In announcing positive results from a trial evaluating donanemab, Eli Lilly reported that the monoclonal antibody drug slowed cognitive decline among people with Alzheimer’s disease. The study results are comparable to those of the competitor drug lecanemab, which has received accelerated approval from the Food and Drug Administration (FDA). However, while the preliminary results released for donanemab are promising, researchers caution that the full results are necessary to assess its clinical usefulness and weigh the benefits against potential side effects.
Targeting Amyloid Protein
Both donanemab and lecanemab target amyloid protein, and the clinical trial results support the so-called amyloid hypothesis of Alzheimer’s disease. That is, that amyloid contributes to dementia by accumulating in the brain and causing neuronal damage. According to neuroscientist Jeffrey Cummings, of the University of Nevada, Las Vegas, the findings are “transformative in an enormously important way from a scientific point of view.” However, Marsel Mesulam, a neurologist at Northwestern University in Chicago, cautions that the modest effects reported suggest that factors other than amyloid play a role in the progression of Alzheimer’s disease. “We’re heading to a new era — there’s room to cheer, but it’s an era that should make us all very sober, realizing that there will be no single magic bullet,” he said.
Next Steps for Donanemab
According to the press release, study participants who received donanemab, when compared to a control group, had 35 percent less clinical decline over 18 months and 40 percent less decline in the ability to perform daily tasks. Upon their release of the complete results, Eli Lilly will seek approval from the FDA. If approved, donanemab would become the third Alzheimer’s treatment to receive FDA approval in two years, following lecanemab and aducanumab.
Comparisons and Concerns
For the donanemab trial, unlike the study of lecanemab, participants stopped taking the drug after their amyloid levels decreased to a certain level. Some experts expressed concern about the potential for the disease to come back or intensify upon discontinuation of the drug. Longer-term follow-up studies are deemed necessary to address this risk. Eli Lilly found that donanemab worked best in individuals with moderate levels of the protein tau, which also accumulates in the brain in association with Alzheimer’s progression. The nature of the relationship between amyloid and tau and how each contributes to disease progression are not fully understood. “If we could understand that better, we might understand why removing amyloid might have a clinical effect,” suggested Brent Forester, a geriatric psychiatrist at McLean Hospital in Belmont, Massachusetts.
Side Effects and Missing Information
Side effects associated with both lecanemab and donanemab include amyloid-related imaging abnormalities (ARIAs), a spectrum of MRI findings that can signal swelling or bleeding in the brain. Eli Lilly reported that ARIA rates were higher among donanemab recipients compared to those who received a placebo, and that three people with ARIAs died. Concerns about information not reported in the announcement, such as donanemab’s efficacy in individuals with high levels of tau, highlight the need for more comprehensive data.
While the results are promising, questions remain about the significance of the effects and the impact of donanemab on the absolute rate of decline in Alzheimer’s patients. Researchers emphasize the importance of long-term studies and a cautious approach when considering the risk-benefit balance of these drugs. Some experts have expressed caution that focusing on amyloid-targeting drugs may hinder the development of treatments aimed at other aspects of Alzheimer’s disease. Additionally, the cost of Alzheimer’s drugs and their potential strain on the healthcare system is a growing concern.
Still, the initial results of the donanemab trial are promising. While further research is needed, these results provide “further support that this therapy will have some role with the right patients at the right time in illness,” said Forester. “I’m cautiously optimistic.”
QPS is a GLP- and GCP-compliant contract research organization (CRO) delivering the highest grade of discovery, preclinical and clinical drug research development services. Since 1995, it has grown from a tiny bioanalysis shop to a full-service CRO with 1,200+ employees in the U.S., Europe and Asia. Today, QPS offers expanded pharmaceutical contract R&D services with special expertise in neuropharmacology, DMPK, toxicology, bioanalysis, translational medicine and clinical development. An award-winning leader focused on bioanalytics and clinical trials, QPS is known for proven quality standards, technical expertise, a flexible approach to research, client satisfaction and turnkey laboratories and facilities. Through continual enhancements in capacities and resources, QPS stands tall in its commitment to delivering superior quality, skilled performance and trusted service to its valued customers. For more information, visit www.qps.com or email [email protected].