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）：皮下注射COG 1410治疗阿尔茨海默病的安全性和毒性研究：一种基于载脂蛋白-E的治疗方法，不针对淀粉样蛋白-β阿尔茨海默病的背景：阿尔茨海默病（AD）是痴呆的主要原因和第六大死亡原因，影响540万美国患者及其1300万护理人员。与中风，心脏病和其他疾病的死亡人数近年来一直在下降不同，从2000年到2006年，AD的死亡人数增加了47%。这种增长没有显示出停止的迹象，因为美国65岁及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患者将平行增加到1600万。由于没有有效的治疗方法，医疗保险和医疗补助在AD患者的护理上花费了1，480亿美元，约占其合并计划的20%，而家庭护理人员在护理患有AD的亲属上花费了至少940亿美元。这些数据强烈支持开发有效的抗阿尔茨海默病治疗剂的巨大需求，不仅可以减轻患者及其家人的疼痛和痛苦，而且还可以减少为这些阿尔茨海默病患者提供医疗保健所产生的快速增长的私人和公共债务。COG 1410在阿尔茨海默病中的应用：Cognosci开发了一系列创新的神经保护和抗炎“COG”化合物，包括COG 1410，其基于载脂蛋白-E-3的结构和活性。我们的同行评审出版物表明，这些COG化合物特异性结合SET，SET是一种已知的蛋白磷酸酶2A（PP 2A）抑制剂。COG/SET复合物的形成降低了SET对PP 2A的抑制作用，从而允许再活化，使得“COG”处理的细胞或动物中PP 2A磷酸酶活性水平增加（Christensen等人，2011）。虽然PP 2A占大脑中所有磷酸酶活性的70%，但文献报道，与年龄匹配的健康对照相比，AD大脑中的SET水平显著增加;并且与年龄匹配的健康对照相比，AD大脑中的PP 2A磷酸酶活性水平显著降低。为了恢复AD脑中SET和PP 2A活性的健康平衡，我们提出添加COG 1410将拮抗SET，从而允许PP 2A酶活性水平增加到健康水平并使脑恢复正常。使用我们的CVN-阿尔茨海默氏症小鼠，我们证明皮下施用COG 1410导致磷酸化tau/神经元缠结样病理学减少，淀粉样斑块样病理学减少，并且显著改善学习和记忆行为（Vitek等人，2012 a，Vitek等人，2012 b）。本申请中提供的额外数据显示，所有这些COG 1410介导的变化在我们的CVN-阿尔茨海默病模型中是显著的。这些数据，以及许多关于“COG”化合物在动物模型中作用的同行评议出版物，构成了将COG 1410引入阿尔茨海默氏症人群的这一转化提议的科学基础。工作计划概述：为了将COG 1410转化为临床并降低与商业化相关的风险（请参见所附提案中的详细信息），我们建议进行所有必要的研究，以获得用于皮下注射COG 1410治疗阿尔茨海默病适应症的研究性新药（IND）申请的批准，然后进行I期人体临床试验。为了实现这一目标，本1期SBIR申请将在大鼠和犬中进行皮下给予COG 1410的剂量范围探索研究，以确定将用于2期SBIR研究的SC-COG 1410的低、中和高剂量。在大鼠和犬的药代动力学和毒代动力学的确定性和GLP研究中，2期SBIR研究将采用低、中和高剂量的SC-COG 1410每日给药，持续28天。这些PK/TK研究的结果，连同已经完成的安全性研究，以及COG 1410的GMP合成、包装和稳定性评价，将被纳入IND包装中，并提交给FDA批准。一旦获得批准，则可以在人类受试者中完成皮下注射COG 1410的临床1A期单次给药剂量递增和1B期重复给药剂量递增的2C期/3期-SBIR研究。随着临床研究表明皮下COG 1410可以安全地给予人类受试者，我们将实现一个重要的里程碑，降低风险，并使实质性的商业化活动得以进行。