The results from two Phase III trials announced this week show Novo Nordisk’s GLP-1 agonist drug semaglutide, approved at different doses to treat both obesity and type 2 diabetes, is not effective at reducing symptoms of Alzheimer’s disease.
The Evoke and Evoke+ trials both failed to meet their primary endpoints, a significant change in the Clinical Dementia Rating–Sum of Boxes (CDR–SB) score after two years of treatment. The CDR-SB is a composite score of different early Alzheimer’s symptoms like memory and ability to perform daily tasks.
The Danish big pharma will now discontinue development of semaglutide for this indication. This echoes similar results seen last year for liraglutide, an older GLP-1 agonist also developed by Novo Nordisk.
Although GLP-1 receptor agonists were first developed to treat type 2 diabetes and later obesity, some early evidence suggested they may also have anti-Alzheimer’s effects. Research showed they have neuroprotective effects in animal and cellular studies, reducing oxidative stress, limiting deposition of beta-amyloid plaques, and decreasing tau phosphorylation. Despite these early hopes, trials in humans have not shown significant benefits against Alzheimer’s.
Evoke and Evoke+ were very similar trials including 1,855 and 1,953 people respectively, who were randomized to treatment with semaglutide or placebo for three years. The participants were aged 55–85 years and had mild cognitive impairment or mild dementia due to Alzheimer’s disease.
“Based on the significant unmet need in Alzheimer’s disease as well as a number of indicative data points, we felt we had a responsibility to explore semaglutide’s potential, despite a low likelihood of success. We are proud to have conducted two well-controlled Phase III trials in Alzheimer’s disease that meet the highest standards of research and rigorous methodology,” said Martin Holst Lange, MD, PhD, chief scientific officer and executive vice president of Research and Development at Novo Nordisk, in a press statement.
“While semaglutide did not demonstrate efficacy in slowing the progression of Alzheimer’s disease, the extensive body of evidence supporting semaglutide continues to provide benefits for individuals with type 2 diabetes, obesity, and related comorbidities.”
Originally a 1-year extension period was planned for the two trials but will now be discontinued due to the negative results. Novo’s Nasdaq stock dropped more than five percent as a result of the announcement.
It remains to be seen whether Eli Lilly’s tirzepatide, a dual GLP-1 receptor and gastric inhibitory polypeptide receptor agonist, will have any beneficial effects in people with neurodegenerative diseases like Alzheimer’s in late-stage trials.
