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：
8641021
负责人：
Erik Ian Tucker
金额：
$ 96.72万
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 2016-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8641021
关键词：
Acute Acute myocardial infarction Address Adverse effects Animal Model Animals Anticoagulation Apoptosis Applications Grants Area Autoantibodies Award Binding Biological Assay Bleeding time procedure Blood Platelets Blood Vessels Blood coagulation Blood flow Blood specimen Cardiac Cause of Death Cell Line Cell surface Cells Cessation of life Coagulation Process Complex Coronary Care Units Coronary Stenosis Coronary artery Cyclic GMP Cytoprotection Defense Mechanisms Development Disease Disease Progression Dosage Forms Dose Drug Kinetics Early treatment Emergency Situation Emergency treatment Enzyme Activators Enzymes Evolution Factor Va Fibrin Functional disorder Generations Grant Hemorrhage Hemostatic function Hirudin Hirudins Hospitalization Hospitals Hour Human Immune response Immunoglobulin G Impairment Infarction Ischemia Ischemic Stroke Left Measures Medical Modeling Monitor Mus Muscle Myocardial Infarction Myocardial Ischemia Myocardium Outcome Papio Patients Perfusion Pharmaceutical Preparations Pharmacology Phase Plasma Pre-Clinical Model Prevention Primates Protein C Recombinants Reperfusion Injury Reperfusion Therapy Research Risk Rupture Safety Signal Transduction Site Small Business Innovation Research Grant Stenosis Stroke prevention Surface Testing Therapeutic Thrombin Thrombin Time Assay Thrombomodulin Thrombosis Thrombus Time Toxicology Treatment Cost United States United States National Institutes of Health Vascular Graft activated Protein C analog artery occlusion attack victim base blood vessel occlusion commercialization drug candidate high risk human subject immunogenicity improved in vivo innovation man mortality mouse model muscle necrosis neutralizing antibody novel pre-clinical prevent product development programs receptor secondary outcome success therapeutic protein treatment strategy

项目摘要

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.

描述（由申请人提供）：冠状动脉动脉的迅速阻塞，随后的急性心肌缺血是美国急性心肌梗塞（AMI）和美国死亡的最普遍的主要原因。早期再续新化和抗血栓疗法可促进再灌注并改善梗塞完成之前给药的结果。但是，大多数心脏病受害者没有接受因果治疗来支持再灌注或抑制进展前的进展，因为目前的治疗虽然有效，但很难提供并承担严重或致命的出血的风险。较少严重的病例活到医院，有时在距离发病一小时内，这些患者的因果结局的结果相当好；然而，在最关键的初始几分钟到几个小时内，许多受害者都没有因果关系。尽管有医疗进展，但超过三分之一的AMI受害者死于其疾病，急性死亡率超过了所有其他死亡原因。由于时间是停止末端肌肉梗死和延迟治疗的快速发展的本质，因此有许多生命的生命，因此对安全治疗的医疗需求很大。需要采取安全的紧急措施，可以在患者到达医院之前，最早在介绍时不限于任何患者。我们的产品候选者是一种重组选择性蛋白C活化剂（PCA）酶Procasetm，旨在满足这种未满足的需求。 PCA是重组凝血酶类似物。 ProCase是一流的，独特的候选药物，目前无需进行比较或竞争。注入后的Procase与细胞受体结合，并通过多种机制在局部起作用，包括通过生成内源性活化蛋白C（APC）在血管内表面上诱导有效的防御机制，以及对血小板受体GPIB的竞争抑制。内源性蛋白C激活是一种天然和重要的防御机制，通常通过细胞保护作用（抗凋亡）信号传导起作用，并通过灭活血浆因子VA和VIIIA。利用这种自然机制，Procase会产生内源性APC，可保护细胞免受凋亡的影响，并抑制没有全身抗凝和止血障碍的血管闭塞。以前，我们已经证明了几个PCA在灵长类动物和小鼠中的血栓形成和中风预防的临床前模型中的安全性和功效。现在，我们假设在急性心肌缺血期间给药时，Procase可能具有明显的心脏保护潜力，并且会中断进行性冠状动脉闭塞，从而导致迅速发展不可逆的心肌坏死。我们最初的研究目标是在可逆的心肌缺血模型中评估Procase的治疗潜力。此快速轨道I/II SBIR赠款应用程序的具体目的是：1）在AMI的小鼠模型中评估Procase治疗的治疗潜力； 2）确定在实验性血管占主导性血栓形成过程中procase治疗的抗血栓形成潜力； 3）定义Procase的药代动力学； 4）评估灵长类动物中Procase的免疫原性。如果成功的话，这项研究将支持以下假设：选择性血管内蛋白C激活是一种有希望的早期治疗策略，可以中断急性心肌缺血在其发展为急性心脏功能障碍或末端AMI之前的进展。达到我们的里程碑将促使正式产品开发启动，以促进可疑和/或经过验证的心肌缺血的紧急治疗。