Therapeutic Thrombin Analogs

描述(由申请人提供)：项目摘要/摘要使用溶栓/抗血栓药物组织纤溶酶原激活剂(tPA，激活酶(R))治疗急性缺血性中风(AIS)是有限的，因为可能会出现严重的出血副作用。即使是在发达的城市地区，tPA治疗的急性缺血的第一个症状(“针刺时间”)也可能持续数小时，因为在溶栓治疗之前，需要在医院环境下确定诊断。因此，对于安全的、没有出血风险的抗血栓药物，在出现急性心脑血管事件迹象时，可以立即作为紧急措施使用，这是一个重大的未得到满足的医疗需求。为了直接满足这一需求，我们公司一直在开发一种安全治疗AIS的新型抗血栓药物。候选产品是一种生物工程重组选择性蛋白C激活酶(PCA)，它在不增加出血风险的情况下具有强大的抗血栓作用。我们的专利PCA分子ProCase“(E-WE凝血酶)的部分作用是通过靶向细胞递送增加血栓形成部位抗凝剂、纤溶原和细胞保护酶--内源性激活蛋白C(APC)的表面浓度。这种独特的作用机制使E-WE凝血酶能够靶向病理性血栓，而不会使重要的止血失效。在灵长类动物中，低至1g/kg的剂量是抗血栓作用，没有全身抗凝或任何止血作用。E-WE凝血酶的第一批毒性和稳定性现已发布，与FDA的预研新药(Pre-IND)会议计划于2013年底举行。我们快速通道SBIR I/II期赠款的所有关键里程碑都已经达到：1)证明使用我们的原型PCA早期治疗实验性AIS，我们可以在没有止血损害的情况下改善小鼠的神经预后；2)建立一种在药学上可接受的E-WE凝血酶剂型，3)开发一种无血清生产工艺，以及4)在Charles River实验室进行的一项临床前急性剂量递增研究中，确定E-WE凝血酶缺乏明显的毒性&>100倍。我们还建立了适当的放大方法来大量生产E-WE凝血酶，足以进行所有临床前和人体研究。我们的IIB阶段目标将支持关键的产品开发里程碑：1)完成ProCase的临床前GLP毒理学研究；2)生产一批用于GLP稳定性和人类临床研究的cGMP ProCase；3)准备并提交IND申请以测试ProCase在急性缺血性中风中的治疗；4)在第一阶段临床试验中评估ProCase在健康志愿者中的安全性、耐受性、药代动力学和药效学。这项SBIR IIB期桥梁奖，加上已经获得的资金，最终将支持完成一项第一阶段的人类安全性研究，研究这种独特的、可能挽救生命的抗血栓药物候选药物。

DESCRIPTION (provided by applicant): Project Summary/Abstract Treatment of acute ischemic stroke (AIS) with the thrombolytic/antithrombotic agent tissue plasminogen activator (tPA, Activase(R)) is limited due to the potential for severe hemorrhagic side effects. The first symptoms of acute ischemia to tPA treatment ("time to needle") can span hours, even in developed urban areas, since an established diagnosis in a hospital setting is required before thrombolytic therapy. Consequently, there is a major unmet medical need for safe antithrombotic agents with no risk of bleeding that can be administered immediately as an emergency measure upon signs of acute cardio- and cerebrovascular events. To directly address this need, our company has been developing a novel antithrombotic agent for the safe treatment of AIS. The product candidate is a bioengineered recombinant selective protein C activator enzyme (PCA) that has potent antithrombotic effects without increasing hemorrhagic risks. Our proprietary PCA 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 ¿g/kg are antithrombotic without systemic anticoagulation or any antihemostatic effects. The first toxicity and stability batch of E-WE thrombin has now been released, and a pre-investigational new drug (pre-IND) meeting with the FDA is being scheduled for late 2013. All of the critical milestones for our Fast-Track SBIR Phase I/II grant have been reached by: 1) Demonstrating that early treatment of experimental AIS with our prototype PCA, WE thrombin, improves neurological outcomes without hemostatic impairment in mice, 2) Establishing a pharmaceutically acceptable dosage form of E-WE thrombin, 3) Developing a serum-free production process, and 4) Determining that E-WE thrombin lacks demonstrable toxicity at >100-fold the expected human dosage in a preclinical acute dose escalation study at Charles River Labs. We have also established the appropriate scale-up methodology to produce E-WE thrombin in bulk amounts sufficient to perform all preclinical and human studies. Our Phase IIB aims that will support critical product development milestones are to: 1) Complete preclinical GLP toxicology studies of ProCase, 2) Manufacture a cGMP lot of ProCase for GLP stability and human clinical studies, 3) Prepare and file an IND application to test ProCase in acute ischemic stroke, and 4) Evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of ProCase in healthy volunteers in a phase 1 clinical trial. This SBIR Phase IIB Bridge Award, matched by already secured funds, will ultimately support the completion of a phase 1 first-in-human safety study investigating this unique and potentially life-saving antithrombotic drug candidate.