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

摘要：认知治疗公司（CogRx）正在开发用于神经退行性疾病的CT 1812， 路易体痴呆症（Dementia with Lewy Bodies，DLB）这种一流的小分子候选药物选择性地 取代与突触处神经元受体结合的Aβ寡聚体，并保护突触免受毒性寡聚体的伤害 影响，清除它们从大脑进入脑脊液（CSF）。CT 1812还置换α-突触核蛋白 寡聚体与体外神经元的结合。CT 1812目前在轻度至中度患者中进行II期试验 阿尔茨海默病（AD），在那里它已被发现是安全的，一般耐受性良好。给药时 每天一次，持续28天，CT 1812显著降低AD患者的突触变性浓度， 脑脊液中的标志物。与Aβ寡聚体类似，α-突触核蛋白寡聚体与神经元结合并引起突触功能障碍 和损失，在DLB中观察到随着疾病进展扩散到整个脑。80%的患者 DLB反映了尸检时Aβ和α-突触核蛋白的病理学。DLB患者可能同时具有两种类型的 低聚物，并且应该受益于用CT 1812治疗。 本临床试验项目拟进行一项2期随机、双盲、安慰剂对照、为期6个月的 一项评价每日100 mg和300 mg剂量CT 1812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和探索性疗效 测量（蒙特利尔认知评估[莫卡]，认知药物研究组合[CDR]，临床医生 波动评估[CAF]、埃普沃思嗜睡量表[ESS]、运动障碍协会-统一 帕金森氏病评定量表-第三部分[MDS-ADRS 3]，阿尔茨海默氏病合作研究- 临床总体印象变化[ADCS-CGIC]、ADCS-日常生活活动能力[ADL]和神经精神 基线、3个月和6个月时的库存[NPI]）。血浆和CSF的其他测量 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 进展蛋白标志物（Aβ和α-突触核蛋白单体、总tau蛋白和磷酸化tau蛋白）和突触 损伤/神经变性生物标志物（神经颗粒蛋白、突触结合蛋白、突触体相关蛋白25 [SNAP-25]和神经丝光[NFL]）将允许药物相关性 浓度与突触损伤和认知表现的测量。用这个进行研究 患者人群将利用正在进行的CT 1812 AD开发工作， 有机会研究DLB的临床候选治疗方法，DLB是一种没有改变疾病的适应症 治疗是存在的。本研究的完成将提供CT 1812在DLB患者中疗效的初步评估 这将为CT 1812的进一步临床开发所需的后续关键试验的设计提供信息。

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.