A Randomized, Double-Blind, Placebo-Controlled, Parallel-Group, Phase 2 Study to Evaluate the Safety and Efficacy of CT1812 in Subjects with Dementia with Lewy Bodies

一项随机、双盲、安慰剂对照、平行组、2 期研究，旨在评估 CT1812 在路易体痴呆受试者中的安全性和有效性

• 批准号: 10674687
• 负责人: ANTHONY O CAGGIANO
• 金额: $ 847.91万
• 依托单位: COGNITION THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-15 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10674687
• 关键词: Activities of Daily Living; Adverse event; Alzheimer' s Disease; Alzheimer' s disease patient; Amyloid beta-Protein; Autopsy; Binding; Binding Sites; Biological Markers; Biology; Brain; Cell membrane; Centers of Research Excellence; Cerebrospinal Fluid; Cerebrospinal Fluid Proteins; Clinical; Clinical Treatment; Clinical Trials; Cognition; Cognitive; Complex; Conduct Clinical Trials; Data; Dementia; Dementia with Lewy Bodies; Development; Disease; Disease Progression; Dose; Double-Blind Method; Drowsiness; Equipment and supply inventories; Family; Family Caregiver; Functional disorder; Headache; Health Care Costs; In Vitro; Lewy Body Dementia; Light; Measurement; Measures; Mediating; Mental disorders; Modification; Molecular; Movement Disorder Society Unified Parkinson' s Disease Rating Scale; Nerve Degeneration; Neurons; Outcome; Parkinson Disease; Pathology; Patients; Pharmaceutical Preparations; Pharmacodynamics; Phase; Phase II Clinical Trials; Placebo Control; Placebos; Plasma; Quality of life; Randomized; Research; Research Personnel; Safety; Shapes; Synapses; Synaptosomes; Testing; Therapeutic; Universities; abeta oligomer; alpha synuclein; clinical candidate; clinical development; clinical efficacy; cognitive function; cognitive performance; cognitive testing; cooperative study; design; drug candidate; experience; healthy volunteer; impression; improved; investigator-initiated trial; monomer; neurodegenerative dementia; neurofilament; neurogranin; neuropsychiatry; novel; off-label use; patient population; phase 2 study; phase II trial; phosphoneuroprotein 14; preclinical study; prevent; primary outcome; programs; protein biomarkers; protein complex; receptor; safety assessment; safety outcomes; sigma-2 receptor; small molecule; symptom treatment; synaptosomal-associated protein 25; synaptotagmin; targeted biomarker; tau Proteins; tau-1; therapeutic candidate

ABSTRACT: Cognition Therapeutics, Inc. (CogRx) is developing CT1812 for neurodegenerative conditions, including Dementia with Lewy Bodies (DLB). This first-in-class small molecule drug candidate selectively displaces Aβ oligomers bound to neuronal receptors at synapses and protects synapses from toxic oligomer effects, clearing them from the brain into the cerebrospinal fluid (CSF). CT1812 also displaces α-synuclein oligomer binding to neurons in vitro. CT1812 is currently in a Phase 2 trial in patients with mild to moderate Alzheimer's disease (AD), where it has been found to be safe and generally well-tolerated. When administered once daily for 28 days to AD patients, CT1812 significantly reduced concentrations of synaptic degeneration markers in CSF. Similar to Aβ oligomers, α-synuclein oligomers bind to neurons and cause synaptic dysfunction and loss, spreading throughout the brain as disease progression is observed in DLB. Eighty percent of patients with DLB reflect both Aβ and α-synuclein pathology at autopsy. Patients with DLB likely have both types of oligomers and should benefit from treatment with CT1812. This clinical trial project proposes to conduct a Phase 2 randomized, double-blind, placebo-controlled, six-month study to evaluate the safety, tolerability, and exploratory efficacy of CT1812 at 100 mg and 300 mg daily doses in mild to moderate DLB patients (N=40/group). Trial endpoints will include safety as well as exploratory efficacy measures (Montreal Cognitive Assessment [MoCA], Cognitive Drug Research Battery [CDR], Clinician Assessment of Fluctuation [CAF], Epworth Sleepiness Scale [ESS], Movement Disorder Society – Unified Parkinson's Disease Rating Scale – Part III [MDS-UPDRS3], The Alzheimer's Disease Cooperative Study – Clinical Global Impression of Change [ADCS-CGIC], ADCS-Activities of Daily Living [ADL], and Neuropsychiatric Inventory [NPI]) at baseline, 3 months, and 6 months. Additional measurements of plasma and CSF concentrations of drug, target engagement biomarkers (including Aβ and α-synuclein oligomers), disease progression protein markers (Aβ and α-synuclein monomer, total and phosphorylated tau protein) and synaptic damage/neurodegeneration biomarkers (neurogranin, synaptotagmin, synaptosomal-associated protein 25 [SNAP-25], and neurofilament light [NFL]) at baseline and at 6 months will allow correlation of drug concentrations with measures of synaptic damage and cognitive performance. Conducting a study with this patient population will leverage the ongoing CT1812 development efforts for AD and will provide a near-term opportunity to investigate a clinical candidate therapeutic in DLB, an indication for which no disease-modifying treatments exist. Completion of this study will provide an initial assessment of CT1812 efficacy in DLB patients that will inform design of subsequent pivotal trials necessary for further clinical development of CT1812.

摘要：认知治疗公司(CogRx)正在开发针对神经退行性疾病的CT1812， 包括路易体痴呆(DLB)。这种一流的小分子药物候选药物选择性地 取代与突触上神经元受体结合的β寡聚体并保护突触免受毒性寡聚体的影响 作用，将它们从大脑清除到脑脊液(CSF)中。CT1812还取代了α-突触核蛋白 低聚物在体外与神经元结合。CT1812目前处于轻中度患者的2期试验中 阿尔茨海默病(AD)，已被发现是安全的，通常耐受性良好。当给药时 对于AD患者，CT1812每天一次，持续28天，显著降低突触变性的浓度 脑脊液中的标志物。与β寡聚体类似，α-突触核蛋白寡聚体与神经元结合并导致突触功能障碍 以及丢失，随着疾病的进展在DLB中蔓延到整个大脑。80%的患者 尸检同时反映Aβ和α-突触核蛋白病理。DLB患者可能同时患有这两种类型的 低聚物，并应受益于CT1812的治疗。 该临床试验项目建议进行2期随机、双盲、安慰剂对照、为期6个月的临床试验 评价CT1812每日100 mg和300 mg剂量的安全性、耐受性和探查效果的研究 轻至中度DLB患者(N=40例/组)。试验终点将包括安全性和探索性疗效。 措施(蒙特利尔认知评估[MoCA]、认知药物研究组合[CDR]、临床医生 波动评估[CAF]，爱普沃斯嗜睡量表[ESS]，运动障碍社会--统一 帕金森氏病评定量表-第三部分[MDS-UPDRS3]，阿尔茨海默病合作研究- 临床总体变化印象[ADCS-CGIC]、ADCS-日常生活活动[ADL]和神经精神病学 库存[NPI])按基准、3个月和6个月计算。血浆和脑脊液的附加测量 药物浓度、靶向结合生物标志物(包括Aβ和α-突触核蛋白寡聚体)、疾病 进展蛋白标记物(Aβ和α-突触核蛋白单体、总的和磷酸化的tau蛋白)与突触 损伤/神经变性生物标记物(神经颗粒素、突触素、突触体相关蛋白25 [Snap-25]和神经丝光线[NFL])将允许药物相关性 通过测量突触损伤和认知表现来集中注意力。用这个进行一项研究 患者群体将利用正在进行的针对AD的CT1812开发工作，并将在短期内提供 有机会研究DLB的临床候选治疗方法，这是一个没有疾病修改的适应症 治疗方法是存在的。这项研究的完成将为CT1812在DLB患者中的疗效提供初步评估 这将为CT1812进一步临床开发所需的后续关键试验的设计提供信息。