Therapeutic Thrombin Analogs

描述（由申请人提供）：项目总结/摘要由于潜在的严重出血性副作用，使用溶栓/抗血栓药物组织纤溶酶原激活剂（tPA，Activase（R））治疗急性缺血性卒中（AIS）受到限制。从急性缺血到tPA治疗的第一个症状（“到针的时间”）可能持续数小时，即使在发达的城市地区也是如此，因为在溶栓治疗之前需要在医院进行确诊。因此，在出现急性心脑血管事件体征时，可作为紧急措施立即给药的安全、无出血风险的抗血栓药物是一个重大的未满足的医疗需求。为了直接满足这一需求，我们公司一直在开发一种新型抗血栓药物，用于AIS的安全治疗。候选产品是一种生物工程重组选择性蛋白C激活酶（PCA），具有强效抗血栓形成作用，而不会增加出血风险。我们专有的PCA分子ProCase”（E-WE凝血酶）被设计为通过靶向细胞递送在形成血凝块的部位增加抗凝剂、纤维蛋白溶解原和细胞保护酶、内源性活化蛋白C（APC）的表面浓度而部分起作用。这种独特的作用机制使E-WE凝血酶能够靶向病理性血凝块，而不会使重要的止血功能失效。在灵长类动物中，低至1 μ g/kg的剂量具有抗血栓作用，而无全身抗凝或任何抗止血作用。E-WE凝血酶的第一个毒性和稳定性批次现已发布，与FDA的研究前新药（pre-IND）会议定于2013年底举行。我们的快速通道SBIR第I/II阶段赠款的所有关键里程碑都已达到：1）证明用我们的原型PCA（WE凝血酶）早期治疗实验性AIS改善了小鼠的神经学结果而没有止血损伤，2）建立E-WE凝血酶的药学上可接受的剂型，3）开发无血清生产方法，和4）在Charles River Labs的临床前急性剂量递增研究中，确定E-WE凝血酶在>100倍的预期人类剂量下缺乏可证实的毒性。我们还建立了适当的放大方法，以批量生产足以进行所有临床前和人体研究的E-WE凝血酶。我们的第IIB阶段旨在支持关键产品开发里程碑：1）完成ProCase的临床前GLP毒理学研究，2）生产ProCase的cGMP批次用于GLP稳定性和人类临床研究，3）准备并提交IND申请以测试ProCase在急性缺血性卒中中的作用，以及4）评估安全性、耐受性、药代动力学，和药效学的ProCase在健康志愿者中的1期临床试验。这项SBIR IIB期桥梁奖，与已经获得的资金相匹配，将最终支持完成一项1期首次人体安全性研究，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.