Topline results from the phase 3 EVOKE and EVOKE+ studies of oral semaglutide in early Alzheimer’s disease (AD) show that the trials did not meet their primary endpoints, Novo Nordisk announced.

The two randomized, double-blinded trials enrolled 3808 adults aged 55-85 with mild cognitive impairment or mild dementia due to AD with confirmed amyloid positivity. 

Participants were randomly allocated to once-daily oral semaglutide 14 mg or placebo for 156 weeks (104-week main treatment phase and 52 week extension) in addition to standard care. 

The two trials did not confirm superiority of semaglutide vs placebo in the reduction of AD progression as measured by the change in Clinical Dementia Rating - Sum of Boxes score compared to baseline, the company reported.

While treatment with semaglutide resulted in improvement of AD-related biomarkers in both trials, this did not translate into a delay in disease progression, they noted. 

Consistent with previous semaglutide trials, the drug appeared to be safe and well tolerated in this patient population. 

“The decision to pursue an Alzheimer’s disease indication with semaglutide was based on real-world evidence studies, pre-clinical models as well as post-hoc analyses from diabetes and obesity trials,” the company noted. 

Based on the efficacy results observed in the overall study population, the 1-year extension period in the EVOKE and EVOKE+ trials will be discontinued, they said. 

End of the Road or a Path Forward?

“While it is disappointing that the trials did not meet their primary endpoints, they show a fundamental shift in how we approach the development of new Alzheimer’s treatments, expanding beyond amyloid to target the complete pathobiology of the disease,” Howard Fillit, MD, co-founder and chief science officer of the Alzheimer’s Drug Discovery Foundation, said in a statement. 

Riccardo De Giorgi, MD, DPhil, of the Department of Psychiatry at the University of Oxford, England, said in a statement from the UK nonprofit Science Media Center that while the early findings “do feel disappointing,” they represent “only a partial picture.” He noted that full data will be needed to clarify adherence, exposure-response patterns, and whether any subgroups may have benefited.

De Giorgi added that, in his opinion, the biomarker improvements “remain noteworthy. They suggest that semaglutide engaged relevant biological pathways, even if this did not translate into slower clinical progression. The oral formulation, compared with injectable options, may also have influenced outcomes, as sustained adherence in long Alzheimer’s trials is challenging.”

“More broadly, these findings reinforce two possibilities for the field: we may need to re-define the biological processes underlying Alzheimer’s dementia that we target and measure, or we may need to pursue similar agents with stronger brain penetration and more potent metabolic or anti-inflammatory effects,” De Giorgi said. 

Ivan Koychev, PhD, with Imperial College London, UK, also believes the biomarker changes are “encouraging” adding that they “align with the hypothesis that GLP-1-based therapies may exert a disease-modifying effect biologically.”

“However, by the time individuals have mild cognitive impairment or mild dementia, much of the neuronal loss and circuit disruption is already entrenched. At this point in the disease course, even meaningful shifts in fluid biomarkers may not translate into measurable improvements in cognition or daily functioning over a two-year trial,” Koychev told the Science Media Center. 

Also weighing in on the trial results, Joanne Pike, DrPH, Alzheimer’s Association president and CEO, said in a statement, “while these results are not what we had hoped for, they will contribute to our understanding of this devastating and fatal disease.”

“These results will help us refine our understanding of this class of drugs. Though this semaglutide pill did not help against Alzheimer’s, the field will continue to investigate this class of drugs, as they may act differently,” added Maria C. Carrillo, PhD, Alzheimer’s Association chief science officer and medical affairs lead. 

Topline results from the EVOKE and EVOKE+ trials will be presented December 3 at the Clinical Trials in Alzheimer’s Disease conference. Full results will be presented at the 2026 Alzheimer’s and Parkinson’s Diseases Conferences in March 2026.