Investigational Safety and Toxicity Studies of Subcutaneous COG1410 for Alzheimer

皮下注射 COG1410 治疗阿尔茨海默病的安全性和毒性研究

• 批准号: 8583226
• 负责人: MICHAEL PETER VITEK
• 金额: $ 27.32万
• 依托单位: COGNOSCI, INC.
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-01 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8583226
• 关键词: Accounting; Acute; Affect; Age; Alleles; Alzheimer' s Disease; American; Amyloid beta-Protein; Animal Model; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Apolipoprotein E; Behavior; Binding; Brain; Brain Pathology; Businesses; Canis familiaris; Caregivers; Caring; Cause of Death; Cells; Cessation of life; Characteristics; Climate; Clinic; Clinical; Clinical Data; Clinical Research; Clinical Trials; Complex; Data; Dementia; Disease; Dose; Drug Evaluation; Drug Kinetics; Drug Packaging; Effectiveness; Equilibrium; Evaluation; Evaluation Research; Family; Family Caregiver; Goals; Healthcare; Heart Diseases; Human; Impaired cognition; Injectable; Intravenous; Intravenous infusion procedures; Investigational Drugs; Investigational New Drug Application; Investments; Learning; Literature; Measures; Mediating; Medicare/Medicaid; Memory; Memory Loss; Modeling; Mus; Neurology; Neurons; Pain; Pathology; Patients; Peer Review; Peptides; Performance; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Phase I Clinical Trials; Phosphoric Monoester Hydrolases; Population; Protein phosphatase; Proteins; Publications; Rattus; Relative (related person); Reporting; Research Contracts; Rewards; Risk; Route; Safety; Senile Plaques; Series; Small Business Innovation Research Grant; Sterility; Stroke; Structure; Testing; Therapeutic; Toxic effect; Toxicokinetics; Translating; Traumatic Brain Injury; United States; United States Food and Drug Administration; Work; Writing; apolipoprotein E-3; base; commercialization; effective therapy; enzyme activity; good laboratory practice; human subject; improved; inhibitor/antagonist; innovation; meetings; mimetics; neuron loss; programs; public health relevance; safety study; safety testing; subcutaneous; success; tau aggregation; translational study

DESCRIPTION (provided by applicant): Investigational Safety and Toxicity Studies of Subcutaneous COG1410 for Alzheimer's Disease: A Therapeutic Based upon Apolipoprotein-E That is Not Targeted to Amyloid-Beta Background on Alzheimer's Disease: Alzheimer's Disease (AD) is the leading cause of dementia and 6th leading cause of death, affecting 5.4 million American patients and their 13 million caregivers. Unlike stroke, heart disease and other diseases whose deaths have been decreasing in recent years, from 2000 to 2006, there was a 47% increase in deaths from AD. This increase shows no signs of stopping as the population of the US age 65 and older is projected to rise from 36 million in 2005 to 87 million by 2050, with a parallel rise in AD patients to 16 million by 2050. Medicare and Medicaid spend $148 Billion or about 20% of their combined programs on the care of AD patients, as there is no effective treatment, and family caregivers spent at least $94 Billion more on caring for relatives with AD. These data strongly support the enormous need to develop an effective anti-Alzheimer's therapeutic to not only reduce pain and suffering of patients and their families, but to also decrease the rapidly growing private and public debts incurred in providing healthcare for these Alzheimer's patients. Application of COG1410 to Alzheimer's Disease: Cognosci has developed an innovative series of neuroprotective and anti-inflammatory "COG" compounds, including COG1410, which are based upon the structure and activity of apolipoprotein-E-3. Our peer-reviewed publications show that these COG compounds specifically bind to SET, a known inhibitor of Protein Phosphatase 2A (PP2A). The formation of COG/SET complexes reduces SET's inhibitory action on PP2A thus permitting a re-activation so that levels of PP2A phosphatase activity increase in "COG" treated cells or animals (Christensen et al. 2011). While PP2A accounts for 70% of all phosphatase activity in the brain, the literature reports that SET levels are significantly increased in AD brains compared to age-matched healthy controls; and that the levels of PP2A phosphatase activity are significantly decreased in AD brains compared to age-matched healthy controls. To regain a healthy balance of SET and PP2A activities in the AD brain, we propose that adding COG1410 will antagonize SET thereby permitting levels of PP2A enzyme activity to increase to healthy levels and to restore the brain to normal. Using our CVN-Alzheimer's mice, we demonstrated that subcutaneous administration of COG1410 resulted in decreased phospho-tau/neurofibrillary tangle-like pathology, decreased amyloid plaque-like pathology, and significantly improved learning and memory behaviors (Vitek et al. 2012a, Vitek et al. 2012b). Additional data provided in this application show that all of these COG1410-mediated changes are significant in our CVN-Alzheimer's model. These data, together with many peer-reviewed publications on the actions of "COG" compounds in animal models, form the scientific basis for this translational proposal to bring COG1410 to the Alzheimer's population. Work Plan Overview: To translate COG1410 to the clinic and reduce the risks associated with commercialization (please see details in the attached proposal), we are proposing to perform all studies necessary to receive approval of an Investigational New Drug (IND) application for subcutaneous administration of COG1410 for an Alzheimer's indication, followed by performance of Phase 1 human clinical trials. To achieve this goal, this Phase 1 SBIR application will perform the dose range finding studies with subcutaneously administered COG1410 in rats and dogs so as to determine the low, middle and high doses of SC-COG1410 that will be used in Phase 2 SBIR studies. Phase 2 SBIR studies will employ low, middle and high doses of SC-COG1410 on a daily basis for 28-days in definitive and GLP studies of pharmacokinetics and toxicokinetics in rats and dogs. The results of of these PK/TK studies, together with safety studies already completed, and GMP-synthesis, packaging and stability evaluations of COG1410, will be incorporated into an IND package and submitted to the FDA for approval. Once approved, then Phase2C/Phase 3-SBIR studies of clinical Phase 1A single ascending dose and Phase 1B repeat ascending dose studies of subcutaneous COG1410 in human subjects can be completed. With clinical studies showing that subcutaneous COG1410 can be safely given to human subjects, we will have achieved a significant milestone that reduces the risks and enables substantive commercialization activities to proceed.

描述（由申请人提供）：对阿尔茨海默氏病的皮下COG1410的研究安全性和毒性研究：一种基于载脂蛋白-E的治疗性，而不是针对阿尔茨海默氏病的淀粉样蛋白-β背景：阿尔茨海默氏病的主要原因（AD）是抑郁症的主要原因（AD）以及第六大死亡原因，影响了540万美国患者及其1300万护理人员。与中风不同，心脏病和其他疾病近年来死亡人数正在减少，从2000年到2006年，AD死亡人数增加了47％。这一增加没有停止的迹象，因为美国65岁及65岁以上的人口预计将从2005年的3600万增加到2050年的8700万，到2050年，AD患者的平行增长到1600万。由于没有有效的治疗方法，因此十亿或约20％的合并计划在AD患者的护理方面，而家庭护理人员花费了至少940亿美元来照顾AD的亲戚。这些数据强烈支持开发有效的抗阿尔茨海默氏症治疗性的巨大需求，不仅减轻了患者及其家人的疼痛和痛苦，还可以减少为这些阿尔茨海默氏病提供医疗保健而产生的快速增长的私人和公共债务。 COG1410在阿尔茨海默氏病中的应用：Cognosci开发了一系列创新的神经保护性和抗炎的“ COG”化合物，包括COG1410，这些化合物基于载脂蛋白-E-3的结构和活性。我们经过同行评审的出版物表明，这些COG化合物特异性结合了Set，这是一种已知的蛋白质磷酸酶2a（PP2A）的抑制剂。 COG/SET配合物的形成减少了SET对PP2A的抑制作用，因此可以重新激活，因此PP2A磷酸酶活性的水平在“ COG”处理的细胞或动物中增加（Christensen等，2011）。虽然PP2A占大脑中所有磷酸酶活性的70％，但与年龄匹配的健康对照相比，AD大脑中的设定水平显着升高。与年龄匹配的健康对照相比，AD大脑中PP2A磷酸酶活性的水平显着降低。为了恢复AD大脑中的集合和PP2A活性的健康平衡，我们建议添加COG1410会拮抗设置，从而允许PP2A酶活性的水平提高到健康水平并使大脑恢复正常。使用我们的CVN-Alzheimer的小鼠，我们证明了COG1410的皮下给药会导致磷酸化/神经原纤维缠结的病理学降低，淀粉样菌斑样病理学降低，并显着改善了学习和记忆行为（Vitek等人（Vitek等）， Al。本应用程序中提供的其他数据表明，所有这些COG1410介导的变化在我们的CVN-Alzheimer模型中都是显着的。这些数据，以及许多关于动物模型中“ COG”化合物的作用的同行评审出版物，构成了这项翻译建议将COG1410带到阿尔茨海默氏症人口的科学基础。工作计划概述：要将COG1410转换为诊所并降低与商业化相关的风险（请参阅附件提案中的详细信息），我们建议进行所有必要的研究，以批准调查性新药（IND）申请皮下管理申请阿尔茨海默氏症指示的COG1410，然后进行1期人类临床试验。为了实现这一目标，该第1阶段的SBIR应用将在大鼠和狗中使用皮下给药的COG1410进行剂量范围查找研究，以确定将在第2阶段SBIR研究中使用的低，中和高剂量的SC-COG1410。第2阶段的SBIR研究将每天使用低剂量的SC-COG1410，用于大鼠和狗的药代动力学和毒性动力学的确定性和GLP研究。这些PK/TK研究的结果以及已经完成的安全研究，以及COG1410的GMP合成，包装和稳定性评估，将被纳入IND包装中，并提交给FDA以供批准。一旦获得批准，就可以完成对人类受试者中皮下COG1410的临床1a单升剂量和1B相位升剂剂量研究的相2C/阶段3-SBIR研究。通过临床研究表明，皮下COG1410可以安全地授予人类受试者，我们将实现一个重要的里程碑，以降低风险并使实质性的商业化活动能够进行。