Donanemab: An Innovative Medication Paving the Way for Modern Alzheimer’s Therapy

by Hiroshi Tanaka
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Donanemab, a promising new medication for Alzheimer’s disease, is anticipated to receive FDA approval. It demonstrates potential in slowing the cognitive decline of mild-stage patients. Nevertheless, serious side effects and diversity issues in trials, as well as the expected high treatment costs, call for caution.

The FDA is projected to approve donanemab, marking the third Alzheimer’s drug in the market and indicating significant advancements in managing the disease. In patients with mild Alzheimer’s, the drug led to a 35% reduction in cognitive deterioration, though the advantage was less notable in severe cases.

Advancements in Alzheimer’s Therapy

The possible approval of another Alzheimer’s drug by the FDA signals progress in slowing the disease’s progression.

However, these medications are primarily beneficial for those in the early phases of Alzheimer’s. Dr. Gil Rabinovici, the director of the University of California, San Francisco (UCSF) Alzheimer’s Disease Research Center, points out the necessity of additional treatments for those suffering from severe Alzheimer’s.

In his words, this is “just the first step in a new age of molecular therapies for Alzheimer’s and related neurodegenerative disorders.”

Donanemab: A New Hope in Alzheimer’s Medication

Dr. Rabinovici discussed these points in an editorial accompanying the results of the latest donanemab trial, published in JAMA on July 17, 2023. Like its predecessors, aducanumab (Aduhelm) and lecanemab (Leqembi), donanemab is a monoclonal antibody. These drugs combat brain plaques composed of amyloid protein, which interfere with cell functioning and accelerate the spread of tau protein. Both amyloid and tau are implicated in Alzheimer’s disease progression.

Donanemab trials suggested a 35% reduction in cognitive decline compared to a placebo for patients with low-to-moderate tau levels. Similar outcomes were reported with Leqembi, another medication that recently secured FDA approval. Moreover, donanemab trial patients had a 40% lesser risk of progressing from mild cognitive impairment to mild dementia, or from mild to moderate dementia.

The Effectiveness and Risks of Donanemab

Donanemab proved more successful in eliminating amyloid plaques compared to Aduhelm and Leqembi. It also lowered tau concentrations in the blood, but not in a critical area of the brain.

Despite these positive outcomes, Dr. Rabinovici emphasized the need for comprehensive analysis to comprehend how these results impact patient outcomes.

Limitations of Donanemab

Patients with advanced Alzheimer’s showed minimal to no benefits compared to placebo recipients. The drug’s potential severe side effects call for efforts to “aim higher in developing more impactful and safer treatments,” states Dr. Rabinovici, who is affiliated with various prestigious institutions.

Donanemab should be primarily used for patients with mild Alzheimer’s, as indicated by low-to-moderate tau levels. Further trials are in progress to assess the effectiveness of monoclonal antibodies in the disease’s earliest phase, before symptoms manifest.

Potential Side Effects and Cautions

Donanemab, like the other two new Alzheimer’s drugs, was linked with ARIA – amyloid-related imaging abnormalities that could cause brain swelling and microbleeds. Serious ARIA affected 3.7% of patients, including three deaths. Patients with the APOE4 gene, which elevates Alzheimer’s risk, had higher risk levels. As a result, Dr. Rabinovici advises genetic testing prior to monoclonal antibody treatment.

While ARIA has typically been managed safely in clinical trials, Dr. Rabinovici calls for careful handling as these drugs transition to real-world applications. He advocates for restricting access to patients with normal pre-treatment MRIs, conducting routine MRIs, and discontinuing or pausing treatment if ARIA occurs.

Ethical and Feasibility Issues

A significant trial limitation was the insufficient racial and ethnic diversity. Only 8.6% of the 1,251 U.S. participants were non-white, leading to ethical concerns about the results’ applicability to high-risk populations. Dr. Rabinovici refers to studies revealing higher dementia rates among Black and Latino populations.

Considering donanemab’s projected high cost and high patient demand, Dr. Rabinovici proposes limiting the treatment duration to the time needed to clear amyloid plaques from the brain. This strategy could “significantly enhance the feasibility of treatment for patients, clinicians, insurers, and health systems,” he stated.

References:

For comprehensive information about the trial, refer to the following published articles:

“Donanemab in Early Symptomatic Alzheimer DiseaseThe TRAILBLAZER-ALZ 2 Randomized Clinical Trial” and “Amyloid-Targeting Monoclonal Antibodies for Alzheimer Disease” by Dr. Gil D. Rabinovici and Renaud La Joie, published on July 17, 2023, in JAMA.

Co-Author: Renaud La Joie, PhD, of the UCSF Memory and Aging Center and Department of Neurology.

Funding: NIH and Alzheimer’s Association support the research efforts of both authors.

Disclosures: Dr. Rabinovici receives research funding and has provided paid consultancy for Eli Lilly, the manufacturer of donanemab. For additional disclosures, please refer to the original paper.

Frequently Asked Questions (FAQs) about Donanemab

What is donanemab?

Donanemab is a promising new drug developed for Alzheimer’s disease. It is a monoclonal antibody that combats brain plaques composed of amyloid protein, which interfere with cell functioning and accelerate the spread of tau protein, both of which are implicated in Alzheimer’s disease progression.

Is donanemab approved by the FDA?

As of the time the article was written in July 2023, donanemab is expected to receive FDA approval soon.

What are the observed effects of donanemab?

In trials, donanemab was found to slow cognitive decline by 35% in patients with mild Alzheimer’s disease compared to a placebo. Patients in the donanemab trial also had a 40% lower risk of progressing from mild cognitive impairment to mild dementia or from mild to moderate dementia.

Are there any side effects or risks associated with donanemab?

Yes, donanemab, like other new Alzheimer’s drugs, was linked with amyloid-related imaging abnormalities (ARIA), which may include brain swelling and microbleeds. Serious ARIA occurred in 3.7% of patients, including three fatalities. Patients with the APOE4 gene, which increases Alzheimer’s risk, were at higher risk.

What are the limitations of donanemab?

Patients with more advanced Alzheimer’s showed minimal to no benefits compared to those who received the placebo. The trial also lacked racial and ethnic diversity, raising ethical concerns about the applicability of results to high-risk populations. Moreover, the anticipated high cost of the treatment could pose challenges.

Who is Dr. Gil Rabinovici?

Dr. Gil Rabinovici is the director of the University of California, San Francisco (UCSF) Alzheimer’s Disease Research Center. He provided expert insight into the potential of donanemab and the necessary caution that must be taken due to its potential side effects.

More about Donanemab

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