Therapeutic thrombin analogs

描述（由申请人提供）：中风和心脏病发作是导致死亡和严重发病率的主要原因。这项快速通道STTR拨款申请的目标是使we -凝血酶（一种生物工程蛋白C激活酶，用于治疗严重急性血栓性疾病，特别是缺血性中风）的临床前研究成为可能。WE-凝血酶是一种全新的“血栓形成特异性”药物，其部分作用可能是通过增加内源性活化蛋白C （APC）的表面浓度，APC是一种抗凝血、纤原蛋白溶解和细胞保护酶。与其他抗血栓药物不同，we -凝血酶在血流中心或静态伤口血液中几乎没有活性。凝血酶是一种定义明确的先进候选药物，具有抗血栓疗效和止血安全性，已在灵长类动物研究中得到证实。拟议的研究将为WE-凝血酶的新药研究（IND）申请提供信息。现有的抗血栓和溶栓药物，如重组组织型纤溶酶原激活剂（TPA）会引起出血，因此不能以其完全有效剂量使用。此外，TPA需要在缺血性卒中发作后的前3小时内给予。由于只有一小部分中风患者有资格在这么短的时间内接受治疗，TPA很少被使用。因此，与NIH的使命相关，迫切需要更好的药物来治疗中风和其他急性血栓性疾病。该项目直接用we凝血酶解决了这一需求，在小鼠的初步研究中，与TPA相比，we凝血酶在治疗实验性急性缺血性中风方面显示出了更好的结果。第一阶段旨在创造药学上可接受的WE-凝血酶制剂，可以在TPA治疗中风的3小时治疗窗口之外给药。第一阶段的3个具体目标是开发一种稳定的、可注射的we -凝血酶制剂（Aim 1），并确定其在晚期实验性急性缺血性中风（AIS）小鼠中与TPA相比的有效性（Aim 2）和安全性（Aim 3）。证明we凝血酶在AIS中的有效性和安全性是将we凝血酶开发进入II期的里程碑，在此期间，将获得药品GMP级（良好生产规范）we凝血酶并在体外进行评估（目标4和5），随后在ind研究中进行测试，以确定其剂量限制性毒性和潜在副作用（目标6）。成功完成II期将被定义为临床前安全性和有效性数据包-以及足够数量的配方药物适合临床研究。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：血栓阻塞血流可导致急性心脏病发作和中风，这两种疾病在美国仍是导致死亡和严重慢性残疾的三大主要原因之一，部分原因是预防和清除血栓药物的安全性有限。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），用于安全阻断和/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-是一种首个血栓形成特异性候选药物，有可能代表缺血性卒中抗血栓治疗的突破。WE-凝血酶已经被证明在治疗大型灵长类动物的实验性血凝块（血栓形成）方面是有效的，现在它打算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，主要是由于它们的出血副作用。

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.