少右心衰竭，提高生存率，降低复发性 血栓形成并预防肺栓塞患者的长期残疾。 TSI目前拥有IND 对于PE中TS23的II期试验，现在将领先的研究人员汇总为有效的试验，以评估 TS23对中等风险肺栓塞患者的安全性和功效。