Some researchers are celebrating this week’s announcement that a drug candidate for Alzheimer’s disease slowed the rate of cognitive decline for people in a clinical trial by 27%. Others, however, remain hesitant, wanting to see data beyond what was disclosed in a 27 September press release. If the results stand up, the treatment — called lecanemab — would be the first of its kind to show a strong signal of cognitive benefit in a robust trial.
“It’s such a win for our field,” says Liana Apostolova, a neurologist at the Indiana University School of Medicine in Indianapolis.
The results are “quite promising”, says Caleb Alexander, an internal-medicine specialist and epidemiologist at the Johns Hopkins Bloomberg School of Public Health in Baltimore, Maryland, and an advisory committee member for the US Food and Drug Administration (FDA). But, he adds, “we’ll have to see what the full analysis of the trial suggests”. Alexander and others also note that, although the results indicate that lecanemab does provide some clinical benefit, the degree to which it does so is small.
Developed by Eisai, a pharmaceutical company in Tokyo, and biotechnology firm Biogen in Cambridge, Massachusetts, lecanemab is a monoclonal antibody designed to clear clumps of protein from the brain that many think are a root cause of Alzheimer’s disease. This theory, known as the ‘amyloid hypothesis’, holds that the protein amyloid-β accumulates into toxic deposits as the disease progresses, ultimately causing dementia.
Whether or not lecanemab confirms the amyloid hypothesis remains to be seen, researchers say.
“I don’t think one study will prove a very long-standing controversial hypothesis,” says Brent Forester, director of the Geriatric Psychiatry Research Program at McLean Hospital in Belmont, Massachusetts, who helped to run the clinical trial for lecanemab. “But one positive study supports the hypothesis.”
Amyloid is “associated with the problem, but it isn’t ‘the’ problem”, says George Perry, a neurobiologist at the University of Texas at San Antonio and a sceptic of the amyloid hypothesis. “If you modulate it, of course you can have some small benefit.”
Small, but significant
Even a modest benefit would probably be appreciated by the tens of millions of people living with Alzheimer’s disease worldwide. “These are the most encouraging results in clinical trials treating the underlying causes of Alzheimer’s to date,” said the Alzheimer’s Association, a research funder and patient advocacy organization, in a statement.
Last year, the FDA controversially approved aducanumab, another monoclonal antibody developed by Biogen, to treat Alzheimer’s — without a clear signal of cognitive benefit. Two incomplete phase III trials demonstrated that the drug could clear amyloid from the brain, but only one subset of participants showed a slowing in cognitive decline.
By contrast, lecanemab’s phase III trial, called Clarity AD, ran uninterrupted for a full 18 months and slowed decline to a statistically significant extent. The topline results released by Eisai and Biogen describe findings from almost 1,800 people with early-stage Alzheimer’s disease living in more than a dozen countries.
Participants received intravenous infusions of either lecanemab or a placebo every two weeks for the duration of the trial. Their cognition was assessed using an 18-point scale called the Clinical Dementia Rating–Sum of Boxes (CDR–SB). Clinicians calculate a person’s CDR–SB score by interviewing them and their carers, and testing the person’s abilities in areas such as memory and problem solving.
Not only did lecanemab decrease amyloid in people’s brains, but those receiving treatment scored, on average, 0.45 points better on the CDR-SB than those in the placebo group at the 18-month mark.
It’s a “really tiny and almost unnoticeable difference from placebo”, says Rob Howard, a psychiatrist at University College London. Although he and others differ in what a clinically important result would be, they give a range of 0.5 to 2 points.
Still, lecanemab could be approved as a drug on the basis of the data. The question will be whether the benefit it brings is worth the risks. During the trial, about 20% of participants who received lecanemab showed abnormalities on their brain scans that indicated swelling or bleeding, although less than 3% of those in the treatment group experienced symptoms of these side effects. By contrast, during the phase III trials for aducanumab, 40% of participants showed signs of brain swelling on their scans.
The FDA is reviewing lecanemab for ‘accelerated approval’ on the basis of phase II results that showed a decrease in amyloid. The new phase III results could tip the scales in favour of approval, although they are not formally part of the review. The agency expects to announce its decision on 6 January.
“It’s clear that everybody’s going to be watching this one closely — as they should be,” Alexander says. The FDA approved aducanumab using the same programme, he says, so a precedent has been set that could affect future anti-amyloid drugs.
Biotech firm Roche, based in Basel, Switzerland, will release phase III results later this year for its antibody, gantenerumab. And Eli Lilly, in Indianapolis, plans to publish results for its candidate, donanemab, next year.
Researchers say that amyloid is only one component of Alzheimer’s disease, however.
“There is a very detrimental second protein called tau that needs to be addressed,” says Apostolova, who has consulted for Biogen and Eisai. Tau also deposits in the brains of people who have Alzheimer’s. “And tau is actually the one that really strongly correlates with cognitive decline,” she adds.
A multi-drug approach targeting both amyloid and tau “would be the most successful in terms of a relentless neurodegenerative disease such as Alzheimer’s”, Apostolova says.
Forester widens that concept even further, suggesting that people with Alzheimer’s, and their carers, need support beyond medication, including education and guidance on how to manage disease progression.
“All of this has to be a part of holistic dementia care,” Forester says. “You can’t intervene with a drug in a vacuum.”