HLS Potent, novel inhibitor of fibrinolytic hemorrhage- Phase II

HLS 强效、新型纤溶性出血抑制剂 - II 期

• 批准号: 9766367
• 负责人: Sun Yong Jeong
• 金额: $ 132.1万
• 依托单位: TRANSLATIONAL SCIENCES, INC.
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-05 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9766367
• 关键词: Active Sites; Acute; Address; Adverse event; Affinity; Antifibrinolytic Agents; Behavior; Biological Response Modifier Therapy; Biology; Bioreactors; Blood - brain barrier anatomy; Blood Vessels; Blood coagulation; Businesses; Cardiac Surgery procedures; Cardiovascular system; Cessation of life; Chinese Hamster Ovary Cell; Clinical; Clinical Data; Clinical Trials; Coagulation Process; Complication; Cyclic GMP; Data; Development; Dose; Drug Kinetics; Emergency Situation; End stage renal failure; Evaluation; Fibrin; Fibrinolysis; Gastrointestinal Hemorrhage; Goals; Growth; Gynecologic Surgical Procedures; Health Care Costs; Hemorrhage; Human; Immunoglobulin G; Injury; Ischemic Stroke; Kidney Diseases; Kidney Failure; Life; Mediating; Modeling; Monoclonal Antibodies; Morbidity - disease rate; Mus; National Heart, Lung, and Blood Institute; National Institute of Neurological Disorders and Stroke; New Agents; Operative Surgical Procedures; Orthopedic Surgery procedures; Parents; Patients; Penetration; Perinatal; Pharmacodynamics; Pharmacologic Substance; Pharmacology; Phase; Pilot Projects; Placenta; Plasma; Plasmin; Plasmin Inhibitor; Plasminogen Activator; Pre-Clinical Model; Pregnancy; Production; Property; Recombinants; Recovery; Repeat Surgery; Reporting; Research; Risk; Role; Safety; Seizures; Serine Protease; Serious Adverse Event; Small Business Innovation Research Grant; Specificity; Structure; Subarachnoid Hemorrhage; Surgical complication; Talents; Testing; Therapeutic; Therapeutic Studies; Thoracic Surgical Procedures; Thromboembolism; Thrombosis; Time; Tissues; Toxicology; Tranexamic Acid; Transfusion; Translational Research; Trauma; Traumatic Brain Injury; Venous; antibody engineering; cell bank; cross reactivity; effective therapy; hexanoic acid; human tissue; improved; in vivo; in vivo Model; inhibitor/antagonist; interest; liver transplantation; manufacturing process; meetings; mortality; neurosurgery; nonhuman primate; novel; novel therapeutics; pharmacokinetics and pharmacodynamics; phase I trial; platelet function; pre-clinical; preclinical safety; prevent; prostate surgery; small molecule; targeted treatment

This SBIR Application is responsive to NHLBI Small Business Topics of Special Interest (therapeutics) that are of high programmatic interest (HLS-17-04). Hemorrhage or bleeding is a serious or fatal complication of surgery. Antifibrinolytic agents that inhibit plasmin-mediated fibrinolysis can significantly reduce blood loss, emergency reoperation, morbidity and death in patients with severe hemorrhage. Antifibrinolytic agents have been reported to have value in cardiac surgery, orthopedic surgery, liver transplantation, vascular surgery, thoracic surgery, gynecological surgery, end-stage renal disease, peripartum bleeding, gastrointestinal bleeding, prostate surgery, neurosurgery, trauma, traumatic brain injury, intracerebral bleeding and subarachnoid hemorrhage. However, current antifibrinolytic agents have properties that limit their efficacy and may cause serious complications including: low potency, poor specificity, accumulation in renal disease and penetration of the blood brain barrier and placenta. Safer, more specific and potent antifibrinolytic agents may prevent thousands of deaths per year. To address this need, Translational Sciences, Inc. seeks to produce a safe, high-affinity, ultra- specific, antifibrinolytic monoclonal antibody as the first new agent to treat severe hemorrhage in more than 50 years. This novel antifibrinolytic acts as a non-competitive, direct inhibitor and has greater specificity and potency than any known agent. It blocks fibrinolysis in human plasma with several thousand-fold greater potency than the currently used, small molecule antifibrinolytic agents such as epsilon amino caproic acid (EACA) or tranexamic acid. As a monoclonal antibody this antifibrinolytic is unlikely to cross the blood brain barrier, which avoids the risk of seizures associated with tranexamic acid. Also unlike tranexamic acid or EACA, this agent will not significantly cross the placenta, making it a more attractive agent for use in severe, pregnancy-associated hemorrhage. In vivo, this antifibrinolytic was significantly more potent at stopping hemorrhage than clinical doses of EACA. By virtue of its exquisite potency and specificity, this antifibrinolytic agent has extraordinary potential for improving the treatment of severe and fatal bleeding. We project that, by comparison to currently available agents, this novel antifibrinolytic will significantly reduce the need for transfusions, reoperations and mortality in bleeding patients—without serious adverse events. This proposal follows a successful Phase I project, which converted this potent monoclonal antibody into a recombinant, first-in-class, antifibrinolytic agent. In this Phase II proposal, we will follow FDA guidance to develop this novel therapeutic for the treatment of severe clinical hemorrhage, by pursuing master cell bank creation, bioreactor production and testing, pivotal safety-toxicology studies, as well as pre-IND and IND submission.

此SBIR应用程序响应NHLBI特别感兴趣的小型企业主题 （治疗剂）具有高度程序性兴趣（HLS-17-04）。 出血或出血是手术的严重或致命并发症。抑制纤维蛋白溶解的抗纤维蛋白溶解剂 纤溶酶介导的纤溶可显著减少失血量、急诊再手术、发病率 严重出血患者死亡。据报道，抗纤维蛋白溶解剂具有 在心脏手术、骨科手术、肝移植、血管手术、胸外科手术、 妇科手术、终末期肾病、围产期出血、胃肠道出血， 前列腺手术、神经外科、创伤、创伤性脑损伤、脑出血和 蛛网膜下腔出血然而，目前的抗纤维蛋白溶解剂具有限制其活性的性质。 疗效和可能导致严重的并发症，包括：低效力，特异性差，积累 肾脏疾病和血脑屏障和胎盘的渗透。更安全，更具体， 有效的抗纤维蛋白溶解剂每年可防止数千人死亡。 为了满足这一需求，Translational Sciences，Inc.旨在生产一种安全、高亲和力、超 特异性抗纤维蛋白溶解单克隆抗体作为第一个治疗重症出血的新药， 超过50年。这种新的抗纤溶药物作为一种非竞争性的直接抑制剂， 比任何已知的药剂都具有更强的特异性和效力。它阻断人血浆中的纤维蛋白溶解， 比目前使用的小分子抗纤维蛋白溶解剂的效力大几千倍 如N-氨基己酸（EACA）或氨甲环酸。作为单克隆抗体， 抗纤溶药物不太可能穿过血脑屏障，从而避免了癫痫发作的风险。 氨甲环酸也不像氨甲环酸或EACA，这种药剂不会显著穿过 胎盘，使其成为一个更有吸引力的代理用于严重的，妊娠相关出血。在 在体内，这种抗纤维蛋白溶解剂在止血方面比临床剂量的 EACA。凭借其精致的效力和特异性，这种抗纤维蛋白溶解剂具有非凡的 改善重度和致死性出血治疗的潜力。我们预测，与 这种新的抗纤维蛋白溶解剂将显著减少输血的需要， 出血患者的再手术率和死亡率-无严重不良事件。这项建议 遵循一个成功的第一阶段项目，该项目将这种有效的单克隆抗体转化为 重组的，一流的，抗纤维蛋白溶解剂。在本II期提案中，我们将遵循FDA 指导开发这种用于治疗严重临床出血的新型治疗药物， 进行主细胞库创建、生物反应器生产和测试、关键安全毒理学 研究，以及pre-IND和IND提交。