Blockbuster GLP-1 Diabetes and Weight Loss Drugs Fails in Alzheimer’s Trial
Novo Nordisk, the drugmaker behind Wegovy and Ozempic, took a longshot gamble, and lost. Its GLP-1 drug semaglutide failed to treat Alzheimer’s across two large trials.
Based on studies suggesting people taking a glucagon-like peptide-1 (GLP-1) could be less likely to develop Alzheimer’s, Novo Nordisk set up two large trials of its drug, semaglutide — sold as the popular diabetes and obesity drugs Ozempic and Wegovy. On Nov. 24, the company announced that the drug altered some biomarkers of Alzheimer’s but ultimately failed to slow cognitive decline.
“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,” Martin Holst Lange, chief scientific officer at Novo Nordisk said in a press release. “We sincerely thank all participants and their caregivers for their meaningful contributions.”
The class of drugs, derived from the protein in the venom of the Gila monster, a large black lizard with pink-orange markings, has sparked a revolution in the treatment of metabolic disease. GLP-1s have excelled in treating not only obesity and diabetes, but also sleep apnea, cardiovascular disease, and liver scarring. And, before this week’s announcement, many had hoped that Alzheimer’s might soon be added to that list.
The ABCs of GLP-1 drugs
GLP-1 is a natural hormone released after eating, which stimulates the pancreas to regulate blood glucose levels and signals to the brain that the body is full.
“These drugs are mimicking that hormone and they’ve been made longer acting — so they stay in your system for a longer period of time,” University of Virginia endocrinologist Dr. Heather Ferris told Being Patient in a LiveTalk. When combined with changes in diet and exercise, this class of drugs outperforms other diabetes and obesity medications.
The first GLP-1 drug, exenatide, hit the market in 2005, and since then, companies have engineered more effective versions. Novo Nordisk’s GLP-1, sold as Wegovy or Ozempic, and Eli Lilly’s tirzapetide, sold as Mounjaro, are relative newcomers to the market today. Mounjaro also mimics another hormone called glucose-dependent insulinotropic polypeptide (GIP). Many more GLP-1 drugs are in development.
GLP-1 for Alzheimer’s?
Both obesity and diabetes, which are treated by GLP-1 drugs, are major risk factors for Alzheimer’s. People who take these medications are less likely to develop the disease, raising the possibility that it could also treat the disease. But this connection was never certain. Drugs that treat other Alzheimer’s risk factors, like herpes virus infection or high cholesterol, don’t seem to benefit people with the disease in well-controlled clinical trials. Another GLP-1 drug, liraglutide, ultimately failed in clinical trials for Alzheimer’s, despite showing some signal that it might slow cognitive decline. Despite lowering disease biomarkers, Novo Nordisk’s semaglutide failed to buck the trend.
What the experts say
The negative data was disappointing for many neurologists.
“It would have been great for our patients to have access to a safe, orally administered treatment with other potential benefits,” Dr. Eric Reiman, the executive director of the Banner Alzheimer’s Institute told Being Patient.
To some, like Dr. Nathaniel Chin, medical director of the Wisconsin Alzheimer’s Disease Research Center, the results were not surprising. “There wasn’t really clear evidence that GLP-1s were going to directly impact the actual mechanisms” of Alzheimer’s neurodegeneration, he told Being Patient.
Laura Nisenbaum, executive director of drug development at the Alzheimer’s Drug Discovery Foundation, remained optimistic. “One thing that I reflect on and consider is that even some of the early anti-amyloid therapies that ultimately failed to slow disease progression did show some change in the Alzheimer’s biomarkers,” she told Being Patient.
All the experts told Being Patient that it might still be worth targeting people with Alzheimer’s biomarkers before symptoms set in.
What’s next for Novo Nordisk?
On Dec. 3, the Danish drugmaker will present more extensive data from its two large Phase 3 trials of semaglutide, involving 3,808 total participants. Since the trial failed, the company also announced that they’re halting the one-year open label extension trial period, where all participants including those who initially received the placebo, would have the opportunity to take the drug.
Despite the lack of efficacy, Chin emphasized the trial was “impressive” and well conducted. The biomarker data might point to specific groups of people who might still benefit and provide more information or how these drugs impact the biology of Alzheimer’s. “It just wasn’t the outcome people were hoping for.”
UPDATE: November 27 9:10AM ET. Added comments from neurologists and researchers about the trial’s findings.
