For the second time, an experimental drug has been proven to cut back the cognitive decline related to Alzheimer’s illness. On 3 May, pharmaceutical firm Eli Lilly introduced in a press launch that its monoclonal antibody donanemab slowed psychological decline by 35% for some individuals in a 1,736-person trial — a fee corresponding to that for competitor drug lecanemab. But researchers warn that till the total outcomes are printed, questions stay as to the drug’s medical usefulness, in addition to whether or not the modest profit outweighs the danger of dangerous unwanted side effects.
Like lecanemab, donanemab targets amyloid protein, which is believed to trigger dementia by accumulating within the mind and damaging neurons. The trial outcomes present robust proof that amyloid is a key driver of Alzheimer’s, says Jeffrey Cummings, a neuroscientist on the University of Nevada, Las Vegas. “These are transformative in an enormously essential method from a scientific perspective,” he provides. “They’re terrific.”
But Marsel Mesulam, a neurologist at Northwestern University in Chicago, is extra cautious. “The outcomes which might be described are extraordinarily important and spectacular, however clinically their significance is uncertain,” he says, including that the modest impact means that components aside from amyloid contribute to Alzheimer’s illness development. “We’re heading to a brand new period — there’s room to cheer, but it surely’s an period that ought to make us all very sober, realizing that there can be no single magic bullet.”
In the press launch, Eli Lilly stated that individuals with gentle Alzheimer’s who acquired donanemab confirmed 35% much less medical decline over 18 months than did those that acquired a placebo, and 40% much less decline of their capacity to carry out day by day duties. The firm says that it’s going to current the total outcomes at a convention in July and publish them in a peer-reviewed journal. It plans to use for approval by the US Food and Drug Administration (FDA) within the subsequent two months.
Promising therapies
FDA approval would make donanemab the third new Alzheimer’s therapy in two years. In January, the company granted accelerated approval to lecanemab, made by Biogen in Cambridge, Massachusetts, and Eisai in Tokyo. A examine1 printed in November confirmed that lecanemab slowed cognitive decline in 1,800 sufferers by 27% over 18 months. The FDA had beforehand permitted aducanumab, additionally made by Biogen and Eisai, on the premise of proof that it might scale back amyloid plaques within the mind, though it’s nonetheless unclear whether or not this results in a significant medical profit for folks with the illness.
Eli Lilly’s donanemab trial differed from Biogen’s lecanemab one in that individuals stopped taking the drug as soon as their amyloid ranges had dropped under a sure threshold. “The rationale is, if the goal is gone, why preserve taking pictures?” Cummings says. According to the press launch, about half of the trial individuals had been in a position to cease taking the drug in lower than one yr.
Diana Zuckerman, president of the National Center for Health Research, a non-profit assume tank in Washington DC, worries that stopping the drug might trigger the illness to rebound or worsen, as is the case with many psychiatric medicine. She warns that longer-term follow-up research can be wanted. “Any time you’re doing something that impacts the mind, you actually do should be cautious,” she says.
Eli Lilly additionally discovered that donanemab labored finest in folks whose brains contained solely average ranges of one other protein, known as tau, that can also be related to Alzheimer’s development. The firm had calculated its outcomes amongst its 1,182 trial individuals who had average tau ranges, however stated that the development was nonetheless statistically important once they mixed these sufferers with the 552 who had excessive ranges of tau.
Brent Forester, a geriatric psychiatrist at McLean Hospital in Belmont, Massachusetts, says it’s “fascinating” that eradicating amyloid additionally impacts tau: the connection between the 2 proteins, and their respective roles in illness development usually are not absolutely understood. “If we might perceive that higher, we would perceive why eradicating amyloid might need a medical impact,” he says.
Bleeding and seizures
Like lecanemab, donanemab carries a excessive threat of unwanted side effects — significantly a set of situations known as amyloid-related imaging abnormalities (ARIA) that may result in seizures and bleeding within the mind. Researchers assume that by attacking amyloid plaques, the antibodies inadvertently weaken blood vessels within the mind, and the results are particularly pronounced amongst people who find themselves taking anticoagulant medicine. Eli Lilly’s press launch stated that ARIA charges had been a number of occasions greater in individuals who acquired donanemab than in those that acquired placebos, and three sufferers within the trial died after experiencing the situation.
“The facet impact is the largest concern for all of us proper now,” says Forester, who led earlier trials of donanemab and is at the moment engaged on a lecanemab trial. He provides that individuals with gentle cognitive impairment perform pretty properly, and that even three deaths may be sufficient to sign that the danger of unwanted side effects outweighs the advantage of taking the drug.
Questions additionally stay about info that’s lacking from the announcement, together with whether or not donanemab labored in any respect amongst individuals who had excessive ranges of tau. “This entire publication-by-press-release is admittedly dangerous,” Zuckerman says.
Furthermore, the outcomes that Eli Lilly launched present solely a slowing of cognitive decline relative to the placebo group, reasonably than how a lot donanemab impacts absolutely the fee of an individual’s decline. It’s unclear, Zuckerman says, whether or not that distinction is nice sufficient to be noticeable to folks with Alzheimer’s and their households.
With a minimum of three monoclonal antibodies quickly to be in the marketplace, Mesulam worries that pleasure round them will lower drug firms’ enthusiasm for growing medicine for Alzheimer’s targets aside from amyloid. “The subsequent 20 to 25 years can be taken up by higher amyloid medicine,” he says. The Alzheimer’s market is more likely to be very profitable for drug firms — lecanemab, as an illustration, prices greater than US$26,000 per yr of therapy — however Mesulam worries that the price of Alzheimer’s medicine will pressure the US health-care system.
Still, the preliminary outcomes present “additional help that this remedy may have some function with the appropriate sufferers on the proper time in sickness”, Forester says. “I’m cautiously optimistic.”
This article is reproduced with permission and was first printed on May 4, 2023.
