For the second time, an experimental drug has been shown to reduce cognitive decline associated with Alzheimer’s disease. On May 3, pharmaceutical company Eli Lilly announced in a press release that its monoclonal antibody donanemab slowed mental decline by 35% for some participants in a 1,736-person trial – a rate comparable to that of competitor drug lecanemab. But the researchers warn that until the full results are published, questions remain about the drug’s clinical usefulness, as well as whether the modest benefit outweighs the risk of harmful side effects.
Like lecanemab, donanemab targets the amyloid protein, which is believed to cause dementia by building up in the brain and damaging neurons. The trial results provide strong evidence that amyloid is a key contributor to Alzheimer’s disease, says Jeffrey Cummings, a neuroscientist at the University of Nevada, Las Vegas. “These are transformative in a hugely important way from a scientific perspective,” he adds. “They are great.”
But 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 questionable,” he says, adding that the modest effect suggests that factors other than amyloid contribute to the progression of Alzheimer’s disease. “We are heading into a new era – there is room to rejoice, but it is an era that should make us all very sober, realizing that there will be no one magic bullet.”
In the press release, Eli Lilly said people with mild Alzheimer’s disease who received donanemab experienced 35% less clinical decline over 18 months than those who received placebo, and 40% of their ability to perform daily tasks. The company says it will present the full results at a conference in July and publish them in a peer-reviewed journal. It plans to seek approval from the US Food and Drug Administration (FDA) within the next two months.
Promising treatments
FDA approval would make donanemab the third new treatment for Alzheimer’s disease in two years. In January, the agency granted accelerated approval to lecanemab, made by Biogen in Cambridge, Massachusetts, and Eisai in Tokyo. A study1 published in November showed that lecanemab slowed cognitive decline in 1,800 patients by 27% over 18 months. The FDA previously approved aducanumab, also made by Biogen and Eisai, based on evidence it could reduce amyloid plaques in the brain, although it’s still unclear whether this leads to significant clinical benefit. for people with the disease.
Eli Lilly’s donanemab trial differed from Biogen’s lecanemab trial in that people stopped taking the drug once their amyloid levels fell below a certain threshold. “The reason is if the target is gone, why keep shooting?” Cummings said. According to the press release, about half of the trial participants were able to stop taking the drug within a year.
Diana Zuckerman, president of the National Center for Health Research, a nonprofit think tank 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 cautions that longer-term follow-up studies will be needed. “Anytime you’re doing something that affects the brain, you really have to be careful,” she says.
Eli Lilly also found that donanemab worked better in people whose brains had only moderate levels of another protein, called tau, which is also associated with the progression of Alzheimer’s disease. The company had calculated its results among its 1,182 trial participants who had moderate levels of tau, but said the improvement was still statistically significant when they combined those patients with the 552 who had high levels of tau. tau.
Brent Forester, a geriatric psychiatrist at McLean Hospital in Belmont, Massachusetts, says it’s “fascinating” that amyloid removal also affects tau: the relationship between the two proteins and their respective roles in progression of the disease are not fully understood. “If we could understand this better, we might understand why removing amyloid might have a clinical effect,” he says.
Bleeding and seizures
Like lecanemab, donanemab carries a high risk of side effects — specifically a set of conditions called amyloid-related imaging abnormalities (ARIAs) that can lead to seizures and bleeding in the brain. Researchers believe that by attacking amyloid plaques, the antibodies inadvertently weaken blood vessels in the brain, and the effects are especially pronounced in people taking blood thinners. Eli Lilly’s press release stated that ARIA levels were several times higher in people who received donanemab than in those who received placebos, and three patients in the trial died after being diagnosed with the disease. disease.
“The side effect is the biggest concern for all of us right now,” says Forester, who has led previous donanemab trials and is currently working on a lecanemab trial. He adds that people with mild cognitive impairment function quite well and that even three deaths could be enough to signal that the risk of side effects outweighs the benefits of taking the drug.
Questions also remain about missing information in the ad, including whether donanemab worked at all in people who had high tau levels. “All this press release publishing is really bad,” Zuckerman says.
Additionally, the results published by Eli Lilly only show a slowing of cognitive decline compared to the placebo group, rather than the amount of donanemab affecting a person’s absolute rate of decline. It’s unclear, says Zuckerman, whether this difference is large enough to be noticeable by people with Alzheimer’s disease and their families.
With at least three monoclonal antibodies soon to hit the market, Mesulam fears the excitement around them will dampen pharmaceutical companies’ enthusiasm for developing drugs for Alzheimer’s disease targets other than amyloid. “The next 20 to 25 years will be occupied by better amyloid drugs,” he says. The Alzheimer’s disease market is likely to be very lucrative for pharmaceutical companies – lecanemab, for example, costs more than $26,000 a year to treat – but Mesulam fears that the cost of Alzheimer’s drugs will increase. Alzheimer’s does weigh on the American healthcare system.
Still, the early results provide “additional support that this therapy will have some role with the right patients at the right time of illness,” says Forester. “I am cautiously optimistic.”
This article is reproduced with permission and was first published on May 4, 2023.
