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• Alzheimer’s disease, the most common form of dementia, affects some 6 million people in the United States.
• While treatments can help manage Alzheimer’s symptoms, there is no cure yet.
• Now, a third disease-modifying treatment that clears amyloid plaques from the brain has shown positive results in a phase 3 trial.
• Donanemab, a monoclonal antibody, slowed cognitive decline by 35% in people in the early stages of Alzheimer’s but was less effective in those with more advanced Alzheimer’s.

Dementia affects more than 55 million people worldwide, hard on problems and up to 70% of those people have Alzheimer’s disease, characterized by the buildup of two proteins, amyloid and tau.

Currently available treatments can help manage symptoms but not change the course of the disease. However, new disease-modifying treatments are showing the potential to slow the progress of the disease.

In an international phase 3 trial, donanemab, produced by Eli Lilly, slowed cognitive decline by 35% compared with placebo.

However, the effects were seen only in people with mild cognitive impairment or who were in the early stages of Alzheimer’s. Those with more advanced Alzheimer’s did not benefit from the medication.

“Today’s full results support what we heard about donanemab back in May, that the drug is able to slow down the progression of Alzheimer’s disease by more than 20%. This study adds to the growing evidence that treating people as early as possible may be more beneficial, with the effects of donanemab greater in people who were at an earlier stage of the disease.”
— Dr. Richard Oakley, associate director of research and innovation at Alzheimer’s Society

The trial results are published in the Journal of the American Medical Association.

8 countries involved

The 18-month, phase 3 trial took place in 277 medical research centers and hospitals in 8 countries. The researchers enrolled a total of 1,736 people, ages 60–85 years (mean 73 years), with early symptomatic Alzheimer’s — either mild cognitive impairment or mild dementia.

All participants showed some amyloid and tau pathology on PET imaging. They were divided into low/medium tau and higher tau pathology groups.

The researchers assigned the participants randomly into treatment (860 people) and placebo (876) groups. For the 72 weeks of the study, patients were given either donanemab or placebo every four weeks by intravenous infusion. A total of 1,320 people completed the trial.

All participants completed the integrated Alzheimer Disease Rating Scale (iADRS) at the start of the trial and after 76 weeks.

Encouraging results from donanemab

At 76 weeks, both groups — low/medium tau and combined — showed some slowing in disease progression.

For the low/medium tau (those in the earlier stages of Alzheimer’s), the progression was 35.1% slower for the people on donanemab than for those on placebo. For the combined group, progression slowed by 22.3%.

Although the researchers saw only a small reduction in tau levels during the trial, there were significant reductions in amyloid plaque levels in the treatment group.

For patients taking donanemab, brain amyloid plaques reduced at all time points, with 80% (in low/medium tau population) and 76% (combined) of participants achieving amyloid clearance at 18 months.

Dr. Emer MacSweeney, CEO and Medical Director at Re:Cognition Health, and Principal Investigator for the donanemab TRAILBLAZER-ALZ 2 study in the UK, told Medical News Today: “The results of the study are positive, demonstrating that donanemab is capable of clearing toxic levels of amyloid protein plaque in the brain, restoring amyloid in the brain to ‘normal levels’ below the 20 centiloid level on PET amyloid imaging.”

“And this removal of toxic amyloid protein correlates with a slowing in the progression of Alzheimer’s disease and its symptoms,” she added.

Third amyloid-clearing drug for Alzheimer’s

Donanemab is one of three new monoclonal antibody treatments for Alzheimer’s. Like the others, aducanumab (Aduhelm) and lecanemab (Leqembi), it is one of the first disease-modifying treatments for the disease.

All three drugs work by clearing the amyloid plaques that are characteristic of Alzheimer’s. However, early trials showed little evidence that by clearing the plaques, the medications also slowed cognitive decline.

Both aducanumab and lecanemab have been given accelerated approval by the U.S. Food and Drug Administration (FDA) following promising trial results. The manufacturers hope that, following these trial results, donanemab will soon follow suit.

Concerns about side effects

Although these results are encouraging, donanemab, in common with aducanumab and lecanemab, does have some side effects. This trial saw more side effects in people who carry the APOE ε4 gene (which increases Alzheimer’s risk) than in non-carriers.

As well as infusion-related reactions, most of which were mild to moderate, some people did have amyloid-related imaging abnormalities (ARIA), a potentially serious side effect.

ARIA can cause symptoms or may be symptom-free and only detected by MRI scan. In this trial, Dr. MacSweeney told us, 37% of the participants taking donanemab developed ARIA, but fewer than 7% had any symptoms. In the placebo group, 15% had ARIA.

Few of the ARIA caused severe problems, although three individuals taking donanemab died due to complications of ARIA during the trial.

“It’s also important to note that side effects did occur, although serious side effects only occurred in 1.6% of people receiving the drug. Regulators will need to balance these side effects against the benefits of the drug,” Dr. Oakley said.

An accompanying editorial in JAMA raised concerns about the cohort of participants, 91.5% of whom were white.

This concern was echoed by Dr. Oakley: “We should also note that the majority of people who took part in this trial were white — it’s crucial that in future trials we see more diversity to prove that new drug treatments have similar effects for everyone living with Alzheimer’s disease,” he said.

Steps on the road to combating Alzheimer’s

Even given these concerns, the trial results are another step toward effective treatments for Alzheimer’s. Dr. MacSweeney told us that further trials are underway to address the safety concerns, particularly how to minimize ARIA.

This trial has shown that donanemab is effective at clearing amyloid plaques, and it can slow cognitive decline in people in the earlier stages of Alzheimer’s.

Dr. Oakley, for one, is optimistic.

“This is truly a turning point in the fight against Alzheimer’s and science is proving that it is possible to slow down the disease. Treatments like donanemab are the first steps towards a future where Alzheimer’s disease could be considered a long-term condition alongside diabetes or asthma. People may have to live with it, but they could have treatments that allow them to effectively manage their symptoms and continue to live fulfilled lives.”
— Dr. Richard Oakley

However, he cautioned that, without early diagnosis, the medication’s potential might not be realized:

“Diagnosis will be key to the access of any new treatments. We can’t have a situation where treatments are approved for use in the UK, but people aren’t diagnosed early or accurately enough to be eligible. We need early, and accurate diagnoses available for everyone.”

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