Novo’s Alzheimer’s Hail Mary for semaglutide fails in EVOKE Phase 3 trials

Novo Nordisk A/S disclosed that its bid to expand the repertoire of GLP-1 receptor agonist semaglutide to Alzheimer’s disease (AD) has failed. After two years of testing in more than 3,000 patients across the twin Phase 3 EVOKE and EVOKE+ trials, topline results showed semaglutide did not demonstrate a statistically significant slowing of clinical decline in patients with early-stage Alzheimer’s.

Novo Nordisk was encouraged to explore the potential of the blockbuster obesity drug in AD after real-world and retrospective data suggested that patients taking GLP-1 agonists for type 2 diabetes or obesity had a lower incidence of dementia. Preclinical work supported the hypothesis that GLP-1R agonism might exert neuroprotective effects through anti-inflammatory, vascular, metabolic, and other AD-relevant pathways.

Launched in 2021, EVOKE and EVOKE+ were global, randomized, double-blind, placebo-controlled trials comparing once-daily oral semaglutide 14 mg with placebo in adults aged 55–85 with biomarker-confirmed mild cognitive impairment due to AD or mild AD dementia. The two studies enrolled more than 3,500 participants combined and were designed as parallel “replication trials” that could, if successful, immediately support a regulatory filing—a strategy Novo itself once described as a “lottery ticket.”

According to Novo’s announcement, semaglutide did produce favorable effects on certain disease-related biomarkers, but these improvements were insufficient to deliver a measurable clinical benefit. The company will not proceed with a planned one-year extension and intends to present full data at upcoming scientific meetings.

No active industry trials remain for GLP-1Rs in Alzheimer’s

AllSci data indicate that GLP-1 receptor agonists—including semaglutide—have shown the ability in preclinical studies to reduce amyloid-beta deposition, mitigate neuroinflammation, and improve cognitive performance, particularly spatial memory. Mechanistic studies suggest GLP-1R agonism can alleviate central insulin resistance, reduce oxidative stress, and modulate key neurodegeneration-linked signaling pathways such as PI3K/Akt, ERK, JNK, and GSK-3β, raising early hopes of disease-modifying potential (see here ).

Although several academic groups continue investigating semaglutide or liraglutide in Alzheimer’s and related dementias, no industry-sponsored clinical trials of GLP-1R agonists for AD remain active following the setback in EVOKE/EVOKE+.