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.

抽象的。 β-淀粉样蛋白（Aβ）蛋白的可溶性低聚物是最潜在的神经活性结构形式 该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 阿尔茨海默氏病（AD）（Selkoe and Hardy 2016，Viola and Klein 2015）。针对Aβ的安全有效的药物 低聚物应预防并扭转这种突触毒性。 CT1812是第一个选择性移位的药物 突触受体部位的低聚物，并将大脑的低聚物清除到脑脊液（CSF）。 这些第一类药物通过取代与突触下神经元受体结合的Aβ低聚物来起作用。他们 通过变构调节低聚物受体的关键蛋白质调节剂来实现这一目标（Sigma- 2/PGRMC1蛋白复合物），从而破坏了寡聚物结合位点的稳定并增加了率 低聚物，然后将其清除到CSF中。结果，CT1812恢复了突触数和认知 在临床前AD小鼠模型中的性能（Izzo等，2014a，b）。 该临床试验项目提案，以评估三剂CT1812对认知的安全性和效率 在II期随机，双盲，安慰剂对照平行组临床试验中的功能 中度广告患者。这项试验提案测试CT1812每天一次给患者一次进行6个月，以及 旨在衡量突触快速抑制引起的短期认知改善。 由于针对Aβ低聚物的治疗应预防并逆转突触毒素 疾病并在疾病的整个临床过程中有效，该药物正在接受 轻度至中度的阿尔茨海默氏病。该试验将直接检验AD和AD的Aβ低聚物假设 CT1812改善阿尔茨海默氏症患者认知下降症状的有效性。 我们建议在160Aβ阳性轻度至中度阿尔茨海默氏症患者中进行试验（MMSE 18-26） 每天接受三剂CT1812或安慰剂之一，持续6个月，并进行认知测试（ADAS- COG14，ADCS-ADL，CDR-SB）在基线时为3和6个月。我们的主要目的是评估安全性和 CT1812提高认知功能的有效性。我们的次要目的是评估CT1812对 与阿尔茨海默氏病和突触损伤相关的血清和CSF蛋白生物标志物的变化 （包括神经素蛋白和SNAP25）。 我们假设突触功能的快速增加将与可检测的症状改善相关 在本概念验证验证期内的个别患者中。在广告患者中完成这项研究的研究将 告知随后的长期疾病修饰阶段III试验的设计和方法。 CT1812临床发展的进步将大大改善3600万人的生活 全球遭受广告和MCI的痛苦，由于AD而没有疾病改良药物治疗 存在。