Therapeutic Protein C Activator for Myocardial Ischemia

项目摘要 心脏病发作或急性心肌梗死（AMI）是美国的主要死亡原因， 每年有70万受害者。急性心肌梗死最常见的原因是进行性血栓性冠状动脉 闭塞，也称为ST段抬高型心肌梗死（STEMI）。早期治疗促进心脏 再灌注可以显著改善结果。虽然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没有这种能力， STEMI患者必须单独依靠溶栓治疗。然而，目前的溶栓剂，如组织溶栓剂， 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 完全是因为担心出血因此，止血安全性存在重大治疗差距 可以单独使用或可以改善当前治疗的功效的抗血栓形成和血栓溶解药物。 治疗不会增加出血。为了满足这一需求，我们公司开发了第一个- 安全治疗心脏病发作的同类抗血栓药物。候选产品是生物工程 重组选择性蛋白C激活酶，其具有有效的抗血栓形成作用而不增加 出血风险。我们的专有分子ProCase（E-WE凝血酶）被设计为部分通过以下方式发挥作用： 增加抗凝剂、纤溶酶原和细胞保护酶的表面浓度， 内源性活化蛋白C（APC），通过靶向细胞递送在形成血凝块的部位。这 独特的作用机制使E-WE凝血酶能够靶向病理性血凝块，而不会使重要的 止血。在灵长类动物中，低至1 µg/kg的剂量具有抗血栓作用，而无需全身抗凝或任何 抗止血作用。我们的快速通道SBIR第I/II阶段赠款的所有关键里程碑都已达到 通过证明：1）E-WE凝血酶在小鼠AMI模型中有效; 2） E-WE凝血酶安全地阻断灵长类动物血管移植物血栓闭塞; 3）我们的灵敏血液检测可以 测量血浆中的药物暴露水平;以及4）E-WE凝血酶的有限重复施用不 引起灵长类动物的免疫反应。我们的IIB阶段旨在支持关键产品开发 里程碑是：1）确定联合E-WE凝血酶的抗血栓疗效和止血安全性 2）完成E-WE凝血酶与tPA联合的桥接临床前GLP毒理学研究; tPA;和3）将E-WE凝血酶制造转移到能够商业规模生产的设施。我们 目前正处于将E-WE凝血酶推向治疗STEMI的人体试验的关键时刻， 最终所有急性冠状动脉综合征（ACS）患者。这SBIR第IIB阶段桥梁奖，由一个匹配 已经获得的和待定的资金将直接导致临床试验的启动 研究这种独特的、可能挽救生命的抗血栓候选药物。

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.