What Promising Trials Mean for Treatment

Juvenile Alzheimer's disease, MRI scan

MRI scans show contractions around the front and sides of the brain in people with early-onset Alzheimer’s disease.Credit: Zephyr/SPL

An experimental drug has been shown for the second time to reduce cognitive decline associated with Alzheimer’s disease. On May 3, drugmaker Eli Lilly said in a press release that the company’s monoclonal antibody donanemab delayed mental decline by 35% in some participants in his 1,736-person trial. Announced. But the researchers warn that until full results are published, questions remain about the drug’s clinical utility and whether the modest benefits outweigh the risks of adverse side effects.

Like lecanemab, donanemab targets amyloid proteins. Amyloid proteins are thought to cause dementia by accumulating in the brain and damaging neurons. The study results provide strong evidence that amyloid is a key factor in Alzheimer’s disease, says Jeffrey Cummings, a neuroscientist at the University of Nevada, Las Vegas. “These are transformative in ways that are very important from a scientific point of view,” he adds. “They are great.”

But Marcel Meslam, a neurologist at Chicago’s Northwestern University, is more cautious. “While the results described are very important and impressive, their clinical relevance is questionable,” he said, suggesting that factors other than amyloid contribute to the progression of Alzheimer’s disease. “We are heading into a new era, one where there is room to cheer, but it is a time when we should all be very sober, recognizing that there is no magic bullet.” ”

Eli Lilly said in a press release that patients with mild Alzheimer’s disease who received donanemab had 35% less clinical decline over 18 months and 40% less ability to perform daily tasks than those who received placebo I said less. The Indianapolis, Indiana-based company said it will announce full results at its July meeting and publish them in a peer-reviewed journal. I plan to apply.

Promising treatment

FDA approval makes donanemab the third new treatment for Alzheimer’s disease in two years. In January, the FDA granted accelerated approval to lecanemab, manufactured by Biogen of Cambridge, Massachusetts, and Eisai of Tokyo.the study1 A study published in November showed that lecanemab slowed cognitive decline by 27% over 18 months in 1,800 patients. The FDA had previously approved aducanumab, also manufactured by Biogen and Eisai, based on evidence that it could reduce amyloid plaques in the brain, but this is a clinically relevant drug for people with the disease. It is not yet known whether it will lead to commercial benefits.

Lilly’s donanemab trial differed from Biogen’s lecanemab trial in that people stopped taking the drug when their amyloid levels fell below a certain threshold. If it’s gone, why keep shooting,” Cummings says. About half of the trial participants were able to stop taking the drug within his year, according to his release.

Diana Zuckerman, director of the National Center for Health Research, a nonprofit think tank in Washington, D.C., worries that, as with many psychotropic drugs, stopping the drug could make the disease relapse or worsen. She warns that longer-term follow-up will be needed.

Eli Lilly also found that donanemab was most effective in people whose brains contained only moderate levels of another protein called tau, which is also linked to the progression of Alzheimer’s disease. We calculated results for 1,182 trial participants with moderate tau levels, but stated that the improvement was statistically significant even when combining these patients with 552 patients with high tau levels. I was.

Brent Forrester, a geriatric psychiatrist at McLean Hospital in Belmont, Massachusetts, says it’s “fascinating” that removing amyloid also affects tau. Their respective roles in disease progression are not fully understood. “If we could understand it better, we might understand why amyloid clearance has clinical benefits,” he says.

bleeding and seizures

Like lecanemab, donanemab carries a high risk of side effects, particularly a set of conditions called amyloid-associated imaging abnormalities (ARIA) that can lead to brain attacks and bleeding. By attacking amyloid plaques, researchers believe the antibodies inadvertently weaken blood vessels in the brain, an effect that is particularly pronounced among people taking anticoagulants.Eli Lilly According to a press release from , the incidence of ARIA in people who received donanemab was several times higher than those who received placebo, and three patients in the trial died after experiencing the condition.

“Side effects are the biggest concern for all of us right now. It may be enough to show that the advantages of

Questions also remain about information missing in the announcement, such as whether donanemab worked at all among people who had high levels of tau. Zuckerman says.

Furthermore, the results published by Eli Lilly show only a slowing of cognitive decline compared to the placebo group, not how much the dose of donanemab affects the absolute rate of decline in people. Zuckerman says it’s unclear whether it’s big enough for Alzheimer’s patients and their families to notice.

Mesulam fears that at least three monoclonal antibodies will soon be on the market, and that the excitement around them could dampen drug companies’ enthusiasm for developing drugs against Alzheimer’s targets other than amyloid. “The next 20 to 25 years will be spent on better amyloid drugs,” he says. The Alzheimer’s market is likely to be very lucrative for pharmaceutical companies, with lecanemab, for example, costing more than US$26,000 annually, but Meslam said the cost of Alzheimer’s drugs would strain the U.S. healthcare system. I am concerned that

Still, the early results “further support that this therapy has something to do with the right patients at the right time of the disease,” says Forrester. “I’m cautiously optimistic.”

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