Mechanism of action of oligomer-displacing Alzheimer investigation drug, CT1812:Receptor interactions and signaling pathways

寡聚物置换阿尔茨海默病研究药物 CT1812 的作用机制：受体相互作用和信号通路

• 批准号: 10002168
• 负责人: NICHOLAS John IZZO
• 金额: $ 72.92万
• 依托单位: COGNITION THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-30 至 2021-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10002168
• 关键词: Alzheimer' s Disease; Amyloid beta-Protein; Area; Autophagocytosis; Binding; Binding Sites; Biological Assay; Brain; Cell surface; Cerebrospinal Fluid; Chemicals; Clinical; Data; Defect; Dementia; Development; Disease; Dose; Epidermal Growth Factor Receptor; Impaired cognition; Investigational Drugs; Knowledge; Label; Ligands; Ligation; Link; Lipids; Literature; Marketing; Measures; Messenger RNA; Molecular Mechanisms of Action; NPC1 gene; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Pathology; Pathway interactions; Patients; Pattern; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Phase II Clinical Trials; Phase III Clinical Trials; Phase Ia Trial; Pick Disease of the Brain; Placebos; Plant Roots; PrP; Proteins; Publishing; Rare Diseases; Regulation; Role; Safety; Signal Pathway; Site; Small Business Innovation Research Grant; Small Interfering RNA; Structure; Synapses; Synaptic Receptors; Synaptic plasticity; Technology; abeta oligomer; cholesterol biosynthesis; cholesterol trafficking; clinical development; cognitive performance; commercialization; healthy volunteer; innovation; knock-down; mouse model; neurodegenerative dementia; novel; protein complex; receptor; response; sigma-2 receptor

Aβ oligomers are considered the most toxic structural form of Amyloid beta, causing synaptotoxic changes underlying cognitive decline in Alzheimer’s disease. CogRx has developed the world’s first highly brain penetrant drug that selectively displaces oligomers from synaptic receptor sites and clears oligomers from the brain into the cerebrospinal fluid (CSF). This first-in-class drug, CT1812, allosterically modulates a key protein regulator of oligomer receptors (the sigma-2/PGRMC1 protein complex), destabilizing the oligomer binding site, increasing the off-rate of AβOs and allowing rapid clearance into the CSF, however the interactions between the receptor components and their role in downstream signaling pathways are unknown. CT1812 restores synapse number and cognitive performance to normal in AD mouse models. CT1812 has been demonstrated to be safe and well-tolerated in healthy volunteers dosed once daily for 14 days in a placebocontrolled Phase 1a trial, and is currently being evaluated in a follow-on placebo-controlled safety trial in AD patients. The study will provide critical information about the mechanism of action of this innovative differentiated and first in class compound. Successful commercialization of this drug will require partnership with a large pharmaceutical company to support Phase 2 and 3 clinical trials and marketing, and detailed understanding of the molecular mechanism of action of CT1812 has been cited by potential development partners as being a critical requirement for engaging in such a partnership. CogRx has no other support available for elucidating the details of CT1812’s mechanism of action. This Fast-Tract SBIR proposal will provide crucial details about this novel mechanism of action and will enable the application of the proprietary portfolio of sigma-2 ligands at CogRx to other diseases. This information will increase the chance for partnering opportunities necessary for the clinical development of CT1812 for AD patients and will expand the pipeline portfolio of CogRX into new clinical areas involving autophagy pathways.

A β寡聚体被认为是β淀粉样蛋白毒性最强的结构形式，可引起突触毒性变化 潜在的认知能力下降CogRx已经开发出世界上第一个高度大脑 一种选择性地从突触受体部位置换寡聚体并从突触受体部位清除寡聚体的渗透药物， 脑进入脑脊液（CSF）。这种一流的药物，CT1812，变构调节一种关键蛋白质 寡聚体受体（sigma-2/PGRMC 1蛋白复合物）的调节剂，使寡聚体结合不稳定 位点，增加A β O的解离速率，并允许快速清除到CSF中，然而， 受体组分之间的相互作用及其在下游信号传导途径中的作用尚不清楚。CT1812 在AD小鼠模型中恢复突触数量和认知性能至正常。CT1812已经 在安慰剂对照组中，健康志愿者每天给药一次，持续14天，证明安全且耐受性良好 1a期试验，目前正在AD的后续安慰剂对照安全性试验中进行评价 患者这项研究将提供有关这种创新的作用机制的关键信息。 区别开来，是同类化合物中的第一个。这种药物的成功商业化将需要合作伙伴关系 与一家大型制药公司合作，以支持2期和3期临床试验和营销，并详细介绍了 对CT1812作用的分子机制的理解已被潜在的开发引用 这是参与这种伙伴关系的一个关键要求。CogRx没有其他支持 可用于阐明CT1812的作用机制的细节。该快速通道SBIR提案将 提供了关于这种新的作用机制的关键细节，并将使专利的应用 CogRx的sigma-2配体组合用于其他疾病。这些信息将增加合作的机会 为AD患者CT1812的临床开发提供了必要的机会，并将扩大产品线 CogRX产品组合进入涉及自噬途径的新临床领域。