The announcement that lecanemab, a drug candidate for Alzheimer’s disease slowed the rate of cognitive decline by 27% in a large, late-stage clinical trial, has sparked renewed optimism in a field that has had numerous false dawns, writes MedicalBrief. It also offers the manufacturer a second chance following its disastrous launch of Aduhelm, which despite scant evidence last year won regulatory approval for Alzheimer’s and has since bombed commercially.
Nature quotes Dr Caleb Alexander, an advisory committee member for the US Food and Drug Administration (FDA) and an internal-medicine specialist and epidemiologist at the Johns Hopkins Bloomberg School of Public Health as saying that the results are “quite promising”. 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 – contained in a press release from the pharmaceutical companies Biogen and Eisai – indicate that lecanemab does provide some clinical benefit, the degree to which it does so is small. 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. The companies plan to present more detailed results in November.
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 Dr Brent Forester, director of the Geriatric Psychiatry Research Program at McLean Hospital in 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.”
The New York Times writes that the results boost lecanemab’s chances of winning approval and offer renewed hope in a fields where even a modest benefit is 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.
Cognitive decline in the group of volunteers who received lecanemab, administered via intravenous infusion, was reduced by 27% compared with the group receiving a placebo in the clinical trial, which enrolled nearly 1 800 participants with mild cognitive impairment or mild Alzheimer’s.
The trial was the largest to date to test the amyloid hypothesis. Aduhelm was designed to work in a similar way. As with previous anti-amyloid drugs, some patients taking lecanemab experienced brain swelling or brain bleeding, but the prevalence of these side effects was lower than with Aduhelm and other experimental medications.
Eisai had already applied for accelerated approval, the type of approval given to Aduhelm. This allows the FDA to greenlight drugs if they have uncertain evidence of benefit but affect a disease’s biological pathway in a way that is considered reasonably likely to benefit patients.
The company said it would first continue with the accelerated approval process, with an FDA decision expected by early January, and then use the newer data to seek full approval. (Accelerated approval requires companies to do further trials and prove their drug works.)
Ivan Cheung, chairman and chief executive of Eisai, said the results represented “the first definitively positive large clinical trial to show you can indeed slow down Alzheimer’s disease at this very early symptomatic stage”. He said that the drug started to show a benefit to patients about six months after they began taking it and that the benefit increased until the trial ended, 18 months after patients started on the drug.
Some experts said the drug’s ability to slow cognitive decline — by 0.45 on an 18-point scale — was modest at best and might not be a difference that patients in the mild early stages of the disease would notice. Cheung said the company considered the results “very clinically meaningful,” but he added: “Of course, there are different opinions out there on defining what clinical meaningfulness is for this stage of disease.”
Dr Lon Schneider, director of the California Alzheimer’s Disease Center at the University of Southern California, said the effect “is small and would not be considered by many as a minimally clinically important difference”. However, he added, “others would strongly disagree and say it’s clinically meaningful.”
Other companies are also developing treatments that could shake up the market for Alzheimer’s drugs, which before Aduhelm had not seen a novel treatment for two decades. Before the end of this year, Roche is expected to report data from two studies of a drug known as gantenerumab.
The FDA is expected to make a decision on whether to grant accelerated approval to an Alzheimer’s drug from Eli Lilly, known as donanemab by early January, with results from a larger study of that drug due in the middle of next year.
See more from MedicalBrief archives:
America’s Veteran Affairs shuns controversial Alzheimer’s drug, noting ‘known safety signal’
Biogen’s Alzheimer’s drug gets cautiously optimistic review
US and EU approval sought for ‘ground-breaking’ Alzheimer’s drug
Two experimental drugs fail to halt Alzheimer’s disease