Novel Methods for Dissolving Blood Clots

溶解血栓的新方法

• 批准号: 8252082
• 负责人: Guy L Reed
• 金额: $ 78.4万
• 依托单位: TRANSLATIONAL SCIENCES, INC.
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-01 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8252082
• 关键词: Acute; Adverse effects; Adverse event; Affect; Aftercare; Alteplase; American; Anticoagulation; Antiplasmin; Behavior; Binding; Biomanufacturing; Bioreactors; Blood Clot; Blood Coagulation Factor; Blood coagulation; Brain hemorrhage; Cessation of life; Chinese Hamster Ovary Cell; Chronic; Clinical; Clinical Data; Clinical Trials; Coagulation Process; Complication; Conduct Clinical Trials; Consumption; Cyclic GMP; Cytolysis; Development; Diagnosis; Direct Costs; Dose; Drug Kinetics; Drug usage; Embolism; Feasibility Studies; Fibrinogen; Fright; Goals; Health Care Costs; Heart; Hemorrhage; Human; Investigation; Ischemic Stroke; Lead; Leg; Legal patent; Link; Lung; Methods; Metric; Modeling; Monoclonal Antibodies; Morbidity - disease rate; Pain; Patients; Pharmaceutical Preparations; Pharmacodynamics; Phase; Plasmin Inhibitor; Plasminogen Activator; Pre-Clinical Model; Preparation; Process; Production; Prophylactic treatment; Pulmonary Embolism; Randomized Clinical Trials; Recovery; Recurrence; Research; Resources; Risk; Safety; Small Business Technology Transfer Research; Specificity; Stroke; Swelling; Symptoms; Talents; Technology; Testing; Therapeutic; Thromboembolism; Thrombosis; Thrombus; Time; Tissues; Toxicology; Translational Research; Travel; Universities; Venous; Venous Thrombosis; Wisconsin; Work; antibody engineering; base; commercialization; cost; cross reactivity; disability; drug candidate; effective therapy; human tissue; improved; in vivo; in vivo Model; inhibitor/antagonist; meetings; mortality; neurotoxicity; nonhuman primate; novel; novel strategies; pre-clinical; preclinical study; prevent; research and development; safety testing; synergism; therapeutic target

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.

描述（由申请人提供）：每年，多达 200 万美国人患有静脉血栓栓塞 (VTE)。 VTE 是腿部的血凝块（静脉血栓形成），可能会传播到肺部（肺栓塞）。据估计，10-20%的VTE患者死亡，每年直接费用高达100亿美元。尽管诊断和预防方面取得了进展，抗凝这一已有 50 年历史的疗法仍然是静脉血栓栓塞最常用的治疗方法。抗凝的缺点包括：1）它不能溶解现有的凝块或血栓； 2）高达50%的患者出现血栓后症状（疼痛、肿胀、慢性疮）； 3) 它与高达 30% 的患者复发性静脉血栓栓塞有关； 4）有显着的出血风险； 5）从未被证明可以拯救生命 随机临床试验。组织纤溶酶原激活剂（TPA）和其他血栓溶解药物可以更好地预防血栓后症状，但使用的高剂量是：1）仅部分成功溶解血栓； 2) 显着增加出血风险，并且，3) 并不能降低死亡率。显然，需要一种更安全、更有效的治疗方法来挽救生命、减少残疾并降低与静脉血栓栓塞相关的医疗费用。 通过成功完成这项多阶段 STTR 研究的第一阶段部分，我们（Translational Sciences, Inc. [TSI]）发现了一种通过独特机制溶解血栓的分子——使纤溶酶的主要抑制剂失活。通过协同作用，该分子增加了 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，这种新方法可以大大降低与 VTE 相关的发病率、死亡率和费用。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合临床试验研究的溶凝生物治疗剂 (Lysimab)。 II 期 STTR 的目标是通过以下方式显着推进 Lysimab 的人体试验：1) 在肺栓塞人源化模型中确定 Lysimab 和 TPA 体内的最佳（安全/有效）治疗剂量组合； 2) 在 GMP 条件下生产和纯化 10 g Lysimab，3) 研究 Lysimab 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 第二阶段 STTR 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大型制药合作伙伴形成战略联盟，该合作伙伴拥有为 FDA 批准 Lysimab 进行临床试验所需的临床、监管和财务资源。我们预计，TPA/a2AP-I 联合疗法每年可以使 17,000-36,000 名患者额外存活，并减少血栓后症状及其相关费用 50% 以上。在完成第二阶段项目并将商业化责任转移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好处。 公共卫生相关性：每年有多达 200 万美国人患静脉血栓栓塞 (VTE)，每年直接损失高达 100 亿美元。然而，尽管诊断和预防方面取得了进步，但抗凝这一已有 50 年历史的疗法仍然广泛用于 VTE 治疗，尽管它不能溶解血栓，且伴有严重的副作用，而且从未在随机临床试验中被证明可以挽救生命。这个多阶段 STTR 项目旨在开发一种新型 VTE 疗法，可以显着减少死亡、残疾以及数十亿美元的直接和间接 VTE 相关成本。