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: 10187183
• 负责人: ANTHONY O CAGGIANO
• 金额: $ 1076.47万
• 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/10187183
• 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; Drug Targeting; Equipment and supply inventories; Family; Family Caregiver; Functional disorder; Headache; Health Care Costs; In Vitro; 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; 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; preclinical study; prevent; primary outcome; programs; protein biomarkers; protein complex; receptor; 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）正在为神经退行性条件开发CT1812， 包括Lewy身体（DLB）的痴呆症。这个第一类小分子药物有选择地 取代与突触下神经元受体结合的Aβ低聚物，并保护突触免受有毒低聚物的影响 影响，将它们从大脑清除到脑脊液（CSF）。 CT1812还取代α-突触核蛋白 在体外与神经元结合的寡聚物。 CT1812目前正在为轻度至现代患者进行2期试验 阿尔茨海默氏病（AD），发现它是安全的，通常耐受性良好。管理时 每天一次对AD患者进行28天，CT1812显着降低了突触变性的浓度 CSF中的标记。与Aβ低聚物类似，α-突触核蛋白低聚物与神经元结合并引起突触功能障碍 在DLB中观察到疾病进展，损失在整个大脑中传播。百分之八十的患者 DLB在尸检时反映了Aβ和α-突触核蛋白病理。 DLB患者可能有两种类型的 低聚物，应受益于CT1812的治疗。 这项临床试验项目提案提案要进行2期随机，双盲，安慰剂对照的六个月 研究以100 mg和300 mg剂量的CT1812的安全性，耐受性和探索性效率 在轻度至中度DLB患者中（n = 40/组）。试验终点将包括安全性和探索效率 措施（蒙特利尔认知评估[MOCA]，认知药物研究电池[CDR]，临床医生 评估波动[CAF]，Epworth嗜睡量表[ESS]，运动障碍社会 - 统一 帕金森氏病评级量表 - 第三部分[MDS-UPDRS3]，阿尔茨海默氏病合作研究 - 变化的临床全球印象[ADCS-CGIC]，日常生活的ADCS活性[ADL]和神经精神病学 基线，3个月和6个月的库存[NPI]）。血浆和CSF的其他测量 药物的浓度，靶标生物标志物（包括Aβ和α-突触核蛋白低聚物），疾病 进展蛋白标记物（Aβ和α-突触核蛋白单体，总和磷酸化的tau蛋白）和突触 损伤/神经变性生物标志物（神经素，突触毒素，突触体相关蛋白25 [SNAP-25]和基线和6个月时的神经丝光[NFL]）将允许药物相关 具有突触损伤和认知性能的度量的浓度。对此进行研究 患者群体将利用正在进行的CT1812 AD开发工作，并将提供近期 在DLB中调查临床候选疗法的机会，这是没有疾病修改的指示 存在治疗。这项研究的完成将对DLB患者的CT1812效率进行初步评估 这将为CT1812进一步临床开发所需的随后的关键试验设计提供信息。