Donanemab May Slow Alzheimer’s Progression

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The drug donanemab significantly slowed the clinical progression of Alzheimer’s disease among patients with mild cognitive impairment or mild dementia, according to a study published this week in JAMA.

Donanemab is an antibody designed to target and remove beta-amyloid proteins that have clumped together to form plaques in the brain. It is manufactured by Eli Lilly and Company, which stated in a news release that it has submitted the drug for U.S. Food and Drug Administration (FDA) approval and expects regulatory action by the end of this year. Eli Lilly funded the study.

John Sims, M.D., senior medical director at Eli Lilly, and colleagues conducted a phase 3 randomized clinical trial including participants aged 60 to 85 years with early symptomatic Alzheimer’s disease who had amyloid and tau pathology (abnormal tau proteins and amyloid plaque are considered markers of Alzheimer’s). Participants were randomized to receive either donanemab (700 mg for the first three doses and 1,400 mg thereafter) or placebo, administered intravenously every four weeks for up to 72 weeks.

The study participants received MRIs at 4, 12, 24, 52, and 76 weeks to monitor amyloid plaque abnormalities, with additional MRIs scheduled at investigators’ discretion. (Amyloid-related imaging abnormalities, which include temporary brain swelling, are associated with the investigational interventions targeting amyloid proteins. Patients with these abnormalities may experience headache and confusion, as well as more severe symptoms.)

The participants’ cognition and daily functioning were assessed using the integrated Alzheimer’s Disease Rating Scale (iADRS). They were also assessed using the Clinical Dementia Rating Scale, the Alzheimer’s Disease Assessment Scale, and the Alzheimer’s Disease Cooperative Study-Instrumental Activities of Daily Living scale.

Among 1,736 participants, 68.1% had low/medium tau pathology and 31.8% had high tau pathology (higher tau deposits in the brain are associated with greater memory and/or attention problems). When comparing iADRS measures between baseline and 76 weeks, Alzheimer’s disease progressed 22.3% more slowly in all participants receiving donanemab compared with the placebo group. In those with low/medium tau levels, the disease progressed 35.1% more slowly in participants receiving donanemab compared with the placebo group. Similarly, donanemab significantly slowed disease progression according to the three other scales the authors used in the study. At 76 weeks, disease progression with donanemab in the participants with low/medium tau was delayed by 4.36 months on the iADRS and 7.53 months on the Clinical Dementia Rating Scale.

The incidence of death was 1.9% in the donanemab group and 1.1% in the placebo group. Three participants with serious amyloid-related imaging abnormalities in the donanemab group died. Either amyloid-related imaging abnormalities or microhemorrhages occurred in 36.8% of participants receiving donanemab and 14.9% of those receiving the placebo.

“If approved by the FDA for the treatment of mild cognitive impairment and mild dementia due to Alzheimer’s disease, this will be the third disease-modifying medication available for the treatment of this devastating illness,” Rajesh Tampi, M.D., M.S., past president of the American Association for Geriatric Psychiatry, told Psychiatric News. “However, widespread use of this medication may remain elusive, due to the need for facilities that can conduct infusions and the monitoring of [amyloid-related imaging abnormalities] using MRI scans.”

In June 2021, aducanumab was the first amyloid antibody to receive FDA approval for Alzheimer’s disease, but it was met with controversy. Earlier this year, the FDA approved the second such drug, lecanemab.

One potential benefit of donanemab is that it requires infusions every four weeks compared with lecanemab’s every two week schedule, pointed out Eric Widera, M.D., Sharon Brangman, M.D., and Nathaniel Chin, M.D., in an accompanying commentary. Widera is a professor of medicine in the Division of Geriatrics at the University of California, San Francisco; Brangman is a distinguished service professor of geriatrics medicine in the Department of Geriatrics at SUNY Upstate Medical University; and Chin is an associate professor in the Division of Geriatrics and Gerontology at the University of Wisconsin-Madison Department of Medicine.

Widera, Brangman, and Chin noted that while slowing the progression of a disease by several months may seem small, as was the case with donanemab, this “can be clinically and personally meaningful” for patients and their families.

The results, they continued, illustrate Alzheimer’s complexity. “The exceptional ability of drugs such as donanemab and lecanemab to remove amyloid, paired with their rather subtle effect on the rate of decline in cognitive and functional measures, suggests that amyloid is likely not the only factor that contributes to Alzheimer disease progression,” they wrote.

Tampi pointed out that equitable access to donanemab may be an issue. A high cost would make this drug unavailable for many patients with Alzheimer’s unless Centers for Medicare and Medicaid Services (CMS) and other payers covered the cost.

In April 2022, CMS announced that it would only cover amyloid-based Alzheimer’s therapy for patients who are enrolled in clinical trials. That decision, CMS stated, also applied to antibodies the FDA may approve in the future.

Other experts echoed Tampi’s points. The study found the greatest benefit in people with mild symptoms of Alzheimer’s, but minoritized groups are typically diagnosed at later stages, Jennifer Manly, Ph.D., and Kacie Deters, Ph.D., wrote in an accompanying commentary. Manly is a professor of neuropsychology at the Gertrude H. Sergievsky Center and the Taub Institute for Research in Aging and Alzheimer’s disease at Columbia University and Deters is an assistant professor in the Brain Research Institute at the University of California, Los Angeles.

“Clinicians and the public will need to weigh the potential benefit of treatment (delay of progression of about 4 months on average) with the financial and quality-of-life costs of infusions, MRI monitoring, and risk of amyloid-related imaging abnormalities and brain volume loss,” Manly and Deters wrote. ■