Analysis-Undeterred by Novo Nordisk failure, scientists consider GLP-1s as Alzheimer's prevention

By Julie Steenhuysen

CHICAGO (Reuters) -Novo Nordisk's highly anticipated but ultimately unsuccessful Alzheimer's trials were a long shot for the maker of blockbuster drugs Ozempic and Wegovy, but scientists are still asking if GLP-1 drugs should be tested to prevent the disease in people at risk.

Novo's trials tested Rybelsus, an older pill form of semaglutide, the same main ingredient in Ozempic and Wegovy injections. The drug failed to meet the studies' primary goal of delaying cognitive decline in hundreds of people with early-stage Alzheimer's disease.

But in a release scant on details, the Danish drugmaker said Rybelsus did improve some unspecified Alzheimer’s-related biological processes in both trials - clues that could help guide new studies, Alzheimer's experts said.

That leaves open "a tiny window of hope that in future this drug might be effective if used earlier as a preventative strategy," said Professor Tara Spires-Jones, director of the Centre for Discovery Brain Sciences at the University of Edinburgh.

Spires-Jones noted that diabetes and obesity are both associated with increased risk of developing Alzheimer’s, conditions that are treated effectively with the GLP-1 drugs now taken by millions of people.

"Future trials are needed to confirm whether GLP-1 drugs might be effective in preventing Alzheimer’s disease,” she said.

Other GLP-1 drugs include Novo rival Eli Lilly's Zepbound and Mounjaro, which also hit an additional target called GIP.

DETAILS EXPECTED NEXT WEEK

Novo plans to discuss the findings at an Alzheimer's conference in San Diego on December 3.

Dr. Eric Reiman, chief executive of the Banner Alzheimer's Institutes in Arizona, said the results are disappointing but do not rule out GLP-1s for people at risk of the disease but who don't yet have symptoms.

"I'm eager to see the trials' biomarker findings and other details of the study next week, including any findings that might help the field consider its potential benefits in cognitively unimpaired people," he said.

Dr. Zaldy Tan, a geriatrician at Cedars-Sinai in Los Angeles, said Novo's cancellation of the one-year follow-up trial suggested to him that "it wasn't promising at all."

Nevertheless, he said he is waiting to hear about other outcome measures, such as changes in Alzheimer's-related proteins in the blood. 

DATA SHOW EARLY GLP-1s CUT DEMENTIA RISK

Novo's trials focused on people with early Alzheimer's disease as confirmed by the presence of clumps of a protein called beta amyloid in their brain, the target of the two approved treatments for the mind-wasting condition.

Much of the evidence from large population studies suggesting a potential benefit from GLP-1s comes from studies of people with diabetes who are at increased risk of vascular dementia, a condition marked by damage in small blood vessels in the brain.

An April study in JAMA Neurology of medical records from nearly 400,000 people with diabetes aged 50 and older found that those taking GLP-1s had a 33% reduced risk of developing dementia. 

"When we look back at very large populations, people who got GLP-1s appeared to not get Alzheimer's disease as frequently as people who did not take it or who took different diabetes medications," said Dr. Steven DeKosky of the University of Florida's Alzheimer’s Disease Research Center in Gainesville, who was part of that study team.

Even before Novo's preliminary results were released, Dr. Mary Sano, a Mount Sinai Alzheimer's researcher and an investigator in the trials, expressed concern that the focus on testing the drug in patients with confirmed Alzheimer's may have inadvertently excluded many people with diabetes and potentially vascular dementia from the trial. 

Ivan Koychev, clinical associate professor in neuropsychiatry at Imperial College London, said in an emailed comment that when the disease is more advanced, preventing further decline in the underlying biology may not be sufficient to show a clinically meaningful benefit.

“This is a recurring theme in Alzheimer’s disease therapeutics," he wrote. "The results reinforce the need to test these agents much earlier, ideally years before symptoms emerge, when neuronal systems are more intact and the potential for clinical benefit is greater."  

(Reporting by Julie Steenhuysen; Editing by Caroline Humer and Bill Berkrot)