Novo Nordisk announced that its Phase III evoke and evoke+ trials of semaglutide in early-stage symptomatic Alzheimer’s disease did not show a significant reduction in disease progression over two years. The company released top-line results from the randomized, double-blind studies, which included 3,808 adults from around the world.
Semaglutide, a GLP-1 receptor agonist approved for type 2 diabetes and chronic weight management, was tested against a placebo along with standard care.
This program started after real-world analyses, preclinical studies and post-hoc findings from diabetes and obesity trials suggested it might have effects on Alzheimer’s-related biology worth investigating.
Alzheimer’s disease is the leading cause of dementia and still has few treatment options and a high unmet need.
The evoke and evoke+ trials tested once-daily oral semaglutide 14 mg in individuals aged 55 to 85 with mild cognitive impairment or mild dementia due to Alzheimer’s disease and confirmed amyloid positivity. This 14 mg oral dose matches the formulation approved for type 2 diabetes, not the higher doses used for chronic weight management.
Participants were randomly assigned in a 1:1 ratio to receive semaglutide or placebo for a planned 156-week period, including a 104-week primary phase and a 52-week extension.
The main goal was to measure the change from baseline in the Clinical Dementia Rating – Sum of Boxes (CDR-SB), a standard measure of cognition and daily function. Novo Nordisk reported that semaglutide did not outperform the placebo in slowing CDR-SB progression, meaning the treatment did not postpone disease worsening during the two-year analysis.
The company noted improvements in certain Alzheimer’s-related biomarkers in both studies, but these changes did not lead to measurable clinical benefit. Quantitative CDR-SB data and complete secondary endpoint results have not been released yet and will be shared at upcoming scientific meetings.
Safety findings were in line with the known profile of semaglutide in metabolic conditions. No new safety issues came up, and overall tolerability matched previous experience across millions of patient-years in type 2 diabetes and obesity.
Martin Holst Lange, Novo Nordisk’s chief scientific officer, stated that the program was pursued despite the low likelihood of success because of the unmet need in Alzheimer’s disease, adding that the benefits of semaglutide remain unchanged in its approved uses.
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The Alzheimer’s drug pipeline remains active and diverse, yet showing meaningful clinical effects is still challenging. As of January 1, 2025, researchers were testing 138 experimental drugs in 182 clinical trials, which included 48 Phase III programs, 86 Phase II studies and 48 Phase I studies across 15 biological pathways, such as amyloid, tau, inflammation, neurotransmission, metabolism and synaptic health. Many studies now enroll participants based on specific biomarkers to better match treatments with the underlying biology of the disease.
A 2025 review of 1,681 Alzheimer’s disease trials registered on clinicaltrials.gov between roughly 2000 and December 31, 2023, found that only about 11% moved on to Phase III. Many could not progress past early-stage testing because of insufficient safety or efficacy.
Meanwhile, related developments continue in the field. Lantheus recently moved ahead with an FDA submission for MK-6240, a tau-targeted PET imaging agent meant to help with diagnosis and trial selection. Eisai and Biogen submitted a weekly subcutaneous autoinjector version of lecanemab for early Alzheimer’s disease. This formulation is intended to allow for at-home dosing if approved.
Novo Nordisk will discontinue the one-year extension phase of both trials due to the lack of efficacy observed in the main analysis.
Top-line data will be shared at the Clinical Trials in Alzheimer’s Disease conference on December 3, 2025, with full results coming at the 2026 Alzheimer’s and Parkinson’s Diseases Conference in March.
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