Therapeutic Protein C Activator for Myocardial Ischemia

治疗心肌缺血的蛋白 C 激活剂

基本信息

批准号：
9301688
负责人：
Erik Ian Tucker
金额：
$ 99.81万
依托单位：
ARONORA, INC.
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-03-05 至 2020-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9301688
关键词：
Acute Acute myocardial infarction Address Adjuvant Adverse effects Alteplase American Anticoagulants Anticoagulation Award Biological Assay Biomedical Engineering Bleeding time procedure Blood Blood Vessels Blood coagulation Caring Cause of Death Clinical Clinical Trials Coagulation Process Combined Modality Therapy Coronary Stenosis Development Disease Progression Dose Drug Exposure Drug Interactions Early treatment Emergency Situation Engineering Enzyme Activators Enzymes Fibrinolytic Agents Funding GMP lots Goals Grant Heart Hemorrhage Hemostatic Agents Hemostatic function Hospitals Hour Howard Temin Award Human Immune response Impairment Interruption Iowa Ischemic Stroke Lead Licensing Life Measurable Measures Modality Modeling Monkeys Mus Myocardial Infarction Myocardial Ischemia Papio Pathologic Patients Percutaneous Transluminal Coronary Angioplasty Petechiae Pharmaceutical Preparations Phase Phase I Clinical Trials Plasma Positioning Attribute Primates Production Protein C Proteins Purpura Rattus Recombinants Reperfusion Therapy Risk Rupture Safety Savings Secure Site Small Business Innovation Research Grant Surface Testing Therapeutic Thrombin Thrombolytic Therapy Thrombomodulin Thrombus Time Toxic effect Toxicology United States United States National Institutes of Health Vascular Graft Vascular Graft Occlusion activated Protein C acute coronary syndrome analog attack victim bioprocess cellular targeting commercialization coronary artery occlusion design drug candidate improved improved outcome in vivo innovation nonhuman primate percutaneous coronary intervention pre-clinical pre-clinical research product development programs safety study therapeutic protein thrombolysis treatment strategy

项目摘要

PROJECT SUMMARY Heart attack, or acute myocardial infarction (AMI), is a leading cause of death in the United States, with over 700,000 victims every year. The most prevalent cause of AMI is progressive thrombotic coronary artery occlusion, also known as ST-segment elevation myocardial infarction (STEMI). Early therapy to promote heart reperfusion can dramatically improve outcomes. While percutaneous coronary intervention (PCI) is preferred for early arterial recanalization, up to 70% of patients present to hospitals without this capability, and many STEMI victims must rely on thrombolytic therapy alone. However, current thrombolytics such as tissue plasminogen activator (tPA) are not fully effective, and many patients are excluded from thrombolytic therapy altogether due to bleeding concerns. Consequently, a major treatment gap exists for hemostatically safe antithrombotic and thrombolytic drugs that can be used alone or that can improve the efficacy of current treatments without increased bleeding. To directly address this need, our company has been developing a first- in-class antithrombotic agent for the safe treatment of heart attack. The product candidate is a bioengineered recombinant selective protein C activator enzyme that has potent antithrombotic effects without increasing hemorrhagic risks. Our proprietary molecule, ProCase (E-WE thrombin) has been designed to act in part by increasing the surface concentration of the anticoagulant, profibrinolytic, and cytoprotective enzyme, endogenous activated protein C (APC), at the site of developing blood clots via targeted cellular delivery. This unique mechanism of action allows E-WE thrombin to target pathological blood clots without disabling vital hemostasis. In primates, doses as low as 1 µg/kg are antithrombotic without systemic anticoagulation or any antihemostatic effects. All of the critical milestones for our Fast-Track SBIR Phase I/II grant have been reached to justify progression to Phase IIB by demonstrating: 1) E-WE thrombin is effective in a mouse AMI model; 2) E-WE thrombin safely interrupts vascular graft thrombo-occlusion in primates; 3) Our sensitive blood assay can measure drug exposure levels in plasma; and 4) Limited repeat administration of E-WE thrombin does not evoke an immune response in primates. Our Phase IIB aims that will support critical product development milestones are to: 1) Determine the antithrombotic efficacy and hemostatic safety of combining E-WE thrombin plus tPA in primates; 2) Complete a bridging preclinical GLP toxicology study of E-WE thrombin combined with tPA; and 3) Transfer E-WE thrombin manufacturing to a facility capable of commercial scale production. We are currently at a critical juncture for advancing E-WE thrombin towards human trials to treat STEMI, and ultimately all acute coronary syndrome (ACS) patients. This SBIR Phase IIB Bridge Award, matched by a combination of already secured and pending funds, will lead directly to the initiation of clinical trials investigating this unique and potentially life-saving antithrombotic drug candidate.

项目概要心脏病发作或急性心肌梗死 (AMI) 是美国的一个主要原因，超过每年有 700,000 名患者罹患 AMI，最常见的原因是进行性冠状动脉血栓形成。闭塞，也称为 ST 段抬高型心肌梗死 (STEMI) 促进心脏的早期治疗。再灌注可以显着改善结果，而经皮冠状动脉介入治疗（PCI）是首选。对于早期动脉再通，高达 70% 的患者到医院就诊时不具备这种能力，而且许多患者 STEMI 患者必须仅依靠溶栓治疗，然而，目前的溶栓药物如组织溶栓。纤溶酶原激活剂（tPA）并不完全有效，许多患者被排除在溶栓治疗之外总的来说，由于检查的出血问题，止血安全方面存在重大治疗差距。可单独使用或可提高现有药物疗效的抗血栓和溶栓药物为了直接满足这一需求，我们公司正在开发一种不增加出血的治疗方法。该候选产品是一种生物工程产品，用于安全治疗心脏病。重组选择性蛋白 C 激活酶，具有有效的抗血栓作用，且不增加我们的专有分子 ProCase（E-WE 凝血酶）的设计部分是为了降低出血风险。增加抗凝剂、纤溶酶和细胞保护酶的表面浓度，内源性活化蛋白 C (APC)，通过靶向细胞输送位于形成血栓的部位。独特的作用机制使 E-WE 凝血酶能够靶向病理性血栓，而不会导致生命丧失在灵长类动物中，低至 1 µg/kg 的剂量即可抗血栓，无需全身抗凝或任何其他治疗。我们的快速通道 SBIR I/II 期资助的所有关键里程碑均已达到。通过证明以下内容来证明进入 IIB 期的合理性：1) E-WE 凝血酶在小鼠 AMI 模型中有效；2) E-WE 凝血酶可安全地中断灵长类动物的血管移植物血栓闭塞；3) 我们灵敏的血液检测可以测量血浆中的药物暴露水平；以及 4) 有限重复施用 E-WE 凝血酶不会在灵长类动物中引起免疫反应，我们的 IIB 期目标将支持关键产品的开发。里程碑是： 1) 确定联合 E-WE 凝血酶的抗血栓功效和止血安全性加上 tPA 在灵长类动物中的应用；2) 完成 E-WE 凝血酶联合的桥接临床前 GLP 毒理学研究 tPA；和 3) 将 E-WE 凝血酶生产转移至能够进行商业规模生产的设施。目前正处于将 E-WE 凝血酶推进治疗 STEMI 的人体试验的关键时刻，并且最终所有急性冠脉综合征 (ACS) 患者均获此 SBIR IIB 期桥梁奖。已获得和待决资金的结合将直接导致临床试验的启动研究这种独特且可能挽救生命的抗血栓候选药物。