A Randomized, Double-blind, Placebo-Controlled, Parallel-Group, Phase II Study to Evaluate the Safety and Efficacy of CT1812 in Subjects with Mild to Moderate Alzheimer's Disease

一项随机、双盲、安慰剂对照、平行组、II 期研究，旨在评估 CT1812 在轻度至中度阿尔茨海默病受试者中的安全性和有效性

• 批准号: 10170636
• 负责人: ANTHONY O CAGGIANO
• 金额: $ 27.86万
• 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: 2018-09-15 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10170636
• 关键词: Affinity; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease patient; Amyloid; Amyloid beta-Protein; Binding; Binding Sites; Brain; Cerebrospinal Fluid; Cerebrospinal Fluid Proteins; Clinical; Clinical Trials; Clinical Trials Cooperative Group; Cognition; Cognitive; Disease; Disinhibition; Dose; Double-Blind Method; Effectiveness; Equilibrium; Impaired cognition; Lead; Measures; Memory Loss; Methods; Modification; Monoclonal Antibodies; Neurons; Patients; Pharmaceutical Preparations; Pharmacological Treatment; Phase; Placebos; Production; Proteins; Randomized; Safety; Serum; Site; Structure; Synapses; Synaptic Receptors; Testing; Therapeutic; Time; Toxic effect; Viola; Work; abeta oligomer; clinical development; cognitive function; cognitive performance; cognitive testing; design; improved; individual patient; inhibitor/antagonist; monomer; mouse model; neurogranin; neurotoxic; novel; phase 2 study; phase III trial; pre-clinical; prevent; protein biomarkers; protein complex; receptor; secretase; small molecule; symptomatic improvement; synaptic function

ABSTRACT. Soluble oligomers of beta amyloid (Aβ) protein are the most potent neuroactive structural form of this protein and evidence suggests they cause the synaptotoxic changes resulting in cognitive decline in Alzheimer’s disease (AD) (Selkoe and Hardy 2016, Viola and Klein 2015). A safe and effective drug against Aβ oligomers should prevent and reverse this synaptotoxicity. CT1812 is the first drug that selectively displaces oligomers from synaptic receptor sites and clears oligomers from the brain into the cerebrospinal fluid (CSF). These first-in-class drugs work by displacing Aβ oligomers bound to neuronal receptors at synapses. They accomplish this by allosterically modulating a key protein regulator of oligomer receptors (the sigma- 2/PGRMC1 protein complex), thus destabilizing the oligomer binding site and increasing the off-rate of oligomers, which are then cleared into the CSF. As a result, CT1812 restores synapse number and cognitive performance to normal in preclinical AD mouse models (Izzo et al., 2014a, b). This clinical trial project proposes to evaluate the safety and efficacy of three doses of CT1812 on cognitive function in a Phase II randomized, double-blind, placebo-controlled parallel group clinical trial in mild to moderate AD patients. This trial proposes to test CT1812 administered once daily to patients for 6 months, and is designed to measure the short-term cognitive improvement arising from rapid disinhibition of synapses. Since therapeutics directed against Aβ oligomers should prevent and reverse synaptotoxicity associated with disease and be effective throughout the clinical course of the illness, this drug is being tested in patients with mild to moderate Alzheimer’s disease. This trial will directly test the Aβ oligomer hypothesis of AD and the effectiveness of CT1812 to improve symptoms of cognitive decline in Alzheimer’s patients. We propose to conduct a trial in 160 Aβ-positive mild to moderate Alzheimer’s patients (MMSE 18-26) receiving one of three doses of CT1812 or placebo once daily for 6 months, with cognitive testing (ADAS- Cog14, ADCS-ADL, CDR-SB) at baseline, 3 and 6 months. Our primary aim will be to evaluate the safety and efficacy of CT1812 to improve cognitive function. Our secondary aim is to evaluate the effect of CT1812 on changes in serum and CSF protein biomarkers associated with Alzheimer’s disease and synaptic damage (including neurogranin and SNAP25). We hypothesize that rapid increases in synaptic function will correlate with symptom improvement detectable in individual patients within the duration of this proof of concept trial. Completion of this study in AD patients will inform the design and methods of the subsequent long term disease modification Phase III trials with CT1812. Advancement of CT1812 clinical development would substantially improve the lives of the 36 million people worldwide suffering from AD and MCI due to AD, for whom no disease-modifying pharmacological treatments exist.

摘要。β淀粉样蛋白（Aβ）的可溶性寡聚体是最有效的神经活性结构形式， 这种蛋白质和证据表明，它们引起突触毒性变化，导致认知能力下降， 阿尔茨海默病（AD）（Selkoe和哈代2016，Viola和Klein 2015）。一种安全有效的抗Aβ药物 寡聚体应该防止和逆转这种突触毒性。CT 1812是第一种选择性取代 这些寡聚体可以从突触受体位点释放，并将寡聚体从脑清除到脑脊液（CSF）中。 这些一流的药物通过取代与突触处的神经元受体结合的Aβ寡聚体起作用。他们 通过变构调节寡聚体受体的关键蛋白质调节剂（σ- 2/PGRMC 1蛋白复合物），从而使寡聚体结合位点不稳定，并增加 寡聚体，然后被清除到CSF中。结果，CT 1812恢复了突触数量和认知能力。 在临床前AD小鼠模型中表现为正常（Izzo等人，2014 a，B）。 本临床试验项目旨在评估三种剂量的CT 1812对认知功能障碍的安全性和有效性。 在一项II期随机、双盲、安慰剂对照平行组临床试验中， 中度AD患者。本试验拟对患者每日一次给予CT 1812进行为期6个月的试验， 旨在测量由突触的快速去抑制引起的短期认知改善。 由于针对Aβ寡聚体的治疗应该预防和逆转与Aβ寡聚体相关的突触毒性， 疾病和有效的整个临床过程中的疾病，这种药物正在测试的患者 轻度到中度阿尔茨海默病本试验将直接检验AD的Aβ寡聚体假说和AD的 CT 1812改善阿尔茨海默病患者认知功能下降症状的有效性。 我们计划在160名Aβ阳性轻中度阿尔茨海默病患者（MMSE 18-26）中进行试验 每天一次接受三个剂量的CT 1812或安慰剂中的一个，持续6个月，进行认知测试（ADAS-1）。 Cog14、ADCS-ADL、CDR-SB）。我们的主要目标是评估安全性， CT 1812改善认知功能的功效。我们的第二个目的是评估CT 1812对 与阿尔茨海默病和突触损伤相关的血清和CSF蛋白质生物标志物的变化 （包括神经颗粒蛋白和SNAP 25）。 我们假设突触功能的快速增加与可检测到的症状改善相关 在这个概念验证试验的持续时间内，在AD患者中完成本研究将 为随后的CT 1812长期疾病改善III期试验的设计和方法提供信息。 CT 1812临床开发的进展将大大改善3600万人的生活 全球范围内患有AD和由AD引起的MCI的患者，对其没有改善疾病的药物治疗 存在.