The quest for Alzheimer’s disease (AD) treatments has been a challenging and high-stakes endeavor in modern medicine. Despite decades of research, effective therapies to halt, slow, or reverse the progression of this neurodegenerative disease have remained out of reach. Donanemab, a monoclonal antibody developed by Eli Lilly, removes 70% or more amyloid-beta (Aβ) plaque after seven to twelve months of treatment. However, concerns about safety remain a significant obstacle to its widespread use.
Amyloid plaques, composed of misfolded amyloid-beta protein, accumulate in the brains of AD patients twenty years before cognitive decline. Donanemab works by binding to a specific form of Aβ, facilitating its clearance from the brain by activating the immune cells – microglia. In clinical trials, donanemab has shown a notable ability to reduce plaque burden. In the Trailblazer-ALZ trial, donanemab reduced Aβ by 70% in patients with early AD. However, despite these promising results, the drug’s safety profile has raised concerns, particularly regarding amyloid-related imaging abnormalities (ARIA), which include brain swelling and microbleeds.
ARIA is a side-effect of amyloid-targeting therapies including donanemab. In clinical trials, approximately 25% of patients receiving donanemab experience ARIA, although not all cases were severe. ARIA is thought to occur when the rapid removal of amyloid plaques leads to inflammatory responses in the brain, causing localized swelling, and in some cases, bleeding. These adverse events can be asymptomatic or cause mild symptoms, but in rare cases, they can be serious and lead to death.
The severity of ARIA varies depending on age, APOE ɛ4 genotype (a gene variant associated with higher AD risk), and the level of Aβ burden at baseline. While these side effects were anticipated due to the mechanism of action of amyloid-clearing drugs, their occurrence has led researchers to explore ways to mitigate these risks without compromising the drug’s efficacy.
One area of focus for improving the safety profile of donanemab lies in the titration process. Titration involves starting the treatment as a lower dose and gradually increasing to the target dose, allowing the body to adjust more slowly. Researchers hypothesize that a more gradual increase in donanemab dosage could reduce the risk of ARIA by giving the immune system more time to adjust to the Aβ clearance process.
A recent sub-study of the Trailblazer-ALZ trial investigated the effects of a modified titration schedule, starting patients on a lower dose and increasing it more gradually. The findings suggest that this adjustment significantly decreases the incidence of ARIA, particularly in high-risk patients, such as those with two copies APOE ε4 genotype.
If these safety improvements are confirmed in larger, longer-term trials, donanemab could continue to represent a breakthrough in AD treatment. If the drug can reduce amyloid plaques and slow cognitive decline, the drug has the potential to alter the course of the disease in early stages. Early intervention is crucial, as it has been shown that Aβ plaques begin accumulating decades before the symptoms of dementia appear.
The potential benefits of donanemab are not limited to reducing Aβ burden but could also extend to improving cognitive function and quality of life. However, as promising as these results are, there are still many questions that remain unanswered. Donanemab’s long-term effects on cognitive function, daily life, and overall disease progression are still being evaluated. Additionally, while Aβ plaque reduction is a key goal, it is not clear yet whether this will translate to meaningful clinical benefits for patients. The relationship between amyloid clearance and functional improvement is still debated as other factors such as misfolded tau protein accumulation producing neurofibrillary tangles and cell death causing cognitive decline.
While the adjustment in the titration process presents a promising strategy for improving the safety profile of donanemab, additional research is essential to fully understand broader safety implications. Moreover, continuing investigation into the drug’s impact on long-term outcomes is necessary to determine whether amyloid reduction will ultimately lead to meaningful clinical benefits for patients and their families.
The development of donanemab nonetheless remains an exciting step forward in the search for AD treatments. If safety can be improved through titration, and if its clinical benefits are confirmed in long-term observational studies, it could represent a pivotal moment in the treatment of AD. Furthermore, the insights gained from donanemab’s development may be best used as a preventative treatment for those at risk for AD based on blood-based biomarkers.
Sources:
Donanemab: Small tweak in titration, big gain in safety? ALZFORUM. (2024, November 8). https://www.alzforum.org/news/conference-coverage/donanemab-small-tweak-titration-big-gain-safety
Mintun, M. A., Lo, A. C., Duggan Evans, C., Wessels, A. M., Ardayfio, P. A., Andersen, S. W., … & Skovronsky, D. M. (2021). Donanemab in early Alzheimer’s disease. New England Journal of Medicine, 384(18), 1691-1704.
Petersen, R. C., Aisen, P., Boeve, B. F., Geda, Y. E., Ivnik, R. J., Knopman, D. S., … & Jack Jr, C. R. (2013). Mild cognitive impairment due to Alzheimer disease in the community. Annals of neurology, 74(2), 199-208.