Novo Nordisk says it still thinks GLP-1 drugs could be a promising treatment for Alzheimer’s, despite two major trials last month that found an older drug similar to Ozempic had no effect in slowing early-stage disease.
While GLP-1 drugs have become synonymous with dramatic weight loss, they’ve also become one of the most closely watched experimental approaches for slowing Alzheimer’s, a disease with few treatment options.
That’s why Novo Nordisk’s announcement last month that it discontinued two large trials — evoke and evoke+ — was viewed as a major setback for Alzheimer’s researchers and patient advocates.
“This is not what we hoped for,” Dr. Peter Johannsen, Novo Nordisk’s international medical vice president of obesity and cardiometabolic, said in an interview. “We really did expect a change.”
Scientists have spent years studying how GLP-1 medications affect inflammation, metabolism and blood vessels in the brain — factors long suspected to contribute to Alzheimer’s, said Donna Wilcock, the director of the Center for Neurodegenerative Disorders at the Indiana University School of Medicine. Obesity and diabetes — both treated by GLP-1 drugs — are also risk factors for Alzheimer’s and can cause changes in the brain that look similar to the disease.
“If you look at everything that we currently understand about how the GLP-1s act in the body, all that kind of points to maybe they’ll do something in Alzheimer’s,” Wilcock said.
On Wednesday, Novo Nordisk scientists presented the findings of their Phase 3 trials at the Clinical Trials on Alzheimer’s Disease conference in San Diego. The studies showed an oral version of semaglutide for Type 2 diabetes, sold under the brand name Rybelsus, didn’t slow the progression of memory and thinking problems in older adults. Semaglutide is the active ingredient used in Ozempic and Wegovy.
The trials included almost 4,000 older adults in total with mild cognitive impairment or early-stage Alzheimer’s disease. Participants took either Rybelsus or a placebo for two years. Cognitive decline was measured using a rating scale that focused on six areas: memory, orientation, judgment and problem solving, community affairs, home and hobbies, and personal care.
However, there were signs that the drug was having an effect under the surface, Johannsen said.
Biomarkers — signs that show whether a person is responding to a treatment — suggested reduced inflammation and slower neurodegeneration in people who got Rybelsus. The reductions were modest, at around 10%, compared with a placebo, and Johannsen said it may take closer to 20% or 25% to translate into a real clinical benefit.
“We’re happy to see that it actually moves some of the biomarkers that are very related” to Alzheimer’s, Johannsen said, adding that the company is still reviewing all the data. “We’ll of course assess all of this and then we’ll see what the future brings.”
Too low of a dose?
Dr. Ronald Petersen, a neurologist at the Mayo Clinic in Rochester, Minnesota, who was not involved in the research, said a possible explanation for the disappointing results could be flaws in the trials, including that researchers gave participants too low of a dose.
Participants got the highest available dose of Rybelsus. That dose, however, is far below what’s given in weekly semaglutide injections.
Oral forms of medications also tend to be less effective than injections. That’s because the stomach acid can break down the drug before it reaches the bloodstream.
“Perhaps they were underdosed,” Petersen said. “They’ve got a lower dose than they had used for other indications.”
Johannsen said patients in the trial had high levels of semaglutide in their blood — even slightly higher, on average, than what was seen in some of the diabetes trials using the weekly injections.
“They did get exposed to semaglutide; they did get it into the blood,” he said.
Wilcock said using injections could be risky: The trial was made up of mostly older adults, who are often frail and could face health risks if they lost too much weight.
“If they progress to dementia, they sometimes have issues with diet and food, so do we want to exacerbate those things?” she said.
A different mechanism
Petersen was also critical of how the trials measured cognitive decline.
Researchers relied on the CDR-SB, a standard scale used in Alzheimer’s studies. It’s the same scale that was used in the trials for Leqembi and Kisunla, two drugs that aim to slow the progression of the disease by clearing clumps of protein called amyloid plaques from the brain.
Results presented Wednesday showed the CDR-SB score for people who got Rybelsus was not statistically different from those who did not get the drug.
But GLP-1 drugs don’t target amyloid. They act through different pathways in the brain and body, which means the usual cognitive tests may not be sensitive to the kinds of changes these drugs might produce.
“It could be that drugs like this work on other mechanisms, not Alzheimer’s disease, per se,” Petersen said. “Consequently maybe the CDR is not the best measure. With their mechanism of action, it may be quite different.”
Petersen said that raises a challenge for future trials: A different mechanism may require a different way of measuring how well it works, something regulators may be reluctant to accept.
“They don’t like you testing a drug with a nonspecific target using endpoints that aren’t traditionally tied to what you’re treating,” he said.
Dr. Paul Edison, a professor of neuroscience at Imperial College London who worked with Novo Nordisk on an earlier Alzheimer’s trial, said the participants in the trials may have been treated too late in their disease.
“GLP-1 therapies appear to work upstream, improving insulin signalling, dampening inflammation, and supporting mitochondrial health,” he wrote in an email. “These processes may help prevent or delay early neurodegeneration but may not reverse or halt disease once protein aggregation and synaptic loss are well underway.”
Even though the trials enrolled people with “early Alzheimer’s,” Edison noted that the disease likely had been developing silently for decades.
“For a metabolic-acting drug, this may simply be too late,” he said.
Other forms of dementia
Johannsen suggested it isn’t off the table that the drugmaker could look into testing even earlier in the disease or before people show symptoms.
“That, of course, is a long discussion and very much where the field in many ways is moving,” he said.
Johannsen also said that outside experts have suggested that the company should look into testing the drug for other forms of dementia.
“The reason for choosing Alzheimer’s disease for this program was very much the input from the FDA,” he said.
Petersen said that while the initial results were a “little discouraging,” many in the Alzheimer’s community still believe that GLP-1s can potentially help treat the disease.
“Is it possible that GLP-1s would be best in the preclinical space?” Petersen asked, referring to the earliest stages of the disease, before a person is diagnosed.
Wilcock said she doesn’t think research looking into GLP-1s and Alzheimer’s is “dead.”
“I don’t think it’s a nail in the coffin,” she said.
