Lopez Lopez Cristina, Tariot Pierre N, Caputo Angelika, Langbaum Jessica B, Liu Fonda, Riviere Marie-Emmanuelle, Langlois Carolyn, Rouzade-Dominguez Marie-Laure, Zalesak Martin, Hendrix Suzanne, Thomas Ronald G, Viglietta Vissia, Lenz Rob, Ryan J Michael, Graf Ana, Reiman Eric M
Novartis Pharma AG, Basel, Switzerland.
Banner Alzheimer's Institute, Phoenix, AZ, USA.
Alzheimers Dement (N Y). 2019 Jun 12;5:216-227. doi: 10.1016/j.trci.2019.02.005. eCollection 2019.
Alzheimer's disease (AD) pathology, including the accumulation of amyloid beta (Aβ) species and tau pathology, begins decades before the onset of cognitive impairment. This long preclinical period provides an opportunity for clinical trials designed to prevent or delay the onset of cognitive impairment due to AD. Under the umbrella of the Alzheimer's Prevention Initiative Generation Program, therapies targeting Aβ, including CNP520 (umibecestat), a β-site-amyloid precursor protein cleaving enzyme-1 (BACE-1) inhibitor, and CAD106, an active Aβ immunotherapy, are in clinical development in preclinical AD.
The Alzheimer's Prevention Initiative Generation Program comprises two pivotal (phase 2/3) studies that assess the efficacy and safety of umibecestat and CAD106 in cognitively unimpaired individuals with high risk for developing symptoms of AD based on their age (60-75 years), genotype, and, for heterozygotes ( ε2/ε4 or ε3/ε4), elevated brain amyloid. Approximately, 3500 individuals will be enrolled in either Generation Study 1 (randomized to cohort 1 [CAD106 injection or placebo, 5:3] or cohort 2 [oral umibecestat 50 mg or placebo, 3:2]) or Generation Study 2 (randomized to oral umibecestat 50 mg and 15 mg, or placebo [2:1:2]). Participants receive treatment for at least 60 months and up to a maximum of 96 months. Primary outcomes include time to event, with event defined as diagnosis of mild cognitive impairment due to AD and/or dementia due to AD, and the Alzheimer's Prevention Initiative preclinical composite cognitive test battery. Secondary endpoints include the Clinical Dementia Rating Sum of Boxes, Repeatable Battery for the Assessment of Neuropsychological Status total score, Everyday Cognition Scale, biomarkers, and brain imaging.
The Generation Program is designed to assess the efficacy, safety, and biomarker effects of the two treatments in individuals at high risk for AD. It may also provide a plausible test of the amyloid hypothesis and further accelerate the evaluation of AD prevention therapies.
阿尔茨海默病（AD）的病理变化，包括β淀粉样蛋白（Aβ）的积累和tau病理改变，在认知障碍出现前数十年就已开始。这一漫长的临床前期为旨在预防或延缓AD所致认知障碍发作的临床试验提供了契机。在阿尔茨海默病预防计划一代项目的框架下，针对Aβ的治疗方法，包括β位点淀粉样前体蛋白裂解酶-1（BACE-1）抑制剂CNP520（乌米贝西他）和活性Aβ免疫疗法CAD106，正在临床前期AD患者中进行临床开发。
阿尔茨海默病预防计划一代项目包括两项关键（2/3期）研究，评估乌米贝西他和CAD106在认知未受损但基于年龄（60 - 75岁）、基因型以及杂合子（ε2/ε4或ε3/ε4）脑淀粉样蛋白升高而有发展为AD症状高风险个体中的疗效和安全性。大约3500名个体将被纳入一代研究1（随机分为队列1[CAD106注射或安慰剂，5:3]或队列2[口服乌米贝西他50毫克或安慰剂，3:2]）或一代研究2（随机分为口服乌米贝西他50毫克和15毫克或安慰剂[2:1:2]）。参与者接受至少60个月、最长96个月的治疗。主要结局包括至事件发生时间，事件定义为因AD诊断为轻度认知障碍和/或因AD诊断为痴呆，以及阿尔茨海默病预防计划临床前期综合认知测试组。次要终点包括临床痴呆评定量表总分、可重复神经心理状态评估量表总分、日常认知量表、生物标志物和脑成像。
一代项目旨在评估这两种治疗方法在AD高风险个体中的疗效、安全性和生物标志物效应。它也可能为淀粉样蛋白假说提供合理检验，并进一步加速AD预防疗法的评估。
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