Novel Methods for Dissolving Blood Clots

描述（由申请人提供）：每年，多达200万美国人发生静脉血栓栓塞（VTE）。静脉血栓是腿部的血块（静脉血栓形成），可能会转移到肺部（肺栓塞）。据估计，10-20%的VTE患者死亡，每年的直接费用高达100亿美元。尽管在诊断和预防方面取得了进展，抗凝治疗（一种有50年历史的治疗方法）仍然是静脉血栓栓塞症最常用的治疗方法。抗凝的缺点包括以下：1）它不能溶解现有的凝块或血栓; 2）高达50%的患者发展血栓形成后症状（疼痛、肿胀、慢性溃疡）; 3）它与高达30%的患者中的复发性静脉血栓栓塞有关; 4）它具有显著的出血风险;以及5）它从未被证明可以在高血压患者中挽救生命。 随机临床试验。组织纤溶酶原激活剂（TPA）和其他溶血栓药物在预防血栓后症状方面效果更好，但使用的高剂量药物：1）仅部分成功溶解血栓; 2）显著增加出血风险; 3） 而不是降低死亡率。很明显，需要一种更安全、更有效的治疗方法来挽救生命，减少残疾，降低与静脉血栓栓塞相关的医疗费用。 通过成功完成本多阶段STTR研究的I期部分，我们（Translational Sciences，Inc.）[TSI]）发现了一种分子，通过一种独特的机制--灭活纤溶酶的主要抑制剂--来溶解血栓。通过协同作用，该分子增加TPA的效力和特异性，并且避免TPA相关的出血和神经毒性。TSI广泛的临床前研究表明，这种新方法可以大大降低与VTE相关的发病率、死亡率和成本。在我们的I期STTR可行性研究中，我们按照FDA的指导，成功地将这种分子转化为适用于临床试验研究的血栓溶解生物治疗剂（Lysiumab）。II期STTR的目标是通过以下方式显著推进Lysiumab向人体试验的发展：1）在肺栓塞的人源化模型中确定Lysiumab和TPA的体内最佳（安全/有效）治疗剂量组合; 2）在GMP条件下生产和纯化10 g Lysiumab; 3）研究Lysiumab的组织结合、安全性、药代动力学和药效学; 4）向FDA提交IND。这项工作将与TSI的第二阶段STTR合作伙伴威斯康星州大学一起进行。我们将利用我们大量的临床前数据，与大型制药合作伙伴建立战略联盟，这些合作伙伴拥有进行临床试验以获得FDA批准所需的临床、监管和财务资源。我们预计TPA/a2 AP-I联合治疗每年可使另外17，000 - 36，000名患者存活，血栓形成后症状及其相关费用减少>50%。在第二阶段项目完成并将商业化责任移交给我们的战略合作伙伴后，TSI将研究该平台技术对心脏病和中风患者的潜在益处。 公共卫生相关性：每年，多达200万美国人发生静脉血栓栓塞（VTE），每年的直接费用高达100亿美元。然而，尽管在诊断和预防方面取得了进展，抗凝治疗，一种50年的治疗方法，仍然广泛用于VTE治疗，尽管它不能溶解凝块，它与严重的副作用有关，并且在随机临床试验中从未被证明可以挽救生命。这个多阶段STTR项目旨在开发一种新的VTE治疗方法，可以显着减少死亡，残疾和数十亿美元的直接和间接VTE相关成本。

DESCRIPTION (provided by applicant): Each year, as many as 2 million Americans develop venous thromboembolism (VTE). VTEs are blood clots in the legs (venous thrombosis) that may travel to the lungs (pulmonary embolism). It is estimated that 10-20% of VTE patients die, and the annual direct costs are up to $10 billion. Despite advances in diagnosis and prophylaxis, anticoagulation, a 50-year-old therapy, remains the most commonly used treatment for venous thromboembolism. The drawbacks of anticoagulation include the following: 1) it does not dissolve existing clots or thrombi; 2) up to 50% of patients develop post-thrombotic symptoms (pain, swelling, chronic sores); 3) it is linked to recurrent venous thromboembolism in up to 30% of patients; 4) it has significant bleeding risk; and 5) it has never been shown to save lives in a randomized clinical trial. Tissue plasminogen activator (TPA) and other blood clot-dissolving drugs are better at preventing post-thrombotic symptoms, but the high doses used are: 1) only partially successful at dissolving blood clots; 2) significantly increase bleeding risks and, 3) do not reduce mortality. It is clear that there is a need for a safer, more-effective therapy that savs lives, reduces disability, and lowers health care costs associated with venous thromboembolism. Through our successful completion of the Phase I portion of this multi-phase STTR study, we (Translational Sciences, Inc. [TSI]) have discovered a molecule that dissolves blood clots through a unique mechanism-inactivating the major inhibitor of plasmin. Through synergism, this molecule increases the potency and specificity of TPA, and it avoids TPA-related hemorrhage and neurotoxicity. TSI's extensive pre- clinical studies indicate that this novel approach could substantially reduce the morbidity, mortality and costs associated with VTE. In our Phase I STTR feasibility studies, we successfully converted this molecule, following FDA guidance, into a clot-dissolving biologic therapeutic (Lysimab) suitable for investigation in clinical trials. The Phase II STTR goal is to significantly advance Lysimab toward human trials by: 1) determining optimal (safe/effective) therapeutic dose combinations of Lysimab and TPA in vivo in a humanized model of pulmonary embolism; 2) producing and purifying 10 g of Lysimab under GMP conditions, 3) investigating the tissue binding, safety, pharmacokinetics and pharmacodynamics of Lysimab, and 4) submitting an IND to the FDA. This work will be carried out with TSI's Phase II STTR partner, the University of Wisconsin. We will leverage our substantial pre-clinical data to form a strategic alliance with a big pharma partner with the clinical, regulatory and financial resources needed to conduct clinical trials for FDA approval of Lysimab. We project that a combination TPA/a2AP-I therapy could lead to the survival of an additional 17,000-36,000 patients per year and >50% reduction in post-thrombotic symptoms and their associated costs. Upon completion of this Phase II project and transfer of commercialization responsibilities to our strategic partner, TSI will investigate the potential benefits of this platform technology to heart and stroke victims. PUBLIC HEALTH RELEVANCE: Each year, as many as 2 million Americans develop venous thromboembolism (VTE), and the annual direct costs are up to $10 billion. Yet, despite advances in diagnosis and prophylaxis, anticoagulation, a 50-year-old therapy, remains widely used for VTE treatment despite the fact that it does not dissolve clots, it is associated with serious side-effects and, it has never been shown to save lives in a randomized clinical trial. This multi- phase STTR project seeks to develop a novel VTE therapy that could markedly reduce death, disability, and billions of dollars in direct and indirect VTE-related costs.