Novel Methods for Dissolving Blood Clots

溶解血栓的新方法

• 批准号: 9063997
• 负责人: ANDREW H KANG
• 金额: $ 0.5万
• 依托单位: TRANSLATIONAL SCIENCES, INC.
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9063997
• 关键词: Address; Affect; Agreement; Alteplase; American; Anticoagulation; Antiplasmin; Binding; Biological Markers; Blood Vessels; Blood coagulation; Brain; Brain hemorrhage; Cessation of life; Characteristics; Chinese Hamster Ovary Cell; Chronic; Clinical; Clinical Data; Clinical Trials; Coagulation Process; Combined Modality Therapy; Complication; Cytolysis; Data; Development; Diagnosis; Disease; Dose; Double-Blind Method; Drug Formulations; Drug Kinetics; Elements; Embolism; Evaluation; Funding; Goals; Grant; Health Care Costs; Hemorrhage; Human; Inflammatory; Investigational Drugs; Investigational New Drug Application; Investments; Ischemic Stroke; Lead; Leg; Link; Lung; Lung Transplantation; Medical; Methods; Modeling; Monoclonal Antibodies; National Heart, Lung, and Blood Institute; Pain; Patients; Pharmaceutical Preparations; Pharmacodynamics; Pharmacologic Substance; Phase; Phase I Clinical Trials; Plasminogen Activator; Postphlebitic Syndrome; Preparation; Process; Production; Prophylactic treatment; Pulmonary Embolism; Pulmonary Heart Disease; Pulmonary Hypertension; Qualifying; Randomized; Randomized Clinical Trials; Recommendation; Recurrence; Research; Resources; Risk; Safety; Secure; Small Business Technology Transfer Research; Solutions; Specificity; Stroke; Swelling; Symptoms; Technology; Testing; Therapeutic; Therapeutic antibodies; Thromboembolism; Thrombus; Toxicology; Translational Research; Travel; United States National Institutes of Health; Venous; Venous Thrombosis; base; cell bank; chronic pain; clinical lot; commercialization; cost; cross reactivity; disability; effective therapy; human tissue; improved; in vivo; inhibitor/antagonist; meetings; mortality; neurotoxicity; nonhuman primate; novel; novel strategies; novel therapeutics; phase 1 study; phase 2 study; phase I trial; pre-clinical; preclinical study; prevent; public health relevance; safety study; standard of care; synergism

 DESCRIPTION (provided by applicant): Each year venous thromboembolism (VTE) affects up to 2 million Americans and 24 million people worldwide. VTE patients have blood clots in the legs (venous thrombosis) that may travel to the lungs (pulmonary embolism). Up to 10-20% of VTE patients die, and the annual direct U.S. healthcare costs are ~$10 billion. For more than 50 years anticoagulation has been the standard therapy for VTE. Anticoagulation has many drawbacks: 1) it does not dissolve existing thrombi; 2) up to 50% of patients develop post-thrombotic symptoms (pain, swelling, chronic sores); 3) up to 4% of patients develop chronic thromboembolic pulmonary hypertension (a severe cardiopulmonary disease); 4) it is linked to VTE recurrence in up to 30% of patients; 5) it has significant bleeding risk; and, 6) it has not been proven to save lives in a randomized clinical trial. High doses of tissue plasminogen activator (TPA)-like agents may prevent post-thrombotic complications by dissolving clots, but they: 1) are only partially successful; 2) cause bleeding and, 3) do not reduce mortality. There is a need for a safer, more-effective therapy for VTE that saves lives, reduces disability, and lowers health care costs. We (Translational Sciences, Inc. [TSI]), successfully completed a Phase I-II STTR in which we discovered and developed a therapeutic antibody (Lysimab) that dissolves blood clots through a unique mechanism. Through synergism, Lysimab increases the potency, safety and specificity of TPA, and it avoids TPA-related hemorrhage and neurotoxicity. Following FDA recommendations, in Phase I studies, we successfully developed Lysimab into a stable, clot-dissolving therapeutic suitable for clinical trials. Our Phase II STTR advanced Lysimab through preclinical studies toward human trials by: 1) demonstrating safe/effective, synergistic, therapeutic dose combinations of Lysimab and TPA in vivo in a humanized pulmonary embolism model; 2) producing and purifying Lysimab under GLP conditions; 3) characterizing Lysimab's human tissue binding char- acteristics; 4) demonstrating Lysimab's remarkable safety profile and pharmacokinetics in pivotal safety- toxicology studies in a pharmacologically relevant species; 5) completing a successful FDA pre-IND meeting; 6) raising strategic investment funds for clinical development and, 7) securing competitive selection by the NIH SMARTT regulatory team for FDA IND submission. Building on this progress, this Phase IIb proposal aims to complete a first-in-human, Phase I study of the safety, pharmacokinetics, pharmacodynamics and biomarker efficacy of Lysimab. Then we will leverage our pre-clinical/clinical data to form a strategic alliance with a Pharmaceutical partner to conduct later phase clinical trials for FDA approval of Lysimab. We project that combination TPA-Lysimab therapy could lead to the survival of an additional 17,000-36,000 patients per year and a >50% reduction in post-thrombotic symptoms and their associated costs. Upon completion of this Phase IIb project and transfer of commercialization responsibilities to our strategic partner, TSI will investigate the potential benefits of this platform technology to other patients with thrombotc diseases.

 描述（由申请人提供）：每年静脉血栓栓塞 (VTE) 影响多达 200 万美国人和全球 2400 万人。 VTE 患者腿部出现血栓（静脉血栓），血栓可能会流向肺部（肺栓塞）。高达 10-20% 的 VTE 患者死亡，美国每年的直接医疗费用约为 100 亿美元。 50 多年来，抗凝一直是 VTE 的标准治疗方法。抗凝有很多缺点：1）不能溶解已有的血栓； 2）高达50%的患者出现血栓后症状（疼痛、肿胀、慢性疮）； 3）高达4%的患者出现慢性血栓栓塞性肺动脉高压（一种严重的心肺疾病）； 4) 它与高达 30% 的患者 VTE 复发有关； 5）有显着的出血风险； 6) 随机临床试验尚未证明它可以挽救生命。高剂量的组织纤溶酶原激活剂（TPA）类药物可以通过溶解血栓来预防血栓后并发症，但它们：1）仅部分成功； 2) 导致出血，3) 不会降低死亡率。有 需要一种更安全、更有效的 VTE 治疗方法，以挽救生命、减少残疾并降低医疗保健成本。 我们（Translational Sciences, Inc. [TSI]）成功完成了 I-II 期 STTR，其中我们发现并开发了一种治疗性抗体 (Lysimab)，它通过独特的机制溶解血栓。通过协同作用，Lysimab 提高了 TPA 的效力、安全性和特异性，并避免了 TPA 相关的出血和神经​​毒性。根据 FDA 的建议，在 I 期研究中，我们成功地将 Lysimab 开发为适合临床试验的稳定的溶栓治疗药物。我们的 II 期 STTR 通过临床前研究将 Lysimab 推进到人体试验：1) 在人源化肺栓塞模型中证明 Lysimab 和 TPA 体内安全/有效、协同、治疗剂量组合； 2)在GLP条件下生产和纯化Lysimab； 3）表征Lysimab的人体组织结合特性； 4) 在药理学相关物种的关键安全毒理学研究中证明 Lysimab 卓越的安全性和药代动力学； 5) 成功完成 FDA IND 前会议； 6) 筹集临床开发战略投资资金，7) 确保 NIH SMARTT 监管团队竞争性选择 FDA IND 提交。在此进展的基础上，该 IIb 期提案旨在完成 Lysimab 的安全性、药代动力学、药效学和生物标志物功效的首次人体 I 期研究。然后，我们将利用我们的临床前/临床数据与制药合作伙伴结成战略联盟，进行后期临床试验，以获得 FDA 批准 Lysimab。我们预计，TPA-Lysimab 联合疗法每年可以使 17,000-36,000 名患者额外存活，并将血栓后症状及其相关费用减少 50% 以上。在完成这个 IIb 期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其他血栓疾病患者的潜在益处。