By Deena Beasley and Julie Steenhuysen
(Reuters) -Studies from Novo Nordisk due early next month will give the strongest indication yet of whether blockbuster GLP-1 drugs - a class being used by millions for diabetes and weight loss - can slow progress of Alzheimer's disease.
Two trials, described by Novo as a "lottery ticket," are testing its older diabetes pill Rybelsus that has the same active ingredient - semaglutide - as Ozempic and Wegovy in thousands of people with mild Alzheimer's. The goal is to decrease patients' rate of cognitive decline by at least 20%.
Alzheimer's experts say success would usher in a convenient new treatment to slow progression of the mind-robbing disease defined by toxic amyloid plaques in the brain that affects 50 million people globally.
Regardless of the results, researchers expect to glean important clues for future study into how and why these types of drugs, which include Eli Lilly's Zepbound and Mounjaro, may be useful against the disease.
"It really has a chance to be transformational," Alzheimer's Association Chief Science Officer Maria Carrillo said.
She and other Alzheimer's experts told Reuters it's not clear how drugs that target the GLP-1 receptor impact the brain.
Most of the evidence going into the trials supported the use of GLP-1s in patients who have dementia associated with diabetes and obesity.
The Alzheimer's studies were launched in 2021 based on animal evidence and analysis of human studies showing a reduced risk of dementia or Alzheimer's in diabetes patients treated with GLP-1s, a Novo spokesperson said. A small study of the company's older injectable GLP-1, liraglutide, found it slowed the loss of brain volume in people with mild Alzheimer's.
AFFECT ON BRAIN UNCLEAR
About 60% of dementia patients have Alzheimer's, while the remainder have diseases like vascular dementia, caused by blocked blood flow to the brain. Many have more than one type of dementia.
Because the trials required all participants to have confirmed Alzheimer's disease, it was difficult to recruit patients who also had vascular dementia - common in people with diabetes - because their condition was too advanced to qualify, said Dr. Mary Sano, a Mount Sinai Alzheimer's researcher and investigator on the studies.
Scientists said it remains unclear how GLP-1s in prior studies reduced the risk of dementia. The drug may have had a direct effect in the brain or improvements such as weight loss or reduced inflammation in the body may protect the brain.
And not all GLP-1s are the same. Studies in mice suggest liraglutide, sold as Victoza and Saxenda, can enter the brain more easily than semaglutide, said Dr. Heather Ferris, an endocrinologist at the University of Virginia.
Ferris is expecting "positive, but paltry positive results" from the Novo studies.
Dr. David Knopman, a neurologist at the Mayo Clinic in Rochester, Minnesota, said it is "totally unknown what the link is between the GLP-1 target in the brain and Alzheimer's pathology, and that is not a good sign."
There are currently two drugs approved for slowing Alzheimer's by removing amyloid from the brain, Lilly's Kisunla and Leqembi from Eisai and Biogen. They are given as infusions or injections and were shown in clinical trials to slow disease progression by close to 30%.
They also carry the risk of serious side effects and require regular scans.
RESULTS MAY GUIDE FUTURE TRIALS
Dr. Howard Fillit of the Alzheimer's Drug Discovery Foundation, which funds Alzheimer's research including the liraglutide study, said Novo's trials could shed light on the impact of GLP-1s on age-related changes to brain metabolism that occur before the formation of amyloid plaques.
The studies would be considered clear successes if Rybelsus slows cognitive decline by close to 30%, he said.
If not, the results could help guide future trial design, including potential combinations of GLP-1s with existing Alzheimer's drugs, Fillit said.
Lilly said it continues "to closely monitor the evolving science to better understand" the role of GLP-1s in brain health.
Lilly is currently studying whether Kisunla can prevent Alzheimer's before symptoms arise. That trial is due to conclude in 2027. Eisai and Biogen are conducting a similar study of Leqembi. Eisai said in a statement that if the Novo trials show a significant clinical benefit, semaglutide may be complementary to a drugs like Leqembi.
SUCCESS COULD LIFT NOVO SHARES
If Rybelsus slows cognitive decline in early Alzheimer's, it would be safer and more convenient than amyloid-lowering drugs, experts said. Still, Rybelsus can be challenging as it needs to be taken on an empty stomach, 30 minutes before eating, drinking, or using any other oral medication.
Clear success could bump up Novo's shares by as much as 10%, while a failure could cause them to slump by 5%, Wall Street analysts predicted.
Novo is slated to present its results on December 3 in San Diego at the Clinical Trials on Alzheimer's Disease meeting, although it could announce some data before then.
"An oral medication that was safe is a big deal in terms of marketability. There will be a very low threshold for a drug like that," Knopman said.
(Reporting By Deena Beasley and Julie Steenhuysen; Editing by Caroline Humer and Bill Berkrot)
