Cummings Jeffrey L, Atri Alireza, Feldman Howard H, Hansson Oskar, Sano Mary, Knop Filip K, Johannsen Peter, León Teresa, Scheltens Philip
Chambers-Grundy Center for Transformative Neuroscience, Department of Brain Health, Kirk Kerkorian School of Medicine, University of Nevada, Las Vegas, NV, USA.
Chambers-Grundy Center for Transformative Neuroscience, Department of Brain Health, School of Integrated Health Sciences, University of Nevada, Las Vegas, NV, USA.
Alzheimers Res Ther. 2025 Jan 8;17(1):14. doi: 10.1186/s13195-024-01666-7.
Disease-modifying therapies targeting the diverse pathophysiology of Alzheimer's disease (AD), including neuroinflammation, represent potentially important and novel approaches. The glucagon-like peptide-1 receptor agonist semaglutide is approved for the treatment of type 2 diabetes and obesity and has an established safety profile. Semaglutide may have a disease-modifying, neuroprotective effect in AD through multimodal mechanisms including neuroinflammatory, vascular, and other AD-related processes. Large randomized controlled trials are needed to assess the efficacy and safety of semaglutide in early-stage symptomatic AD.
evoke and evoke+ are randomized, double-blind, placebo-controlled phase 3 trials investigating the efficacy, safety, and tolerability of once-daily oral semaglutide versus placebo in early-stage symptomatic AD. Eligible participants were men or women aged 55-85 years with mild cognitive impairment or mild dementia due to AD with confirmed amyloid abnormalities (assessed by positron emission tomography or cerebrospinal fluid [CSF] analysis). After a maximum 12-week screening phase, an anticipated 1840 patients in each trial are randomized (1:1) to semaglutide or placebo for 156 weeks (104-week main treatment phase and 52-week extension). Randomized participants follow an 8-week dose escalation regimen (3 mg [weeks 0-4], 7 mg [weeks 4-8], and 14 mg [weeks 8-156]). The primary endpoint is the semaglutide-placebo difference on change from baseline to week 104 in the Clinical Dementia Rating - Sum of Boxes score. Analyses of plasma biomarkers, collected from all participants, and a CSF sub-study (planned n = 210) will explore semaglutide effects on AD biomarkers and neuroinflammation.
Enrollment was undertaken between May 18, 2021, and September 8, 2023. Completion of the trials' main phase is expected in September 2025, and the 52-week extension (in which participants and investigators remain blinded to treatment assignment) will continue to October 2026.
evoke and evoke+ are the first large-scale trials to investigate the disease-modifying potential of semaglutide in participants with early-stage symptomatic AD, including exploration of effects on AD biomarkers and neuroinflammation. The trials will provide data on the potential disease-modifying effects of semaglutide and will be important in evaluating its utility in the treatment of early-stage symptomatic AD.
Clinicaltrials.gov, NCT04777396 and NCT04777409. Date: 02/03/2021.
针对阿尔茨海默病（AD）多种病理生理学机制（包括神经炎症）的疾病修饰疗法是潜在的重要新方法。胰高血糖素样肽-1受体激动剂司美格鲁肽已被批准用于治疗2型糖尿病和肥胖症，且具有既定的安全性。司美格鲁肽可能通过神经炎症、血管及其他与AD相关的多模式机制，对AD产生疾病修饰和神经保护作用。需要开展大型随机对照试验来评估司美格鲁肽在早期有症状AD中的疗效和安全性。
evoke和evoke+是随机、双盲、安慰剂对照的3期试验，旨在研究每日一次口服司美格鲁肽与安慰剂相比，在早期有症状AD中的疗效、安全性和耐受性。符合条件的参与者为年龄在55至85岁之间、因AD导致轻度认知障碍或轻度痴呆且经正电子发射断层扫描或脑脊液（CSF）分析确诊有淀粉样蛋白异常的男性或女性。在最长12周的筛查阶段后，预计每个试验中的1840名患者将被随机分配（1:1）至司美格鲁肽组或安慰剂组，为期156周（104周的主要治疗阶段和52周的延长期）。随机分组的参与者遵循8周的剂量递增方案（第0至4周为3毫克，第4至8周为7毫克，第8至156周为14毫克）。主要终点是从基线到第104周临床痴呆评定量表-方框总和得分的司美格鲁肽-安慰剂差异。对所有参与者采集的血浆生物标志物进行分析，以及一项CSF子研究（计划纳入210名）将探索司美格鲁肽对AD生物标志物和神经炎症的影响。
入组时间为2021年5月18日至2023年9月8日。预计试验的主要阶段将于2025年9月完成，52周的延长期（在此期间参与者和研究人员对治疗分配保持盲态）将持续至2026年10月。
evoke和evoke+是首批大规模试验，旨在研究司美格鲁肽在早期有症状AD参与者中的疾病修饰潜力，包括探索其对AD生物标志物和神经炎症的影响。这些试验将提供有关司美格鲁肽潜在疾病修饰作用的数据，并对评估其在治疗早期有症状AD中的效用具有重要意义。
Clinicaltrials.gov，NCT04777396和NCT04777409。日期：2021年3月2日。
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