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

每年，静脉血栓栓塞症影响多达200万美国人和全球2400万人。 静脉血栓栓塞症患者的腿部有血栓(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 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。在较长的时间内，持续性肺血栓可能会导致严重的致残性并发症。 如慢性血栓栓塞性肺动脉高压和右心衰竭 85多年来，抗凝一直是PE的标准治疗方法。抗凝不起作用 溶解血栓，是治疗大量PE的不充分疗法。然而，血栓的治疗- 溶栓剂，如重组组织型纤溶酶原激活剂(r-tPA)，溶解肺血栓以 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，以及 减少血栓形成后症状的效果优于标准的抗凝治疗。然而，r-tPA样蛋白 药物会导致严重或致命的出血，而r-tPA治疗的益处只有在 面临即将死于大规模PE的患者。对于绝大多数患者来说，r-tPA治疗是不安全的， 即使是那些患有中等风险PE的患者，30天的死亡率可能高达10%。 生命，减少PE患者的复发血栓和长期并发症，翻译 Science(TSI)致力于开发一种治疗性的a2ap失活单抗(a2ap-i)作为第一个新的 自从纤溶酶原激活剂疗法首次用于人类以来，安全的溶栓剂类别&60 几年前。这种新疗法的目标是中和体内血栓溶解的主要抑制剂a2AP。 来自我们实验室和其他实验室的广泛研究表明，2AP缺乏症或a2AP-1会解除刹车 激活内源性纤溶作用溶解血栓，引发静脉血栓和肺血栓 自发性地溶解而不引起出血即使在实验性中风中，脑缺血是一种 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，挽救生命。A2ap-i具有非凡的潜力 提高PE的治疗水平。在临床前数据的基础上，我们通过与当前的比较预测 治疗，TS23治疗可显著减少右心衰竭，提高存活率，减少复发 可预防血栓形成和长期残废的肺栓塞患者。TSI目前持有IND TS23在PE中的第二阶段试验，现在聚集了领先的调查人员进行有效的试验，以评估 TS23治疗中危肺栓塞患者的安全性和有效性。

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.