There may soon be another option for an Alzheimer’s drug capable of slowing the progression of the devastating disease.
An experimental Alzheimer’s drug from drugmaker Eli Lilly helped slow cognitive decline in patients in the early stages of the disease, according to the results of a late-stage clinical trial. However, side effects of the drug, called donanemab, were serious in some cases, including swelling of the brain and bleeding in the brain.
Lilly representatives presented the results at the Alzheimer’s Association International Conference in Amsterdam on Monday. The research was simultaneously published in the Journal of the American Medical Association.
The results come on the heels of the Food and Drug Administration’s approval of another Alzheimer’s drug, Leqembi, from Japanese drugmaker Eisai and Massachusetts-based drugmaker Biogen. Leqembi is the first fully approved drug that aims to slow the progression of the disease.
Both drugs are monoclonal antibodies that work by attacking amyloid in the brain, considered a hallmark of Alzheimer’s disease. (Another drug, Biogen’s Aduhelm, works in a similar way, but has fallen out of favor after a congressional investigation found serious flaws in its approval process.)
The idea is that by targeting the amyloid, the progression of the disease could be slowed down.
“This is something we’ve raised as a field for a long time, but Lilly has now solidly demonstrated it,” said Donna Wilcock, director of the Center for Neurodegenerative Disorders at Indiana University School of Medicine. “I am very impressed with the results.”
About 6.7 million adults 65 and older in the United States have Alzheimer’s disease, according to the Alzheimer’s Association.
The success of donanemab and Leqembi is another lynchpin in the long road of Alzheimer’s research. Last year, leading scientists thought it was time to change the direction of research, after several drugs targeted against amyloid failed.
In Lilly’s Phase 3 clinical trial of 1,736 patients with mild cognitive impairment or early-stage disease, donanemab reduced the progression of Alzheimer’s disease by 29% after 18 months compared to placebo. The results were similar to those seen with Leqembi, which led to a 27% decrease over the same time period, although experts note that the results are not directly comparable because the two drugs were not studied together in a single clinical trial.
Patients in the trial received donanemab or a placebo once a month intravenously.
Decline was measured using the Clinical Dementia Rating Scale, which focuses on patients’ performance in six categories: memory, orientation, judgment and problem solving, community affairs, home and hobbies, and personal care.
Patients in the placebo group scored, on average, 2.42 on the scale after 18 months. Those who received donanemab scored, on average, 1.72, a difference of 0.7, or about a 29% slower rate of decline.
“While this is not a cure, we have not finished evaluating whether this could be even more effective as the disease progresses to the point where people have amyloid and have no symptoms,” said Dr. Mark Mintun, Lilly’s vice president of pain. and neurodegeneration research and development, he said during a presentation at the conference. Early Monday, however, a study published in the New England Journal of Medicine reported that a different amyloid-targeting monoclonal antibody called solanezumab failed to slow disease progression in patients with preclinical Alzheimer’s disease.
When Lilly excluded a subset of patients with higher levels of a protein called tau in the brain, which is more difficult to treat, the drug worked even better, slowing progression by 36-48%. In practical terms, those patients had an additional seven and a half months before reaching the same level of cognitive decline as people who received a placebo, according to Lilly.
Lilly’s drug “doesn’t stop the disease, it doesn’t make people better, but it does slow the progression of the disease,” said Dr. Ronald Petersen, a neurologist at the Mayo Clinic in Rochester, Minnesota. “I think that’s clinically meaningful for patients.”
Almost half of the patients who received donanemab showed no signs of cognitive decline during the first year.
The benefits of the treatment appeared to continue over the course of the trial, Mintun said, although many patients had stopped taking the drug about 6 months to a year after the amyloid in their brains had cleared.
Petersen, who has consulted with Lilly in the past but was not involved with donanemab, said that’s important because people can temporarily stop taking the drug once the amyloid runs out, saving them money and reducing the risk of side effects.
What are the side effects of donanemab?
While the Lilly results and the recent approval of Leqembi are a source of hope for patients and their families, the potential of these amyloid-targeted drugs is hampered by concerns about their life-threatening side effects, including inflammation and cerebral haemorrhage.
In what came as a surprise to Eisai, enthusiasm for Leqembi’s approval earlier this month was tempered by the FDA’s decision to put its strongest safety warning label on the drug, called the boxed warning, which noted that these side effects could lead to seizures and death.
Lilly said it has applied for approval in the United States and expects to hear from the FDA by the end of the year. If approved, Petersen said, it would make sense for the agency to include a similar boxed warning, since donanemab’s side effect rates are “as high or higher” than those of Leqembi.
In the Lilly trial, about 37% of patients who received donanemab developed brain swelling or brain bleeding, and about 6% experienced symptoms of the condition. Three patients died as a result.
The risk of side effects, coupled with what is expected to be a high price, may put many families off buying the drug for a loved one.
More about Alzheimer’s disease
However, because Alzheimer’s is such a devastating disease, there are patients and families who are going to want the drug, despite the side effects, said Arthur Caplan, chief of the Division of Medical Ethics at NYU Langone Medical Center. in New York City.
“There will be people who say, ‘My loved one is doomed, and if they have a brain hemorrhage, then so be it,’” he said.
Allan Fisher, a 68-year-old resident of Parkland, Florida, enrolled in the trial in March 2022, about nine months after being diagnosed with early-stage Alzheimer’s disease.
He received monthly infusions of donanemab, which continued until about a month ago when he completed the trial. (A Lilly spokesperson confirmed that Fisher was receiving the drug, not the placebo.) She also had a PET scan and MRI every six months to monitor side effects and see if the amyloid was clearing up. Other than experiencing slight discomfort from the infusions, she said she did not experience any side effects.
“I feel great,” he said.
Although she is no longer taking the medication, Fisher said she believes the medication allowed her to spend more time with her grandson.
His wife, Louise, said they hope he can start taking the drug again in November, when a separate trial will start.
