Investigating changes in fluid biomarkers in early Alzheimer’s disease: design of plasma biomarker analyses and a cerebrospinal fluid sub‐study in the evoke and evoke+ trials of semaglutide versus placebo

Abstract

AbstractBackgroundSeveral studies have generated data supporting a role for glucagon‐like peptide 1 receptor agonists (GLP‐1RA) in the treatment of Alzheimer’s disease (AD). For example, GLP‐1RAs reduced neuroinflammation and phospho‐tau accumulation, provided neuroprotective effects, and improved cognitive function in animal model studies. In patients with AD, GLP‐1RAs preserved cerebral glucose metabolism, favorably affected cognition and cortical volume, and in post‐hoc analyses of randomized clinical trials in type 2 diabetes, reduced cognitive impairment and dementia risk. The phase 3 evoke and evoke+ trials (NCT04777396 and NCT04777409, respectively) will assess the efficacy and safety of oral semaglutide (a GLP‐1RA) versus placebo in early AD. Here, we describe how fluid biomarkers will be investigated.MethodParticipants in the randomized double‐blind, placebo‐controlled evoke and evoke+ trials (N=1,840 per trial) will be randomized 1:1 to oral semaglutide 14 mg once‐daily or matched placebo for 156 weeks. The primary endpoint is change in Clinical Dementia Rating Scale – Sum of Boxes score from baseline to week 104. In both studies, fluid biomarkers will be measured in plasma (all participants [except those in China]) and cerebrospinal fluid (CSF) (a sub‐set of participants). For plasma biomarkers, blood samples will be collected at baseline (week 0) and weeks 52, 104, and 156. For CSF biomarkers, samples will be collected before randomization and at week 78, aiming for around 210 consenting participants (Figure). In each trial, participants will be stratified by CSF sub‐study participation (yes/no) to ensure 1:1 randomization in the sub‐study population. The range of biomarkers analyzed will encompass markers of AD, neuroinflammation, neurodegeneration, blood–brain barrier integrity, oxidative stress, and vascular health (Table).ResultResults from the plasma biomarker analyses and CSF sub‐study of the evoke and evoke+ trials are expected in 2025.ConclusionThese analyses of the evoke and evoke+ studies will investigate the effects of semaglutide on fluid biomarkers in participants with early AD. The analyses will provide insights into the mechanism of action of semaglutide on neuroinflammation and neurodegeneration (and the relationship between the two) in this population.