Therapeutic Protein C Activator for Myocardial Ischemia

治疗心肌缺血的蛋白 C 激活剂

• 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
• 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

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.

项目摘要 心脏病发作或急性心肌梗塞（AMI）是美国的主要死亡原因， 每年700,000个可怕的活动。 AMI最普遍的原因是进行性血栓形成冠状动脉 闭塞，也称为ST段抬高心肌梗塞（STEMI）。早期治疗以促进心脏 再灌注可以极大地改善预后。虽然首选经皮冠状动脉干预（PCI） 对于早期的动脉再续新化，在没有这种能力的情况下，多达70％的患者到医院，许多患者 STEMI可怕的奇迹必须仅依靠溶栓疗法。但是，当前的血栓液（例如组织） 纤溶酶原激活剂（TPA）不完全有效，许多患者被排除在溶栓疗法之外 由于存在出血的问题。因此，存在一个主要的治疗差距 可以单独使用或可以提高电流效率的抗血栓形成和溶栓药物 治疗而不会增加出血。为了直接满足这一需求，我们公司一直在开发 安全治疗心脏病发作的课堂内抗血栓形成剂。产品候选人是生物工程的 重组选择性蛋白C活化剂酶，具有潜在的抗强化作用而不增加 出血风险。我们的专有分子Procase（e-we凝血酶）已设计为部分作用 增加抗凝剂，纤维蛋白水解和细胞保护酶的表面浓度， 内源性激活的蛋白C（APC），通过靶向细胞递送发育的部位。这 独特的作用机理允许e-we凝血酶靶向病理血凝块而无需致命 止血。在私人中，低至1 µg/kg的剂量是抗血栓形成的，没有全身性抗凝或任何 抗XER效应。我们快速轨道SBIR I/II赠款的所有关键里程碑均已达到 通过证明：1）e-we凝血酶在小鼠AMI模型中有效，以证明进展到IIB的合理性； 2） e-we凝血酶安全地中断初级的血管移植血管血栓囊结构； 3）我们敏感的血液测定可以 测量血浆中的药物暴露水平； 4）限制重复给予e-we凝血酶不会 引起初级反应的免疫反应。我们的IIB阶段目标将支持关键产品开发 里程碑是：1）确定结合e-we凝血酶的抗血栓效率和止血安全 加上初级的TPA； 2）完成E-WE凝血酶的桥接临床前GLP毒理学研究 tpa; 3）将e-we凝血酶制造转移到能够生产商业规模的工厂。我们 目前正处于关键的关键时期，以将E-WE凝血酶推向人体试验以治疗STEMI，并且 最终，所有急性冠状动脉综合征（ACS）患者。这个SBIR阶段IIB桥奖，与 已经有保证和未决资金的结合将直接导致临床试验的倡议 研究这种独特的挽救生命的抗血栓形成药物。