Therapeutic Thrombin Analogs

治疗性凝血酶类似物

• 批准号: 8680073
• 负责人: Andras Gruber
• 金额: $ 83.46万
• 依托单位: ARONORA, INC.
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-21 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8680073
• 关键词: Activase; Acute; Address; Adult; Adverse effects; Adverse event; Alteplase; Anticoagulants; Anticoagulation; Bacteria; Biomedical Engineering; Blood coagulation; Cardiovascular system; Cause of Death; Chronic; Clinical; Clinical Research; Coagulation Process; Cyclic GMP; Development; Diagnosis; Dosage Forms; Dose; Double-Blind Method; Drug Kinetics; Early treatment; Emergency Situation; Engineering; Enzyme Activators; Enzymes; Escherichia coli; Event; Fibrinolytic Agents; Freezing; Funding; Grant; Healthcare; Hemorrhage; Hemostatic Agents; Hemostatic function; Hospitals; Hour; Howard Temin Award; Human; Impairment; Investigational Drugs; Ischemia; Ischemic Stroke; Lead; Legal patent; Licensing; Life; Measures; Medical; Methodology; Mus; Needles; Neurological outcome; No-Observed-Adverse-Effect Level; Organ Specificity; Pamphlets; Papio; Pharmaceutical Preparations; Pharmacodynamics; Pharmacology; Phase; Phase I Clinical Trials; Placebo Control; Primates; Process; Production; Protein C; Randomized; Rattus; Recombinants; Reperfusion Therapy; Research Personnel; Risk; Rivers; Route; Safety; Schedule; Secure; Serum; Site; Small Business Innovation Research Grant; Solutions; Stroke; Surface; Symptoms; Testing; Therapeutic; Thrombin; Thrombolytic Therapy; Thrombus; Time; Toxic effect; Toxicology; abstracting; activated Protein C; analog; artery occlusion; cellular targeting; cerebral artery; cerebrovascular; design; disability; dosage; drug candidate; expiration; healthy volunteer; human study; immunogenicity; improved; innovation; meetings; mortality; mutant; novel; phase 1 study; pre-clinical; preclinical safety; prethrombins; product development; programs; prototype; public health relevance; safety study; safety testing; scale up; thrombolysis; urban area; volunteer

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.

项目概述/摘要溶栓/抗栓药物组织纤溶酶原激活剂（tPA，激活酶(R)）治疗急性缺血性卒中（AIS）由于潜在的严重出血副作用而受到限制。即使在发达的城市地区，急性缺血到tPA治疗的第一个症状（“注射时间”）也可能持续数小时，因为在溶栓治疗之前需要在医院进行确定的诊断。因此，对于安全的无出血风险的抗血栓药物，在出现急性心脑血管事件的迹象时，可以作为紧急措施立即给予治疗，这是一个主要的未满足的医疗需求。为了直接解决这一需求，我们公司一直在开发一种新的抗血栓药物，用于安全治疗AIS。候选产品是一种生物工程重组选择性蛋白C激活酶（PCA），具有有效的抗血栓作用，而不会增加出血风险。我们的专利PCA分子ProCase”（E-WE凝血酶）的作用部分是通过增加抗凝血剂、纤溶酶和细胞保护酶、内源性活化蛋白C （APC）的表面浓度，通过靶向细胞递送形成血栓。这种独特的作用机制允许E-WE凝血酶靶向病理性血凝块而不妨碍重要的止血。在灵长类动物中，低至1¿g/kg的剂量是抗血栓的，没有全身抗凝或任何抗止血作用。第一批E-WE凝血酶的毒性和稳定性批次现已发布，并计划于2013年底与FDA进行新药预研究（pre-IND）会议。我们快速通道SBIR I/II期拨款的所有关键里程碑已经达到：1)证明早期使用我们的原型PCA，即WE凝血酶治疗实验性AIS，可以改善小鼠的神经系统预后，而不会出现止血功能障碍；2)建立一种药学上可接受的E-WE凝血酶剂量形式；3)开发无血清生产工艺；4)在Charles River实验室的临床前急性剂量升级研究中，确定E-WE凝血酶没有明显的毒性，其剂量是预期人体剂量的100倍。我们还建立了适当的规模化方法，以生产足够批量的E-WE凝血酶，以进行所有临床前和人体研究。我们的IIB期目标将支持关键的产品开发里程碑：1)完成ProCase的GLP临床前毒理学研究，2)生产ProCase的cGMP批次用于GLP稳定性和人体临床研究，3)准备并提交IND申请以测试ProCase在急性缺血性中风中的作用，4)在健康志愿者的i期临床试验中评估ProCase的安全性、耐受性、药代动力学和药效学。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第一阶段人体安全性研究，研究这种独特的、可能挽救生命的抗血栓候选药物。