Novo Nordisk says it continues to believe that GLP-1 drugs may be a promising treatment for Alzheimer's disease, despite two major tests last month who found that an older drug similar to Ozempic had no effect in slowing down early-stage disease.
While GLP-1 drugs have become synonymous with dramatic weight loss, they have also become one of the most carefully observed experimental approaches to slow Alzheimer's disease, a disease with few treatment options.
That's why Novo Nordisk announcement last month that two large studies were being stopped Evoke and Evoke+ was seen as a major setback for Alzheimer's researchers and patient advocates.
“This is not what we hoped for,” Dr. Peter Johansen, Novo Nordisk's global medical vice president of obesity and cardiometabolics, said in an interview. “We were really expecting a change.”
Scientists have spent years studying how GLP-1 drugs affect inflammation, metabolism and blood vessels in the brain. Factors long suspected to contribute to the development of Alzheimer's diseasesaid Donna Wilcock, director of the Center for Neurodegenerative Disorders at Indiana University School of Medicine. Obesity and diabetes, which are treated with GLP-1 drugs, are also risk factors for Alzheimer's disease and may cause changes in the brain it looks like a disease.
“If you look at everything we now understand about how GLP-1 works in the body, it all points to the fact that maybe they will do something in Alzheimer's disease,” Wilcock said.
On Wednesday, Novo Nordisk scientists presented results from their phase 3 studies at the Alzheimer's Disease Clinical Trials conference in San Diego. An oral version of the type 2 diabetes treatment semaglutide, sold under the brand name Rybelsus, does not slow the progression of memory and thinking problems in older people, the study found. Semaglutide is the active ingredient used in Ozempic and Vegovi.
The trial included nearly 4,000 older adults with mild cognitive impairment or early Alzheimer's disease. Participants took either Ribelsus or a placebo for two years. Cognitive decline was measured using a rating scale focusing on six domains: memory, orientation, judgment and problem solving, social affairs, home and hobbies, and self-care.
However, there were signs that the drug was having hidden effects, Johansen said.
Biomarkers—signs that indicate whether a person is responding to treatment—suggest reduced inflammation and slowed neurodegeneration in people infected with Rybelsus. The reduction was modest, about 10%, compared to placebo, and Johansen said it may take about 20 to 25% to have a real clinical effect.
“We're pleased to see that this does move some biomarkers that are highly associated” with Alzheimer's disease, Johansen said, adding that the company is still analyzing all the data. “We will of course evaluate all of this and then see what the future brings.”
Dose too low?
Dr. Ronald Petersen, a neurologist at the Mayo Clinic in Rochester, Minnesota, who was not involved in the study, said a possible explanation for the disappointing results could be flaws in the studies, including that researchers gave participants too low a dose.
Participants received the highest available dose of Ribelsus. However, this dose is much lower than that prescribed with weekly semaglutide injections.
Oral forms of medication also tend to be less effective than injections. This is because stomach acid can break down the drug before it enters the bloodstream.
“They may have been given an insufficient dose,” Petersen said. “They have a lower dose than other indications.”
Johansen said the patients in the study had high levels semaglutide in their blood—on average even slightly higher than what was observed in some diabetes studies using weekly injections.
“They were actually exposed to semaglutide, it got into their bloodstream,” he said.
Wilcock said using the injections could be risky: The study involved mostly older people, who are often frail and could face health risks if they lose too much weight.
“If they develop dementia, they sometimes have problems with diet and food, do we want to make those problems worse?” she said.
Another mechanism
Petersen was also critical of how the trials measured cognitive decline.
The researchers relied on the CDR-SB, a standard scale used in Alzheimer's disease research. This is the same scale that was used in the tests Lekembi and Kisunla, two drugs that aim to slow the progression of the disease. by clearing protein clumps called amyloid plaques from the brain.
The results, presented Wednesday, showed that the CDR-SB score of people who took Ribelsus was not statistically different from those who did not receive the drug.
But GLP-1 drugs do not target amyloid. They act in different pathways in the brain and body, meaning that routine cognitive tests may not be sensitive to the changes these drugs can cause.
“It's possible that drugs like these target other mechanisms than Alzheimer's disease itself,” Petersen said. “Therefore, perhaps CDRs are not the best measure. Given their mechanism of action, it may be completely different.”
Petersen said that poses a challenge for future trials: A different mechanism might require a different way of measuring how well it works, which regulators might be reluctant to accept.
“They don't like it when you test a drug with a nonspecific target, using endpoints that are not traditionally associated with what you're treating,” he said.
Dr Paul Edison, a professor of neurobiology at Imperial College London who worked with Novo Nordisk on an earlier Alzheimer's study, said trial participants may have received treatment too late.
“GLP-1 therapy appears to work in the opposite direction, improving insulin signaling, reducing inflammation, and maintaining mitochondrial health,” he wrote in an email. “These processes can help prevent or delay early neurodegeneration, but cannot reverse or stop the disease once protein aggregation and synaptic loss are in full swing.”
Although the trial involved people with “early-onset Alzheimer's disease,” Edison noted that the disease had likely developed undetected for decades.
“For a metabolic drug, it may simply be too late,” he said.
Other forms of dementia
Johansen suggested it was possible that the drugmaker could consider testing early in the disease or before people develop symptoms.
“This is certainly a long discussion, and in many ways the field is moving,” he said.
Johansen also said that outside experts have suggested that the company explore testing the drug for other forms of dementia.
“The reason Alzheimer's disease was selected for this program was largely due to input from the FDA,” he said.
Petersen said that although the initial results were “a little discouraging,” many in the Alzheimer's community still believe that GLP-1 could potentially help treat the disease.
“Is it possible that GLP-1s will be superior in preclinical practice?” Petersen asked, referring to the earliest stages of the disease before a person is diagnosed.
Wilcock said she doesn't think research into GLP-1 and Alzheimer's disease is “dead.”
“I don't think this is the nail in the coffin,” she said.
