Novel Methods for Dissolving Blood Clots

描述(由申请人提供)：每年有多达200万美国人患上静脉血栓栓塞症(VTE)。VTE是腿部的血液凝块(静脉血栓形成)，可能会扩散到肺部(肺栓塞)。据估计，每年有10%-20%的VTE患者死亡，每年的直接成本高达100亿美元。尽管在诊断和预防方面取得了进展，但抗凝这一已有50年历史的疗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：1)它不能溶解现有的血栓或血栓；2)高达50%的患者出现血栓后症状(疼痛、肿胀、慢性溃疡)；3)在高达30%的患者中，它与复发的静脉血栓栓塞症有关；4)它有显著的出血风险；以及5)它从未被证明可以挽救生命。 随机临床试验。组织纤溶酶原激活剂(Tpa)和其他溶解血液凝块的药物在预防血栓形成后症状方面效果更好，但使用的大剂量是：1)仅部分溶解血栓；2)显著增加出血风险；3) 而不是降低死亡率。显然，需要一种更安全、更有效的治疗方法，使SAV存活、减少残疾并降低与静脉血栓栓塞症相关的医疗费用。通过我们成功完成这项多阶段STTR研究的第一阶段部分，我们(翻译科学公司。[TSI])发现了一种通过一种独特的机制来溶解血栓的分子--使纤溶酶的主要抑制物失活。通过协同作用，该分子提高了TPA的效力和特异性，并避免了TPA相关的出血和神经毒性。TSI广泛的临床前研究表明，这种新的方法可以显著降低与VTE相关的发病率、死亡率和成本。在我们的第一阶段STTR可行性研究中，我们在FDA的指导下，成功地将这种分子转化为适合临床试验研究的溶解血栓的生物疗法(Lysimab)。第二阶段STTR的目标是通过以下方式显著推进Lysimab的人体试验：1)在人性化的肺栓塞模型中确定Lysimab和TPA的最佳(安全/有效)治疗剂量组合；2)在GMP条件下生产和提纯10克Lysimab；3)研究Lysimab的组织结合、安全性、药动学和药效学；以及4)向FDA提交IND。这项工作将与TSI的STTR第二阶段合作伙伴威斯康星大学一起进行。我们将利用我们大量的临床前数据，与一家拥有临床、监管和财务资源的大型制药公司合作伙伴结成战略联盟，为FDA批准Lysimab进行临床试验。我们预计，TPA/a2AP-I联合治疗每年可以增加17,000-36,000名患者的存活率，血栓后症状及其相关费用减少50%。在完成这个二期项目并将商业化责任移交给我们的战略合作伙伴后，TSI将调查这一平台技术对心脏病和中风患者的潜在好处。 与公共卫生相关：每年有多达200万美国人患上静脉血栓栓塞症(VTE)，每年的直接成本高达100亿美元。然而，尽管在诊断和预防方面取得了进展，抗凝这一已有50年历史的疗法仍然被广泛用于VTE治疗，尽管它不能溶解血栓，它与严重的副作用有关，而且从未在随机临床试验中被证明能挽救生命。这一多阶段的STTR项目寻求开发一种新的VTE疗法，可以显著减少死亡、残疾以及与VTE相关的数十亿美元的直接和间接成本。

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.