Investigational Safety and Toxicity Studies of Subcutaneous COG1410 for Alzheimer

描述(申请人提供)：COG1410皮下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的非针对淀粉样β蛋白的疗法阿尔茨海默病的背景：阿尔茨海默病(AD)是导致痴呆的首要原因和第六大死亡原因，影响着540万美国患者和他们的1300万照顾者。与近年来死亡人数一直在下降的中风、心脏病和其他疾病不同，从2000年到2006年，死于AD的人数增加了47%。这一增长没有停止的迹象，因为美国65岁及以上人口预计将从2005年的3600万增加到2050年的8700万，同时AD患者也将在2050年增加到1600万。由于没有有效的治疗方法，Medicare和Medicaid在AD患者的护理上花费了1480亿美元，约占其合并项目的20%，家庭照顾者在照顾患有AD的亲属上至少多花了940亿美元。这些数据有力地支持了开发有效的抗阿尔茨海默氏症疗法的巨大需求，以不仅减少患者及其家人的痛苦，而且还减少为这些阿尔茨海默氏症患者提供医疗保健而产生的迅速增长的私人和公共债务。COG1410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，包括基于载脂蛋白-E-3的结构和活性的COG1410。我们的同行评议出版物表明，这些COG化合物特异性地结合到SET，一种已知的蛋白磷酸酶2A(PP2A)的抑制剂。COG/SET复合体的形成减少了SET对PP2A的抑制作用，从而允许重新激活，从而使“COG”处理的细胞或动物的PP2A磷酸酶活性水平增加(Christensen等人。2011年)。虽然PP2A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组相比，AD脑中的SET水平显著升高；而与年龄匹配的健康对照组相比，AD脑中的PP2A磷酸酶活性水平显著降低。为了恢复AD脑中SET和PP2A活性的健康平衡，我们认为加入COG1410将拮抗SET，从而允许PP2A酶活性水平增加到健康水平，并使大脑恢复正常。在我们的CVN-阿尔茨海默病小鼠身上，我们证明了皮下注射COG1410可以减少磷酸化tau/神经原纤维缠结样病理，减少淀粉样斑块病理，并显著改善学习和记忆行为(Vitek等人)。2012a，Vitek等人。2012B)。本申请中提供的其他数据显示，在我们的CVN-阿尔茨海默氏症模型中，所有这些由COG1410介导的变化都是显著的。这些数据，加上许多关于“COG”化合物在动物模型中的作用的同行评议出版物，构成了将COG1410引入阿尔茨海默氏症人群的翻译建议的科学基础。工作计划概述：为了将COG1410转化为临床并降低与商业化相关的风险(请参阅所附提案中的详细信息)，我们提议进行所有必要的研究，以获得用于阿尔茨海默氏症适应症的COG1410皮下注射的研究性新药(IND)申请的批准，随后进行第一阶段人体临床试验。为了实现这一目标，这一阶段的SBIR应用程序将在大鼠和狗身上进行皮下注射COG1410的剂量范围寻找研究，以确定将用于第二阶段SBIR研究的SC-COG1410的低、中和高剂量。第二阶段的SBIR研究将每天使用低、中、高剂量的SC-COG1410，为期28天，对大鼠和狗的药代动力学和毒代动力学进行确定性和GLP研究。这些PK/TK研究的结果，连同已经完成的安全性研究，以及COG1410的GMP合成、包装和稳定性评估，将被纳入IND包装并提交FDA批准。一旦获得批准，COG1410在人体内的临床1A期单次递增剂量研究和1B期重复递增剂量研究就可以完成2C期/3期-SBIR研究。随着临床研究表明，COG1410可以安全地用于人体受试者，我们将取得一个重要的里程碑，降低风险，并使实质性的商业化活动得以进行。

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.