Novel Methods for Dissolving Blood Clots

溶解血栓的新方法

基本信息

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
项目类别：
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

项目摘要

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，全球有 2400 万 VTE 患者的腿部出现血栓（静脉血栓），这些血栓可能会转移到肺部（肺栓塞）。 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，抗凝治疗一直在进行。抗凝治疗一直是 VTE 的标准疗法，但有许多缺点：1) 它不能溶解现有的血栓；2) 高达 50% 的患者会出现血栓后症状（疼痛、肿胀、慢性疮）；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) 与高达 30% 的患者复发 VTE 相关； 5) 具有显着的出血风险； 6) 尚未在随机临床试验中证明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形成后并发症，但它们：1) 仅部分成功；2)导致出血，并且，3) 不会降低死亡率。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，其中我们发现并进行了研究。 Lysimab 开发了一种治疗性抗体 (Lysimab)，通过独特的机制溶解血栓，Lysimab 提高了 TPA 的效力、安全性和特异性，并避免了 TPA 相关的出血和出血。根据 FDA 的建议，在 I 期研究中，我们成功地将 Lysimab 开发成一种适合临床试验的稳定的溶栓治疗药物，我们的 II 期 STTR 通过人体试验的临床前研究推进了 Lysimab：1) 证明了安全/有效、协同作用。，在人源化肺栓塞模型中体内使用 Lysimab 和 TPA 的治疗剂量组合；2) 在 GLP 条件下生产和纯化 Lysimab；3) 表征 Lysimab 的人体组织结合； 4) 在药理学相关物种的关键安全性毒理学研究中展示 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) 确保获得 FDA 的竞争性选择。 NIH SMARTT 监管团队负责 FDA IND 提交，在此基础上，该 IIb 期提案旨在完成一项关于安全性、药代动力学、药效学的首次人体 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，为 FDA 批准 Lysimab 进行后期临床试验。我们预计 TPA-Lysimab 联合疗法可能会导致完成该 IIb 期项目并将商业化责任转移至后，每年可增加 17,000-36,000 名患者的生存率，血栓后症状及其相关成本减少 50% 以上。我们的战略合作伙伴 TSI 将研究该平台技术对其他血栓性疾病患者的潜在益处。