A monoclonal antibody that clears brain amyloid plaque shows potential for treating patients with Alzheimer’s disease, the progressive brain disorder that affects about 6.5 million Americans. In a phase 3 randomized clinical trial, donanemab slowed clinical disease progression in amyloid-positive, early symptomatic disease patients over 76 weeks.
About half of the participants on donanemab had no clinical progression at one year. In addition, about one-third of participants in the trial’s placebo arm also did not see their condition progress.
Investigators published in JAMA®, reporting their findings at the 2023 Alzheimer’s Association International Conference.
“Deposition of β-amyloid (Aβ) in the brain is an early event in Alzheimer disease that leads to neurofibrillary tangles composed of tau protein and other characteristic brain changes referred to as the amyloid cascade,” wrote John R. Sims, MD, and colleagues, authors of the TRAILBLAZER-ALZ 2 (NCT04437511) trial.
Amyloid antibodies got off to a rocky start after the Food and Drug Administration (FDA) approved aducanumab (Aduhelm) in 2021. The monoclonal antibody is rarely used now due to problems relating to insurance coverage and safe administration.
“However, the prospects for amyloid antibodies are likely to improve in the immediate future,” wrote Eric W. Widera, MD, Sharon A. Brangman, MD, and Nathaniel A. Chin, MD in a JAMA editorial on the study. In January, the FDA approved lecanimab (Leqembi), another antibody designed for patients with mild cognitive impairment or mild dementia stage of disease.
Researchers evaluated the safety and efficacy of donanemab in 1,736 participants 60–85 years old with early symptomatic Alzheimer's disease and amyloid and tau pathology. Tau is a predictive biomarker for disease progression.
Participants came from 277 medical research centers or hospitals in eight countries. They either had low-medium tau or a high tau (later-stage disease progression) and were randomized to receive donanemab or placebo intravenously every four weeks for more than a year. Those in the donanemab group that met completion criteria were switched to placebo in a blinded manner.
Dr. Sims and his colleagues evaluated the participants over 18 months, using the integrated Alzheimer's Disease Rating Scale (iADRS) and the Clinical Dementia Rating-Sum of Boxes (CDR-SB) to measure cognition and function. Change in integrated iADRS score from baseline to 76 weeks was the study’s primary outcome. A secondary outcome included the change in the sum of boxes of the CDR-SB score.
Slowing disease progression
Donanemab slowed clinical progression among participants with low or medium tau and in the combined low or medium and high tau pathology population. Eighty percent of the low or medium tau participants and 76% in the combined population achieved amyloid clearance at 18 months.
The treatment also performed well in subgroup analyses. Among 214 participants with mild cognitive impairment, donanemab slowed decline by 60% on iADRS and 46% on CDR-SB. In a subgroup analysis of low or medium tau participants based on age, donanemab slowed decline by 48% on iADRS and 45% on CDR-SB in patients under age 75.
The trial delivered clinically meaningful results, yet the authors acknowledged the treatment had safety risks and some limitations. Infusion reactions and amyloid-related imaging abnormalities emerged as the biggest harms to participants.
The donanemab group had a higher incidence of serious adverse events—17.4% compared with 15.8% in the placebo group. Of the participants getting donanemab, 112 had to stop treatment due to adverse events, compared with 38 getting placebo.
“Three deaths were determined to be drug related among participants who developed serious amyloid related imaging abnormalities or brain bleeding and swelling,” noted Jennifer J. Manly, PhD, and Kacie D. Deters, PhD, in another JAMA editorial on the findings.
Donanemab reduced whole-brain volume while increasing ventricular volume. Thirty-seven percent of the donanemab participants had amyloid-related imaging abnormalities compared with 15% in the placebo group. Incidence of microhemorrhage was also twice as high in the donanemab group, noted Manly and Deters.
A post-hoc analysis showed no clinical benefit to participants in the high tau group, compared with placebo. “These results suggest that, in addition to clinical criteria and Aβ biomarker positivity, staging of tau may be critical for identifying patients who would most benefit from Aβ-targeting monoclonal antibody therapy,” Rabinovici and La Joie suggested.
Uncertainty on real-world performance
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There remains significant uncertainty about how effective these drugs will be outside of a highly structured research setting, Dr. Widera said in an interview.
“We see a very small benefit in slowing cognitive decline in this structured research setting with exceptionally close monitoring from experts in the field.” Longer follow up is needed to see if this translates to more meaningful improvements for patients and caregivers, said Dr. Widera, a professor of medicine at the University of California, San Francisco.
Commenters also noted the lack of racial and ethnic diversity in the trial, which included just 24 Black participants, two American Indian/Alaska Native individuals, 11 Asians and 71 Hispanics.
The places now set up to provide lecanimab is and donanemab are the same places that enroll patients in these trials, Dr. Widera said. This means the population served will look very similar to that of the trials—healthy, wealthy and white. “I’m worried about how this is going to roll out,” he added.
Despite these concerns, the TRAILBLAZER-ALZ 2 results underscore the steady progress research is making in the fight against Alzheimer’s, wrote Rabinovici and La Joie. “The emergence of Aβ-targeting monoclonal antibodies may prove to be just the opening chapter in a new era of molecular therapies for AD and related neurodegenerative disorders,” they concluded.
Donanemab’s manufacturer, Eli Lilly & Co., said it anticipates that the FDA will approve the treatment by the end of this year. It has submitted approval requests to other global regulators.
