Sara Reardon, Nature, May 4, 2023
For the second time, an experimental drug has been shown to reduce the cognitive decline associated with Alzheimer’s disease. On 3 May, pharmaceutical company Eli Lilly announced in a press release that its monoclonal antibody donanemab slowed mental decline by 35% for some participants in a 1,732-person trial — a rate comparable to competitor drug lecanemab. But researchers warn that until the full results are published, questions remain as to the drug’s clinical usefulness, as well as whether the modest benefit outweighs the risk of harmful side effects.
Marsel Mesulam, a neurologist at Northwestern University in Chicago is more cautious. “The results that are described are extremely significant and impressive, but clinically their significance is doubtful,” he says, adding that the modest effect suggests factors other than amyloid contribute to Alzheimer’s disease progression. “We’re heading to a new era, there’s room to cheer, but it’s an era that should make us all very sober realizing that there will be no single magic bullet.”
In the press release, Lilly said that people with mild Alzheimer’s disease who received donanemab showed 35% less clinical decline over 18 months compared with those who received a placebo, and 40% less decline in their ability to perform daily tasks. Lilly says that it will present the full results at a conference in July and publish them in a peer reviewed journal. The company plans to apply for approval by the US Food and Drug Administration (FDA) within the next two months.
FDA approval would make donanemab the third new Alzheimer’s treatment in two years. In January, the agency granted accelerated approval to lecanemab, made by Biogen in Cambridge, Massachusetts, and Eisai in Tokyo. A study published in November showed that lecanemab slowed cognitive decline in 1,800 patients by 27% over 18 months. The FDA had previously approved aducanumab, also made by Biogen and Eisai, based on evidence that it could reduce amyloid plaques in the brain, although it is still unclear whether this leads to a meaningful clinical benefit for people with the disease.
Lilly’s donanemab trial differed from Biogen’s lecanemab one in that patients stopped taking the drug once their amyloid levels dropped below a certain threshold. “The rationale is if the target is gone, why keep shooting?” Cummings says. According to the press release, about half of the trial participants were able to stop the drug in less than one year.
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Diana Zuckerman, president of the non-profit National Center for Health Research in Washington DC, worries that stopping the drug could cause the disease to rebound or worsen, as is the case with many psychiatric drugs. She warns that more long-term follow-up studies will be needed. “Any time you’re doing anything that affects the brain you really do have to be cautious,” she says.
Lilly also found that donanemab worked best in patients whose brains contained moderate levels of another protein called tau that is also associated with Alzheimer’s disease progression. The company had calculated its results among its 1,182 participants who had moderate tau levels, but said that the improvement was still statistically significant when they combined these patients with the 552 who had high levels of tau.
Like lecanemab, donanemab carries a high risk of side effects — particularly a set of conditions called amyloid-related imaging abnormalities (ARIA) that can lead to seizures and bleeding in the brain.
“The side effect is the biggest concern for all of us right now,” says Forester, who led earlier trials of donanemab and is currently working on a lecanemab trial. He adds that people with mild cognitive impairment function fairly well and even three deaths may be enough to question whether the risk of side effects outweighs the benefit of taking the drug.
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Questions also remain about information that is missing from the announcement, including whether donanemab worked at all among people who had high levels of tau. “This whole publication-by-press-release is really bad,” Zuckerman says.
Additionally, the results Lilly released only show a slowing of cognitive decline relative to the placebo group rather than how much donanemab affects the absolute rate of a patient’s decline. It’s unclear, Zuckerman says, whether that difference is great enough that it would be noticeable to people with Alzheimer’s and their families.
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