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 Alzheimerʼs Disease

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）。Cognition Therapeutics，Inc. （CogRx）正在开发CT 1812，这是第一种选择性清除有毒低聚物的脑渗透小分子 从大脑进入脑脊液（CSF）。这种候选药物取代了与神经元结合的Aβ O 受体的突触和保护突触的毒性寡聚体的影响。当每天给药一次，持续28 天至轻度至中度AD患者，CT 1812显著降低突触变性的浓度 AD患者CSF中的标志物和磷酸化tau。CT 1812的作用机制可能会停止或减缓 认知能力下降，显著减轻AD患者的痛苦。正在进行的研究COG 0201（SHINE） 由NIA资助的AG 058660基金正在评估两种剂量的CT 1812对 一项2期、随机、双盲、安慰剂对照、平行组临床试验， 中度AD患者。这一重要的概念验证试验将对CT 1812的持续发展至关重要。 发展在这项研究和奖励方面取得了很大进展。研究COG 0201进展顺利 在美国和澳大利亚的九个临床研究中心进行。监管互动导致了 研究设计增加了每例患者的成本;该竞争性修订申请要求 额外的资金，以招募足够的患者，并达到每组患者的适当数量， 充分测量认知功能的变化（N=48/组），并完成完全把握度试验（修订版） AIM 1）。对临床结果的有效评估对CT 1812的进一步发展至关重要。 在AD患者中完成这项研究将为后续疾病的设计和方法提供信息。 使用CT 1812的修改III期试验。CT 1812临床开发的进展将大大提高 改善全球5000万AD患者的生活，对他们来说， 存在药物治疗。

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). Cognition Therapeutics, Inc. (CogRx) is developing CT1812, the first brain penetrant small molecule that selectively clears toxic oligomers from the brain into the cerebrospinal fluid (CSF). This drug candidate displaces AβOs bound to neuronal receptors at synapses and protects synapses from toxic oligomer effects. When administered once daily for 28 days to mild to moderate AD patients, CT1812 significantly reduces concentrations of synaptic degeneration markers in AD patient CSF, and phospho-tau. CT1812's mechanism of action can potentially halt or slow cognitive decline, significantly alleviating the suffering of AD patients. An ongoing study COG0201 (SHINE) funded by the NIA under the award AG058660 is evaluating the safety and efficacy of two doses of CT1812 on cognitive function in a Phase 2 randomized, double-blind, placebo-controlled parallel group clinical trial in mild to moderate AD patients. This important proof of concept trial will be critical for CT1812's continued development. Excellent progress has been made on this study and award. Study COG0201 is proceeding well at nine clinical research sites across the US and Australia. Regulatory interactions have resulted in changes to the study design which have increased per patient costs; this competing revision application requests additional funds to enroll sufficient patients and reach the appropriate number of patients per group and adequately measure changes in cognitive function (N=48/group) and complete a fully powered trial (revised AIM 1). Adequately powered assessment of clinical outcomes is vital to CT1812's further development. Completion of this study in AD patients will inform the design and methods of the subsequent disease modification Phase III trials with CT1812. Advancement of CT1812 clinical development would substantially improve the lives of the 50 million people worldwide suffering from AD, for whom no disease-modifying pharmacological treatments exist.