HLS Potent, novel inhibitor of fibrinolytic hemorrhage- Phase II

此SBIR应用程序响应NHLBI小型企业特别感兴趣的主题 (治疗学)，具有高度的方案兴趣(HLS-17-04)。 出血或出血是手术的严重或致命的并发症。抑制纤溶的抗纤溶药物 纤溶酶介导的纤溶可以显著减少失血量、急诊再手术、并发症 以及严重出血患者的死亡。据报道，抗纤溶药物有 在心脏外科、骨科、肝移植、血管外科、胸外科、 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、脑内出血和 蛛网膜下腔出血。然而，目前的抗纤溶药物具有限制其 并可能导致严重的并发症，包括：效价低，特异性差，蓄积 肾脏疾病以及血脑屏障和胎盘的穿透。更安全、更具体和 有效的抗纤溶药物每年可以防止数千人死亡。 为了满足这一需求，翻译科学公司寻求生产一种安全、高亲和力、超 特异性抗纤溶单抗作为首个治疗重症出血的新药物 50多年了。这种新型的抗纤溶药物是一种非竞争性的直接抑制物，具有 比任何已知的药物都更具特异性和效力。它能阻断人血浆中的纤溶作用 比目前使用的小分子抗纤溶药强几千倍 例如己酸(EACA)或氨甲环酸。作为一种单抗， 抗纤溶药物不太可能穿过血脑屏障，从而避免了与癫痫相关的风险 使用氨甲环酸。与氨甲环酸或EACA不同的是，这种药物不会显著跨越 胎盘，使其成为更具吸引力的药物，用于严重的妊娠相关出血。在……里面 在体内，这种抗纤溶药物在止血方面明显比临床剂量的 EACA。凭借其精妙的效力和特异性，这种抗纤溶剂具有非凡的 有可能改进严重和致命出血的治疗。我们预计，相比于 目前可用的药物，这种新型的抗纤溶剂将显著减少输血需求， 出血患者的再手术和死亡率--没有严重的不良事件。这项建议 继一项成功的第一阶段项目后，该项目将这种强大的单抗转化为 重组、一流的抗纤溶剂。在这个第二阶段的提案中，我们将遵循FDA的做法 指导开发这种治疗严重临床出血的新疗法，由 追求主细胞库的创建、生物反应器的生产和测试、关键的安全性-毒理学 研究，以及IND预赛和IND提交。

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.