Therapeutic thrombin analogs

描述（由申请人提供）：中风和心脏病发作是死亡和严重发病的主要原因。这项快速通道STTR资助申请的目标是使WE-凝血酶的临床前研究成为可能，WE-凝血酶是一种生物工程蛋白C激活酶，用于治疗严重的急性血栓性疾病，特别是缺血性中风。WE-凝血酶是一种全新的“血栓形成特异性”试剂，其可部分地通过增加内源性活化蛋白C（APC）的表面浓度来起作用，所述内源性活化蛋白C是抗凝剂、纤溶酶原和细胞保护酶。与任何其他抗血栓形成药物不同，WE-凝血酶在血流中心或静态伤口血液中几乎无活性。WE-凝血酶是一种定义明确且非常先进的候选药物，具有在确定的灵长类动物研究中验证的抗血栓形成功效和止血安全性。拟议的研究将为WE-凝血酶的研究性新药（IND）申请提供信息。现有的抗血栓形成和血栓溶解药物，如重组组织纤溶酶原激活剂（TPA）会导致出血，因此不能以其完全有效的剂量使用。此外，TPA需要在缺血性卒中发作后的前3小时内给药。由于只有一小部分中风患者有资格在这个狭窄的时间范围内接受治疗，TPA很少被使用。因此，与NIH的使命相关的是，迫切需要更好的治疗中风和其他急性血栓性疾病的药物。该项目直接用WE-凝血酶解决了这一需求，在使用小鼠的初步研究中，与TPA相比，WE-凝血酶在治疗实验性急性缺血性卒中方面显示出了结果益处。I期已经被设计为产生WE-凝血酶的药学上可接受的制剂，其可以在中风中TPA的3小时治疗窗口之外施用。I期的3个具体目标是开发稳定的WE-凝血酶注射制剂（目标1），并确定其在晚期实验性急性缺血性卒中（AIS）小鼠中给药时与TPA相比的疗效（目标2）和安全性（目标3）。WE-凝血酶在AIS中的功效和安全性的证明是将使WE-凝血酶开发进入II期的里程碑，在此期间将获得药物GMP级（良好制造规范）WE-凝血酶并在体外进行评估（目的4和5），随后在IND使能研究中进行测试以确定其剂量限制性毒性和潜在副作用（目的6）。II期的成功完成将被定义为临床前安全性和有效性数据包-以及适合临床研究的足够量的配制药物。在I期和II期之后，将提交IND申请，并在FDA批准后，WE-凝血酶将进入临床开发。公共卫生相关性：阻塞血液流动的血栓会导致急性心脏病发作和中风，这两种疾病仍然是美国三大死亡和严重慢性残疾的原因之一，部分原因是血栓预防和血栓清除药物的安全性有限。拟议项目与公共卫生的相关性在于，它旨在开发一种治疗剂（产品），用于安全地中断和/或清除急性血栓性疾病中的血栓。新的重组治疗酶-WE-凝血酶-是第一种血栓特异性候选药物，有可能代表缺血性卒中抗血栓治疗的突破。我们-凝血酶已经被证明在治疗大型灵长类动物的实验性血栓（血栓形成）方面是有效的-它现在旨在提供一种安全有效的替代现有药物，这些药物都未能从根本上改善中风的发病率和死亡率，主要是由于其出血副作用。

DESCRIPTION (provided by applicant): Stroke and heart attack are the leading causes of mortality and grave morbidity. The goal of this Fast-Track STTR grant application is to enable preclinical investigation of WE-thrombin, a bioengineered protein C activator enzyme for the treatment of severe, acute thrombotic diseases, in particular ischemic stroke. WE- thrombin is a fundamentally new "thrombosis-specific" agent that may act in part by increasing the surface concentration of endogenous activated protein C (APC), which is an anticoagulant, profibrinolytic, and cytoprotective enzyme. Unlike any other antithrombotic drug, WE-thrombin is virtually inactive in the center of the blood stream or in static wound blood. WE-thrombin is a well-defined and far-advanced drug candidate, with antithrombotic efficacy and hemostatic safety verified in definitive primate studies. The proposed research will generate information for an Investigational New Drug (IND) application for WE- thrombin. Existing antithrombotic and thrombolytic drugs, such as recombinant tissue plasminogen activator (TPA) cause bleeding and, thus, cannot be used at their fully effective doses. In addition, TPA needs to be administered within the first 3 hours following onset of ischemic stroke. Since only a small percentage of stroke patients qualify for treatment in this narrow time frame, TPA is seldom administered. Thus, relevant to the mission of NIH, there is an urgent need for better drugs for stroke and other acute thrombotic diseases. The project addresses this need directly with WE-thrombin, which has shown outcome benefits compared to TPA in treating experimental acute ischemic stroke in preliminary studies using mice. Phase I has been designed to create pharmaceutically acceptable formulations of WE- thrombin that can be administered beyond the 3-hour treatment window of TPA in stroke. The 3 specific aims of Phase I are to develop a stable, injectable formulation of WE-thrombin (Aim 1) and to determine its efficacy (Aim 2) and safety (Aim 3) in comparison to TPA when administered in mice with advanced experimental acute ischemic stroke (AIS). Demonstration of efficacy and safety of WE-thrombin in AIS is the milestone that will move WE-thrombin development into Phase II, during which pharmaceutical GMP- grade (good manufacturing practice) WE-thrombin will be obtained and evaluated in vitro (Aims 4 & 5) and subsequently tested in IND-enabling studies to determine its dose-limiting toxicity and potential side effects (Aim 6). Successful completion of Phase II will be defined as a preclinical safety and efficacy data package - and sufficient amount of formulated drug that is suitable for clinical studies. After Phases I and II, an IND application will be submitted, and upon FDA approval, WE-thrombin will be taken into clinical development. PUBLIC HEALTH RELEVANCE: Blood clots that block blood flow can cause acute heart attack and stroke that both remain among the three leading causes of death and severe chronic disability in the U.S., in part due to limited safety of clot-preventing and clot-removing drugs. The relevance of the proposed project to public health is that it is intended to develop a therapeutic agent (product) for safely interrupting and/or removing blood clots in acute thrombotic diseases. The new recombinant therapeutic enzyme - WE-thrombin - is a first-of-its-kind thrombosis-specific drug candidate that has the potential to represent a breakthrough in antithrombotic therapy for ischemic stroke. WE- thrombin has already been shown to be effective in treating experimental blood clots (thrombosis) in large primates - it is now intended to offer a safe and effective alternative to existing drugs that all had failed to fundamentally improve the morbidity and mortality of stroke, primarily due to their bleeding side effects.