Novo Nordisk’s Rybelsus (oral semaglutide) has failed to demonstrate efficacy in a late-stage trial in Alzheimer’s disease, denting hopes of glucagon-like peptide-1 receptor agonists (GLP-1RAs) offering patients new treatment options.
During the Phase III EVOKE (NCT04777396) and EVOKE+ (NCT04777409) studies, the type 2 diabetes pill, which has the same active ingredient as star weight loss drug Wegovy (semaglutide), did not significantly slow Alzheimer’s progression compared with placebo after two years of treatments.
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This was evidenced by Rybelsus’ inability to exhibit a significant change in clinical dementia rating, sum of boxes (CDR-SB) scores from baseline. Despite having no significant impact on disease progression, once-daily treatment with Rybelsus did trigger improvements in Alzheimer’s disease-related biomarkers.
However, it seems that biomarker changes alone were not enough to keep the drug in development within Alzheimer’s disease, as Novo Nordisk is now discontinuing the one-year extension periods for both the EVOKE and EVOKE+ trials.
While Novo Nordisk’s next steps in Alzheimer’s remain unclear, investors have shown their sentiments towards the readout, as the pharma company’s stock dropped 5.8% from DKK 304.65 ($46.90) at market close on 21 November to DKK 287.00 at market close on 24 November. The company’s market cap currently sits at DKK 1.24tr ($191.32bn).
Novo Nordisk is not the only company to run into a roadblock in Alzheimer’s disease as of late, as Johnson & Johnson (J&J) announced it was discontinuing the AuTonomy study (NCT04619420) of posdinemab in the indication on 21 November. In the Phase II trial, the tau binder failed to significantly slow decline in early-stage patients.
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By GlobalDataResults “disappointing but unsurprising”
While the outcome of this trial is disappointing for the industry, patients and physicians alike, Novo Nordisk does not appear to be surprised by this outcome. In a 24 November statement, the company’s CSO and executive VP of R&D, Martin Holst Lange, noted that the studies had a “low likelihood of success”.
The pharma’s sentiments were echoed by Philippa Salter, managing neurology analyst at GlobalData Healthcare, who highlighted the historical challenges in translating data seen in large epidemiological studies into positive Phase III results.
Despite these previous difficulties, Salter noted that key opinion leaders (KOLs) previously interviewed by GlobalData had “consistently highlighted Rybelsus as a promising treatment option, so such a resounding negative result is perhaps a bit surprising”.
“Given that Novo Nordisk is cancelling the one-year extension period for both trials, it seems likely that the potential for GLP-1RAs is low in Alzheimer’s, as the company cannot see the value in keeping the trials running,” Salter added.
She also sees little hope for Rybelsus in the combination setting, as the EVOKE trials were already looking into the role of the GLP-1RA alongside standard of care (SoC) anti-amyloid drugs.
A glimmer of hope for Rybelsus in Alzheimer’s disease
While Salter does not see Rybelsus’ potential in Alzheimer’s disease, Howard Fillit, co-founder and CSO of the Alzheimer’s Drug Discovery Foundation (ADDF), took a different stance, noting that improvements in Alzheimer’s-related biomarkers in both trials could “suggest a path forward for Rybelsus as part of a combination therapy approach”.
In a LinkedIn post, Ivan Koychev, clinical associate professor in neuropsychiatry at Imperial College London, mirrored this sentiment to a degree.
“The pharmacoepidemiological data that originally motivated semaglutide’s evaluation in Alzheimer’s disease consistently pointed toward a preventive signal rather than an effect on symptomatic stages of dementia,” Koychev stated.
“In large real-world datasets, people exposed to GLP-1RAs over many years appear to have a lower risk of ever developing dementia, which suggests an influence on the earliest pathogenic processes rather than on established neurodegeneration,” he added.
This led Koychev to theorise that Rybelsus’ best use case is in the preventive setting. “These findings do not diminish the preventive epidemiological signal,” he said.
“Instead, they point us toward the next logical steps: targeting preclinical stages, leveraging biomarkers to identify those at highest risk, and understanding how metabolic interventions can reshape the trajectory of neurodegeneration before symptoms appear,” Koychev added.
Following the results of the EVOKE studies, Myles Minter, biotech equity research analyst at William Blair, noted that the investment company is now looking to Tau-silencing drugs as the next frontier of Alzheimer’s medicine.
A notable tau silencer in clinical trials is Biogen and Ionis Pharmaceuticals’ antisense oligonucleotide BIIB080. The candidate is currently being assessed in the Phase II CELIA study, which is set to read out in 2026.
Novo Nordisk will present topline results from the EVOKE and EVOKE+ studies at the Clinical Trials in Alzheimer’s Disease (CTAD) conference on 3 December. Full results of the study will debut at the 2026 Alzheimer’s and Parkinson’s Diseases Conferences (AD/PD) in March 2026.
