Alzheimer's Drug Discovery Foundation Responds With Optimism to Disappointing Results from evoke Late Stage Trials

In a statement responding to data from the phase 3 evoke and evoke+ trials that found no impact of the oral glucagon-like peptide-1 (GLP-1) receptor agonist semaglutide on progression of Alzheimer disease (AD), Alzheimer’s Drug Discovery Foundation (ADDF) cofounder and chief science officer said, “Even negative trials move the field forward as they still teach us something. If we look to the early anti-amyloid studies, which were also negative, they offered critical lessons that informed later trials and ultimately helped bring drugs like lecanemab (Leqembi; Eisai) and donanemab (Kisunla; Eli Lilly) to market.¹

"As we dig further into the data, there is much we can learn, including exploring the potential of GLP-1 drugs as a preventive therapy, which may still hold promise.”¹

Biomarker Changes Are Encouraging

Novo Nordisk released topline findings from the evoke and evoke+ phase 3 trials of the oral incretin mimetic at the Clinical Trials on Alzheimer’s Disease (CTAD) meeting this week. Although treatment with the medication, which is currently approved for long-term management of obesity, did not yield statistically significant delay in progression of AD,^2,3 results from a substudy demonstrated nominally signficant reductions of approxiamtely 10% in prominent CSF AD biomarkers pTau 181, pTau217, and npTau205. The exploratory findings also revealed decreased levels of markers of neuroinflammation and neurodegneration.³ While they were modestly statistically significant, reductions were not large enough to translate into clinical benefit. Nonetheless, the ADDF emphasized, the changes will help guide future approaches to AD drug development.¹

“While the data presented at CTAD was disappointing, pursuing this type of high-risk, high-reward research into Alzheimer’s pathobiology is essential to deepening our understanding of the disease and continuing to advance the science,” Fillit added.¹

The ADDF stressed that the trials provide important information for refining future study designs, particularly for therapies that target metabolic and inflammatory pathways. The organization has supported GLP-1–related research for more than a decade, including nearly $1 million in funding beginning in 2011 for Paul Edison, MBBS, PhD, FRCPI, whose phase 2 work with liraglutide informed the foundation for later GLP-1 investigations.¹

Read More: Alzheimer Disease: New Brain Targets and the New Drug Pipeline

“The metabolic pathway remains a compelling area of investigation, and we will continue to pursue rigorous studies to determine how therapies targeting these mechanisms can be optimized and combined to achieve greater impact for patients,” Edison, professor of neuroscience in the faculty of medicine at Imperial College London, said in the ADDF statement.¹

Rationale for evoke and evoke+

The foundation for phase 3 development of semaglutide in AD was built on evidence from preclinical models, real-world data, and post hoc analyses of cardiovascular outcomes studies. This included a target trial emulation using electronic health records from more than 1 million adults with type 2 diabetes, which found a 40% to 70% lower risk of first-time AD diagnosis with semaglutide compared with other antidiabetic therapies.⁴

Over 3 years of follow-up, semaglutide was associated with reduced risk of AD, with a hazard ratio (HR) of 0.33 (95% CI, 0.21–0.51) vs insulin and 0.59 (95% CI, 0.37–0.95) vs other GLP-1 receptor agonists. Among adults aged 60 years and older (mean age 67.9), the 3-year incidence of first-time diagnosis was 0.33% compared with 0.16% in the broader population.⁴

“With more than 70% of the Alzheimer’s drug pipeline now focused on non-amyloid targets, the field is moving steadily toward an era of precision medicine and combination therapies,” Fillit said.¹ “The [evoke] trials are an important part of this progress, demonstrating how large-scale studies of novel pathways can deepen our understanding of [Alzheimer] biology. Even when primary endpoints are not met, biomarker and mechanistic data help illuminate how best to refine, repurpose, or combine therapies. This is exactly how combination treatment strategies have evolved in cancer – and it is the direction [Alzheimer] research must continue to move.”

Novo Nordisk expects to report full results from evoke and evoke+ at the International Conference on Alzheimer’s and Parkinson’s Diseases (AD/PD) in Copenhagen in March 2026.¹

References

1. New data from semaglutide trials provides critical insights to guide next generation of therapies targeting Alzheimer’s pathobiology. News release. Alzheimer's Drug Discovery Foundation. December 4, 2025. Accessed December 5, 2025.

2. Halsey G. Semaglutide fails to slow progression of Alzheimer disease compared to placebo: Novo Nordisk phase 3 trials update. Patient Care. November 24, 2025. Accessed December 3, 2025. https://www.patientcareonline.com/view/semaglutide-fails-to-slow-progression-of-alzheimer-disease-compared-to-placebo-novo-nordisk-phase-3-trial-update

3. Cummings J, Johannsen P, Atri A, et al. evoke and evoke+: Two phase 3 randomised placebo-controlled trials of semaglutide in participants with early-stage Alzheimer’s disease (NCT04777396 and NCT04777409). Presented at: 2025 CTAD Conference; December 1-4; San Diego, CA.

4. Wang W, Wang Q, Qi X, et al. Associations of semaglutide with first-time diagnosis of Alzheimer's disease in patients with type 2 diabetes: Target trial emulation using nationwide real-world data in the US. Alzheimers Dement. 2024;20(12):8661-8672. doi:10.1002/alz.14313