evoke and evoke+: design of two large‐scale, double‐blind, placebo‐controlled, phase 3 studies evaluating the neuroprotective effects of semaglutide in early Alzheimer’s disease

Abstract

BackgroundPreclinical, clinical, and real‐world evidence suggest benefits in Alzheimer’s disease (AD)‐related symptoms and reduced risk of dementia in type 2 diabetes following treatment with glucagon‐like peptide 1 receptor agonists (GLP‐1RA; Figure 1). The phase 3 evoke and evoke+ trials (NCT04777396 and NCT04777409, respectively) will assess the efficacy and safety of the oral GLP‐1RA semaglutide versus placebo in participants with early AD. Here, we present the design of these trials.Methodevoke and evoke+ are two randomized, double‐blind, placebo‐controlled trials (Figure 2) recruiting across 38 countries, with 2 further countries pending (Figure 3). In each trial, a planned 1,840 amyloid‐positive participants (aged 55 to 85 years) with mild cognitive impairment (MCI) due to AD (Clinical Dementia Rating [CDR] global = 0.5) or mild AD dementia (CDR global = 1.0) will be randomized (1:1) to oral semaglutide 14 mg once‐daily (escalated via 3‐ and 7‐mg doses over 8 weeks) or placebo for 156 weeks. Participants may use approved AD treatments if on a stable dose ≥3 months before screening. Other key inclusion criteria are: Mini‐Mental State Examination score ≥22 and Repeatable Battery for the Assessment of Neuropsychological Status delayed memory index score ≤85. The key difference between the trials is the inclusion of ≥20% of participants with significant small vessel co‐pathology in evoke+. The primary endpoint is change in the CDR – Sum of Boxes score from baseline to week 104. Confirmatory secondary endpoints are change in Alzheimer’s Disease Cooperative Study‐Activities of Daily Living‐MCI score, and time to progression to dementia among participants with MCI at baseline. Exploratory endpoints include effects on neurodegeneration and neuroinflammation assessed by changes in plasma and cerebrospinal fluid biomarkers. After week 104, participants will continue their original randomized, double‐blind, placebo‐controlled treatment for a 52‐week extension phase followed by a 5‐week follow‐up, allowing assessment of the long‐term effects of semaglutide. A full list of endpoints is provided in Figure 4.ResultThe evoke and evoke+ read‐outs are expected in 2025.Conclusionevoke and evoke+ will be the first large‐scale phase 3 trials (Ntotal = 3,680) to investigate the hypothesized neuroprotective disease‐modifying effect of semaglutide in early AD.

Clinical Evidence for GLP-1 Receptor Agonists in Alzheimer’s Disease: A Systematic Review

“…Both studies are multi-centered. Participants in one proposed study will be treated with subcutaneous liraglutide [ 15 ] whereas in the other study participants will be treated with oral semaglutide [ 16 ] ( Table 4 ). The rationale for the ELAD study is based on proposed shared pathophysiological mechanisms between T2DM and AD, and hypothesizes a potential for GLP-1 RA to influence AD pathology through multiple mechanisms, including neuroprotection, reducing Aβ plaque formation and neuroinflammation, with supportive evidence from mouse models and a pilot study in AD participants [ 15 ].…”

“…The rationale for the ELAD study is based on proposed shared pathophysiological mechanisms between T2DM and AD, and hypothesizes a potential for GLP-1 RA to influence AD pathology through multiple mechanisms, including neuroprotection, reducing Aβ plaque formation and neuroinflammation, with supportive evidence from mouse models and a pilot study in AD participants [ 15 ]. EVOKE and EVOKE+studies hypothesize a neuroprotective disease-modifying effect of semaglutide in early AD, based on evidence from animal studies showing potential benefits of GLP-1 RA in modifying underlying disease processes including reduction of neuroinflammation and tau phosphorylation and improved memory function, and studies in individuals with T2DM showing an association with lower risk of all-cause dementia and clinically diagnosed AD dementia [ 16 ].…”

Functional and multi-omic aging rejuvenation with GLP-1R agonism

“…Given the extensive range of rejuvenation effects observed, it will be important to evaluate the potential of GLP-1RAs in treating human age-related diseases beyond the current clinical indications for diabetes, obesity and their associated comorbidities. Ongoing phase III trials are investigating the use of GLP-1RA in treating Alzheimer's disease 79 , while we are also conducting a pilot trial focused on cerebral small vessel disease (ClinicalTrials.gov identifier: NCT05356104). Our findings also open the avenue for a nuanced therapeutic strategy that combines a GLP-1RA or mTOR inhibitor with molecular entities that engage disease-specific molecular targets or address issues of selective vulnerability 80 .…”

Beyond lecanemab: Examining Phase III potential in Alzheimer's therapeutics

“…Two placebo‐controlled Phase III trials, EVOKE and EVOKE Plus, are underway to explore the efficacy of 14 mg oral semaglutide in individuals with early‐stage AD 38–40 . Each study will enroll 1840 individuals aged 55–85 years with MCI due to AD or mild AD dementia who test positive for amyloid.…”

“…These findings suggest that GLP-1 RA treatment is linked to a reduced dementia risk in type 2 diabetes patients, potentially decreasing its incidence 37. Two placebo-controlled Phase III trials, EVOKE and EVOKE Plus, are underway to explore the efficacy of 14 mg oral semaglutide in individuals with early-stage AD [38]…”