LONDON: Alzheimer’s trials testing Novo Nordisk’s blockbuster GLP-1 drug semaglutide, despite their failure, underscore a shift toward approaching the brain-ravaging disease as a system of complex pathways that has transformed the field of cancer therapeutics in recent years, experts say.
Only two drugs have been approved to slow Alzheimer’s – Eli Lilly’s Kisunla and Lakembi Issai and Biogen. Both have been shown to delay disease progression by about 30% by removing toxic amyloid plaques from the brain, but progress is being made in identifying other targets and strategies to arrest the disease.
Globally, more than 55 million people have dementia, of which about 60% of cases are caused by Alzheimer’s, which is defined by the presence of amyloid and tau proteins in the brain.
“All diseases of aging, they all need combination therapy,” said Howard Fillitt of the Alzheimer’s Drug Discovery Foundation, one of the experts at a recent Alzheimer’s disease meeting who discussed the research shift. “Targeting just one route is not enough.”
Blood and genetic tests are becoming available to accurately identify biomarkers of the disease, but most diagnoses require a spinal tap or an expensive PET scan. Not all patients are likely to benefit equally from anti-amyloid treatment.
Some studies suggest that black patients may have more than one type of disease and that treating amyloid alone is not enough. Another analysis showed that men did better than women, as did patients with lower levels of tai.
Studies are expected to show that patients treated earlier in the course of the disease do better than patients who already have cognitive impairment.
Proceed to appropriate treatment
Cancer treatment, which once consisted of one-size-fits-all chemotherapy to kill fast-growing cells, has mushroomed into a wide range of drugs targeting specific genetic mutations and other specific signatures of malignant cells, in addition to immunotherapy.
David Watson, CEO of the Alzheimer’s Research and Treatment Center, said current research is “like oncology 20 years ago… It’s very exciting.” He cited advances in finding blood biomarkers for tau, amyloid and other signatures of the disease, as well as the genetic basis of Alzheimer’s, as reasons for optimism.
Novo’s results “underline a critical shift toward the next era of drug development, which will target the many interrelated biological drivers of this complex disease,” Fillitt said.
Oral semaglutide did not provide any cognitive benefit for people with early Alzheimer’s, but in March Novo will provide full test details, including a possible breakdown of patient characteristics, that could provide clues for others.
“We would like to see more prospective subgroup analyses,” including how people were treated early in the disease, said Don Brooks, head of neurodegeneration development at Eli Lilly.
Brooks said Lilly, which makes the top-selling GLP-1 tirzepetide sold as Monjaro and Zepbound, is “still looking” at whether the class has a role in Alzheimer’s. But the Indianapolis-based company’s current GLP-1 brain-health program is focused on alcohol and tobacco use disorders.
Kisunla and Lakembi, which requires close monitoring because of the risk of brain inflammation, are being tested in people with Alzheimer’s who do not yet have symptoms. The Kisunla study is first due in 2027, and Lilly has hinted that interim results could come sooner.
Drugs with multiple targets
Brooks said Lilly’s focus is on improving access to current treatments, but the field is moving quickly, including the development of drugs that target tau.
“One of the other areas to look at would be this idea of co-pathology or mixed dementia,” Brooks said. Many patients have more than one type of dementia and may require multiple treatments.
Biogen will have data on a novel drug targeting tau next year. Other tau drugs have failed, including a recently canceled program by Johnson & Johnson.
Roche recently began late-stage trials of its drug trontinemab, which binds an amyloid antibody to a “brain shuttle,” allowing it to cross the blood-brain barrier, unlike Kisunla or Lekambi.
Trontinemab is safer than current amyloid drugs and studies show it slows disease progression by more than 30% of that seen with those drugs, said Luca Kulik, head of early neuroscience at Roche. It may be a better option for patients with two copies of an Alzheimer’s-related gene that puts them at higher risk of brain swelling or bleeding.
Ennovis Bio is developing drugs with multiple targets. Its experimental drug buntanetape, now in phase 3 testing, targets amyloid, tau, and two other neurotoxic proteins.
Annovis CEO Maria McKecchini said the previous study failed because it allowed for insufficient screening for many participants who did not actually have Alzheimer’s.
“When we removed them with a blood test, we found a highly statistically significant cognitive improvement,” she said. “We assume doctors know what Alzheimer’s and Parkinson’s are… but maybe they don’t.”
(Reporting by Dina Beasley; Editing by Carolyn Hummer and Bill Berkrot)
