Drug slows the progression of Alzheimer’s

Drug slows the progression of Alzheimer’s

Amyloid plaques in the brain are considered a hallmark of Alzheimer’s dementia. © Artur Plawgo/ iStock

Another drug for Alzheimer's has proven successful in a large clinical trial. The monoclonal antibody donanemab can therefore dissolve harmful plaques in the brain at an early stage of the disease and slow down the progression of cognitive decline. However, almost every fourth person treated developed side effects such as cerebral edema. According to experts, donanemab belongs to the first generation of a new era of Alzheimer's drugs. Although the active ingredient has so far only been able to slow down the progression of the disease to a modest extent, it proves that the approach is fundamentally promising and thus paves the way for further new drugs.

In the neurodegenerative disease Alzheimer's, the nerve cells in the brain of those affected gradually die off. Studies show that plaques of misfolded amyloid beta proteins are deposited between nerve cells. In addition, in Alzheimer's, the tau proteins inside the nerve cells are pathologically altered and accumulate to form so-called tau fibrils. Both processes contribute to the destruction of nerve cells. Initial therapeutic approaches are therefore trying to break down the harmful amyloid plaques in the brain. The two active ingredients aducanumab and lecanemab, which follow this approach, have already been approved in the USA. Approval in Europe is still pending, partly because so far only marginal effectiveness has been demonstrated.

Slower deterioration

Now a third potential Alzheimer's drug has proven successful in a phase 3 clinical trial. Like aducanumab and lecanemab, the new drug donanemab is a monoclonal antibody that targets structures of the misfolded beta-amyloid proteins and is intended to dissolve the plaques. For the study, the manufacturer Eli Lilly tested the drug for 18 months on a total of 1,736 Alzheimer's patients from eight countries. Half of the subjects received the drug, the other half a placebo. Neither the patients nor their doctors knew who was getting the real drug and who was getting a placebo.

During the study, the researchers regularly checked the subjects' cognitive performance and everyday skills using established Alzheimer's tests. Over the 18 months, they worsened in all participants. However, cognitive decline progressed more slowly in those who received donanemab. On a scale of 0 to 144 points, the people in the donanemab group worsened by an average of 10.2 points during the study period, and the people in the placebo group by 13.1 points. If the researchers only looked at subjects who were at the beginning of the study in a very early stage of the disease with only a few tau fibrils in the brain, the deterioration in the donanemab group was only 6.02 points compared to 9 in the placebo group, 26 points. "The treatment with donanemab thus significantly slowed down the progression of the disease," summarize the study authors.

Balance between benefit and risk

However, the research team also recorded numerous side effects, some of them serious, in those treated. "In 205 people in the donanemab group, brain scans showed abnormalities such as edema," reports the team. This corresponds to 24 percent of those treated. In 52 of these people, the abnormalities discovered in the imaging were accompanied by noticeable symptoms, in the others they subsided without symptoms. In contrast, in the placebo group, such abnormalities occurred in only 18 patients, none of whom developed noticeable symptoms. Three deaths in the donanemab group and one death in the placebo group were associated with treatment by the reviewers, who did not know which patient was in which group.

"For some patients, the drug appears to have a significant benefit," says University of Bristol dementia neurologist Liz Coulthard, who was not involved in the study. "Due to the significant side effects, it is important that patients are informed about the risks of the treatment so that they can decide whether they want to take the drug or not." Donanemab has not yet been approved, but the successful phase 3 study has provides a basis for applying for approval.

a step in the right direction

The dementia researcher Marc Aurel Busche from University College London, who was also not involved in the study, emphasizes that according to the study, patients in an early stage of the disease who have few tau fibrils in the brain benefit most from the treatment. “From a broader clinical perspective, the data underscores the need to invest in diagnostic tools that can detect Alzheimer's at a stage before overt clinical symptoms are present, that is, at a time when amyloid plaques are already forming accumulated, but the tau fibrils have not yet spread significantly in the brain," he says.

The data also shows that patients who are genetically predisposed to Alzheimer's were particularly affected by side effects. In addition to imaging diagnostics, a genetic test could also be an option prior to treatment in order to assess the risk-benefit ratio for the individual patient. "These first-generation drugs aren't perfect, but they're a big step in the right direction," says Susan Kohlhaas of Alzheimer's Research UK. "These results reaffirm that removing amyloid from the brain can alter the course of Alzheimer's disease and could benefit those affected by this devastating disease if treated at the right time."

Source: John Sims (Eli Lilly and Company, Indianapolis, Indiana) et al., JAMA, doi: 10.1001/jama.2023.13239

Recent Articles

Related Stories