By Deena Beasley
Dec 12 (Reuters) – Alzheimer’s trials testing Novo Nordisk’s blockbuster GLP-1 drug semaglutide, despite their failure, underscore a shift to approaching the brain-wasting disease as a system of complex pathways, much the way the field of cancer therapeutics has been transformed in recent years, experts say.
Just two drugs are approved to slow Alzheimer’s – Eli Lilly’s Kisunla and Leqembi from Eisai and Biogen. Both were shown to delay disease progression by around 30% by removing toxic amyloid plaques from the brain, but progress is being made to identify other targets and strategies for arresting the disease.
Globally, over 55 million people have dementia, with about 60% of those cases caused by Alzheimer’s, defined by the presence of amyloid and tau proteins in the brain.
“All the diseases of aging, they all require combination therapy,” said Howard Fillit of the Alzheimer’s Drug Discovery Foundation, one of the experts at a recent Alzheimer’s disease meeting who discussed the research shift. “Just targeting one pathway isn’t going to be enough.”
Blood and genetic tests to accurately identify biomarkers of the disease are becoming available, but most diagnoses require a spinal tap or expensive PET scan. Not all patients are likely to benefit equally from anti-amyloid treatments.
Some studies suggest Black patients may have more than one type of disease and treating amyloid alone may not be enough. Other analyses have shown that men do better than women, as do patients with lower levels of tau.
Studies are expected to show that patients treated earlier in the course of the disease fare better than those who already have cognitive impairment.
MOVE TO TAILORED 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 precise signatures of malignant cells in addition to immunotherapies.
David Watson, CEO of the Alzheimer’s Research and Treatment Center, said current research “is like oncology 20 years ago… It’s super exciting.” He cited advances in detecting blood biomarkers for tau, amyloid and other signatures of the disease, as well as the genetic underpinnings of Alzheimer’s, as reasons for optimism.
Novo’s results “underscored a critical shift toward the next era of drug development, which will target the many interrelated biological drivers of this complex disease,” Fillit said.
Oral semaglutide provided no cognitive benefit for people with early Alzheimer’s, but Novo in March will provide full trial details, including a likely breakdown of patient characteristics that could yield clues for others.
“We want to see more potential subgroup analyses,” including how people treated earlier in the course of the disease fared, said Dawn Brooks, head of neurodegeneration development at Eli Lilly.
Lilly, which makes top-selling GLP-1 tirzepitide, sold as Mounjaro and Zepbound, is “still watching” whether the class has a role in Alzheimer’s, Brooks said. But the Indianapolis-based company’s current GLP-1 brain-health program is focused on alcohol and tobacco use disorders.
Kisunla and Leqembi, which need to be closely monitored due to the danger of brain swelling, are being tested in people with Alzheimer’s who do not yet have symptoms. The Kisunla study is due first, in 2027, and Lilly has signaled interim results could come earlier.
DRUGS WITH MULTIPLE TARGETS
Brooks said Lilly’s focus is on improving access to current treatments, but the field is moving quickly, including development of drugs that target tau.
“One of the other areas to watch is going to be this idea of co-pathologies or mixed dementia,” Brooks said. Many patients have more than one type of dementia and may need multiple treatments.
Biogen will have data next year on a novel drug targeting tau. Other tau drugs, including a program recently cancelled by Johnson & Johnson, have failed.
Roche recently launched late-stage trials of its drug trontinemab, which links an amyloid antibody to a “brain shuttle” allowing it to cross the blood-brain barrier, unlike Kisunla or Leqembi.
Trontinemab is safer than current amyloid drugs and studies are expected to show it slows disease progression by more than the 30% seen with those drugs, said Luka Kulic, head of early neuroscience at Roche. It could be a better option for patients with two copies of an Alzheimer’s-related gene that puts them at high risk of brain swelling or bleeding.
Annovis Bio is developing a drug with multiple targets. Its experimental drug buntanetap, now in Phase 3 testing, targets amyloid, tau and two other neurotoxic proteins.
Annovis CEO Maria Maccecchini said an earlier study failed because inadequate screening allowed for many participants who did not actually have Alzheimer’s.
“When we eliminated them by blood testing, then we got highly statistically significant cognitive improvement,” she said. “We assume that doctors know what’s Alzheimer’s and Parkinson’s… but maybe they don’t.”
(Reporting By Deena Beasley; editing by Caroline Humer and Bill Berkrot)
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