Therapeutic Protein C Activator for Myocardial Ischemia

描述（由申请人提供）：快速进展的冠状动脉闭塞和随后的急性心肌缺血是美国最常见的急性心肌梗死（AMI）和死亡的主要原因。早期再通和抗栓治疗可促进再灌注，并在梗死结束前改善预后。然而，大多数心脏病患者在到达医院之前没有接受支持再灌注或抑制进展的因果治疗，因为目前的治疗方法虽然有效，但很难提供，并且有严重或致命出血的风险。不太严重的病例活着到达医院，有时在发病后一小时内，这些患者的因果结果相当好；然而，许多受害者在最关键的最初几分钟到几小时内得不到治疗。尽管医疗进步，但超过三分之一的急性心肌梗塞患者死于疾病，急性死亡率超过所有其他死因。由于时间对于阻止晚期肌肉梗死的快速发展至关重要，延迟治疗会使许多人失去生命，因此对安全治疗的医疗需求仍未得到满足。需要一种安全的紧急措施，可以在任何病人身上使用，不受限制，早在病人出现时，在病人到达医院之前。我们的候选产品ProCaseTM是一种重组选择性蛋白C激活剂（PCA）酶，旨在解决这一未满足的需求。pca是重组凝血酶类似物。ProCase是一种一流的，独特的候选药物，目前没有比较或竞争。注射ProCase与细胞受体结合，并通过多种机制局部起作用，包括通过在血管内表面产生内源性活化蛋白C （APC）诱导有效的防御机制和竞争性抑制血小板受体GPIb。内源性蛋白C激活是一种自然而必要的防御机制，通常通过细胞保护（抗凋亡）信号传导和血浆因子Va和viia的失活起作用。利用这一自然机制，ProCase产生内源性APC，保护细胞免于凋亡，抑制血管闭塞，而不会损害全身抗凝和止血功能。我们之前已经分别在灵长类动物和小鼠的血栓形成和中风预防临床前模型中证明了几种pca的安全性和有效性。我们现在假设，当在急性心肌缺血期间给予ProCase时，ProCase可能具有显著的心脏保护潜力，并可以中断导致迅速发展的不可逆心肌坏死的进行性冠状动脉闭塞。我们最初的研究目的是评估ProCase在可逆性心肌缺血动物模型中的治疗潜力。这项快速通道I/II期SBIR拨款申请的具体目的是：1)评估ProCase治疗在AMI小鼠模型中的治疗潜力；2)测定ProCase治疗灵长类动物实验性血管闭塞性血栓形成的抗血栓潜力；3)确定ProCase的药代动力学；4)评估ProCase在灵长类动物中的免疫原性。如果成功，本研究将支持一种假设，即选择性血管内蛋白C激活是一种有希望的早期治疗策略，可以在急性心肌缺血演变为急性心功能障碍或终末期AMI之前中断其进展。达到我们的里程碑将促使正式产品开发的启动，用于疑似和/或证实心肌缺血的紧急治疗。

DESCRIPTION (provided by applicant): Rapidly progressing occlusion of the coronary artery and the subsequent acute myocardial ischemia is the most prevalent primary cause of acute myocardial infarction (AMI) and death in the United States. Early recanalization and antithrombotic therapy promotes reperfusion and improves outcomes when administered before completion of the infarct. However, most heart attack victims do not receive causal treatments to support reperfusion or inhibit progression before they reach the hospital, because current treatments, although effective, are difficult to deliver and carry a risk of severe or fatal hemorrhage. Less severe cases reach the hospital alive, sometimes within an hour from onset, and results from the causal outcomes in these patients are reasonably good; nevertheless, many victims are left without causal treatment in the most critical initial minutes to hours. Despite medical advances, more than a third of AMI victims die of their disease, with acute mortality that surpasses all other causes of death. Since time is of the essence in halting the rapid development of terminal muscle infarction and delayed treatment costs many lives, there is a major unmet medical need for a safe treatment. A safe emergency measure is needed that could be used in any patient, without limitation, as early as at the time of presentation, before the patient reaches the hospital. Our product candidate, a recombinant selective protein C activator (PCA) enzyme, ProCaseTM, is intended to address this unmet need. PCAs are recombinant thrombin analogs. ProCase is a first-in-class, unique drug candidate that currently stands without comparison or competition. Injected ProCase binds to cellular receptors and acts locally by multiple mechanisms, including induction of a potent defense mechanism by generation of endogenous activated protein C (APC) on intravascular surfaces and competitive inhibition of the platelet receptor GPIb. Endogenous protein C activation is a natural and essential defense mechanism that normally acts through cytoprotective (antiapoptotic) signaling, and through inactivation of plasma factors Va and VIIIa. Exploiting this natural mechanism, ProCase generates endogenous APC that protects cells from apoptosis, and inhibits blood vessel occlusions without systemic anticoagulation and hemostasis impairment. We have previously demonstrated the safety and efficacy of several PCAs in preclinical models of thrombosis and stroke prevention in primates and mice, respectively. We now hypothesize that, when administered during acute myocardial ischemia, ProCase may have significant cardioprotective potential and can interrupt progressive coronary artery occlusions that cause rapidly developing irreversible heart muscle necrosis. Our initial research objective is to evaluate the therapeutic potential of ProCase in an animal model of reversible myocardial ischemia. The Specific Aims for this Fast-track Phase I/II SBIR grant application are to: 1) Evaluate the therapeutic potential of ProCase treatment in a mouse model of AMI; 2) Determine the antithrombotic potential of ProCase treatment during experimental vaso-occlusive thrombosis in primates; 3) Define the pharmacokinetics of ProCase; and 4) Evaluate the immunogenicity of ProCase in primates. If successful, this research will support the hypothesis that selective intravascular protein C activation is a promising early treatment strategy to interrupt the progression of acute myocardial ischemia before its evolution into acute cardiac dysfunction or terminal AMI. Reaching our milestones will prompt the initiation of formal product development towards an IND for the emergency treatment of suspected and/or verified myocardial ischemia.