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：Cognition Therapeutics, Inc. (CogRx) 正在开发用于神经退行性疾病的 CT1812， 包括路易体痴呆症 (DLB)。这种一流的小分子候选药物选择性地 取代与突触神经元受体结合的 Aβ 寡聚物，并保护突触免受有毒寡聚物的侵害 影响，将它们从大脑中清除到脑脊液（CSF）中。 CT1812 还取代 α-突触核蛋白 寡聚物在体外与神经元结合。 CT1812目前正处于轻度至中度患者的2期试验中 阿尔茨海默病（AD），已被发现是安全的并且通常具有良好的耐受性。给药时 对 AD 患者每天一次，持续 28 天，CT1812 显着降低了突触变性的浓度 脑脊液中的标记物。与 Aβ 寡聚物类似，α-突触核蛋白寡聚物与神经元结合并导致突触功能障碍 随着 DLB 中观察到疾病进展，损失会扩散到整个大脑。百分之八十的病人 DLB 反映了尸检时 Aβ 和 α-突触核蛋白的病理学变化。 DLB 患者可能同时患有这两种类型 寡聚体，应该受益于 CT1812 的治疗。 该临床试验项目拟进行为期六个月的随机、双盲、安慰剂对照的 2 期临床试验 评估 CT1812 日剂量 100 mg 和 300 mg 的安全性、耐受性和探索性疗效的研究 轻度至中度 DLB 患者（N=40/组）。试验终点将包括安全性以及探索性疗效 措施（蒙特利尔认知评估 [MoCA]、认知药物研究电池 [CDR]、临床医生 波动评估 [CAF]、Epworth 嗜睡量表 [ESS]、运动障碍协会 – 统一 帕金森病评定量表 – 第三部分 [MDS-UPDRS3]，阿尔茨海默病合作研究 – 临床总体印象变化 [ADCS-CGIC]、ADCS-日常生活活动 [ADL] 和神经精神科 基线、3 个月和 6 个月的库存 [NPI]）。血浆和脑脊液的额外测量 药物浓度、靶点参与生物标志物（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、总和磷酸化 tau 蛋白）和突触 损伤/神经变性生物标志物（神经粒蛋白、突触结合蛋白、突触体相关蛋白 25 [SNAP-25] 和神经丝光 [NFL]）在基线和 6 个月时将允许药物相关性 浓度与突触损伤和认知表现的测量。以此进行研究 患者群体将利用正在进行的 CT1812 AD 开发工作，并将提供近期 有机会研究 DLB 的临床候选治疗方法，目前尚无疾病缓解的适应症 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设计提供信息。