Insights From the TRAILBLAZER-ALZ Program: Elevated ARIA Risk with Donanemab Highlights the Need for Vigilant Monitoring

A recently published post-hoc exploratory analysis of the placebo-controlled TRAILBLAZER-ALZ studies revealed that treatment with donanemab (Kisulna; Eli Lilly) is associated with elevated risk for amyloid-related imaging abnormalities (ARIA), as around one-fourth of treated patients experienced ARIA-edema/effusions (ARIA-E). Overall, these reinforce the idea that safety monitoring is necessary with donanemab as with other amyloid-targeting treatments in patients with Alzheimer disease (AD).¹

Published in JAMA Neurology, the analysis comprised 3030 total participants across the TRAILBLAZER-ALZ (NCT03367403) and ALZ 2 (NCT04437511) randomized trials, as well as additional patients from a stand-alone open-label addendum (n = 1047). In the placebo-controlled studies, patients were randomized 1:1, while open-label participants received only donanemab, which was administered every 4 weeks for up to 72 weeks. Across the studies, the mean age was approximately 73.7 years (SD, 6.0) among patients with early-stage AD.

Led by Jennifer A. Zimmer, MD, a pediatric neurologist based in Indianapolis, Indiana, ARIA occurred in 37.0% of donanemab-treated patients in placebo-controlled trials, 32.0% in the open-label addendum, and in 14.2% of those on placebo. ARIA-E occurred in 19.8%-24.4% of donanemab-treated participants and 1.9% of placebo participants, while ARIA-H occurred in 27.2%-31.3% and 13.0%, respectively, with similar rates of isolated ARIA-H (11.7%-12.5%) and macrohemorrhage (0.2%-0.4%) across all groups.

ARIA-E, ARIA-H microhemorrhage, and isolated ARIA-H were mostly mild or moderate in donanemab-treated participants across placebo-controlled trials and the open-label addendum, though serious events (e.g., requiring hospitalization) were more common with moderate to severe radiographic ARIA. Symptomatic ARIA-E was more frequently classified as radiographically severe, with severe cases observed in 27.8% (15/54) and 21.4% (9/42) of symptomatic cases in the trials and addendum, respectively, compared to 3.3% (6/183) and 3.0% (5/165) of asymptomatic cases.

Results showed that most serious ARIA cases (72%; 18 of 25) occurred within the time of the first 3 monthly donanemab infusions. Following the addition of a 4-week MRI scan to the TRAILBLAZER-ALZ 2 trial protocol, the risk of symptomatic ARIA-E was reduced by 36.3% (HR, 0.64; 95% CI, 0.41-0.98; P = .04); however, only 16% of donanemab-treated patients in the study underwent this MRI. Notably, the inclusion of this of this 4-week MRI resulted in a statistically significant 23.9% risk reduction of serious ARIA (HR, 0.76; 95% CI, 0.35-1.65; P = .49).

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In the analysis, APOE ε4 status was strongly associated with ARIA-E risk, with homozygotes (OR, 4.57; 95% CI, 3.27-6.39; P < .001) and heterozygotes (OR, 2.03; 95% CI, 1.55-2.67; P < .001) having higher odds than noncarriers. Risk also increased with the number of baseline microhemorrhages (2-4 vs 0: OR, 2.53; 95% CI, 1.59-4.02; P < .001), presence of superficial siderosis (vs absence: OR, 2.18; 95% CI, 1.18-4.04; P = .01), higher mean arterial pressure (≥107 mm Hg vs <93 mm Hg: OR, 1.73; 95% CI, 1.21-2.48; P = .003), and greater baseline amyloid plaque burden (≥108 CL vs <74 CL: OR, 1.31; 95% CI, 1.00-1.71; P = .05).

A treatment-specific subgroup detection tool (TSDT) identified APOE ε4 and superficial siderosis as the strongest baseline predictors for ARIA-H in both donanemab and placebo groups. In placebo-controlled trials, ARIA-H occurrence rates differed significantly: 34.6% in APOE ε4 homozygotes vs 8.3% in noncarriers, and 52.9% in those with baseline superficial siderosis vs 18.1% without.

In donanemab-treated participants with ARIA-E, 23.8% (57/240) in placebo-controlled trials and 20.3% (42/207) in the open-label addendum reported symptoms. Headache (10.4%-13.5%) and confusional state (3.9%-5.4%) were the most common symptoms. Approximately 80% of participants in the placebo-controlled trials and 90% in the open-label addendum had symptom resolution during the study. In TRAILBLAZER-ALZ 2, of 52 symptomatic participants, 57.7% (n = 30) had mild symptoms, 23.1% (n = 12) had moderate symptoms, and 19.2% (n = 10) had severe symptoms.

Donanemab, an amyloid-targeting therapeutic, was approved in July 2024 as a treatment for patients with mild cognitive impairment and mild forms of AD, with confirmed amyloid pathology. Considered the third approved antiamyloid treatment at the time, donanemab represented the first and only medication with evidence to support stopping treatment when amyloid plaques are removed, potentially leading to lower costs and fewer infusions. The drug’s approval was based on TRAILBLAZER-ALZ 2, a large-scale trial comprising 1736 patients with early-stage AD across 277 medical sites in 8 countries.²

REFERENCES
1. Zimmer JA, Ardayfio P, Wang H, et al. Amyloid-Related Imaging Abnormalities With Donanemab in Early Symptomatic Alzheimer Disease Secondary Analysis of the TRAILBLAZER-ALZ and ALZ 2 Randomized Clinical Trials. JAMA Neurol. Published online March 10, 2025. doi:10.1001/jamaneurol.2025.0065
2. Lilly's Kisunla™ (donanemab-azbt) Approved by the FDA for the Treatment of Early Symptomatic Alzheimer's Disease. News Release. Eli Lilly. Published July 2, 2024. Accessed March 12, 2025. https://investor.lilly.com/news-releases/news-release-details/lillys-kisunlatm-donanemab-azbt-approved-fda-treatment-early