Kisunla Linked to Increased Risk of ARIA in Early AD Treatment

Post hoc analysis of the TRAILBLAZER-ALZ and ALZ 2 trials (NCT03367403 and NCT04437511) and an open-label addendum found that Kisunla (donanemab; Eli Lilly and Company, Indianapolis, IN) treatment significantly increased the risk of amyloid-related imaging abnormalities (ARIA) in patients with early symptomatic Alzheimer disease (AD).

The study included pooled data from 3,030 trial participants (mean age: 73.7 years) and primary outcomnes included ARIA frequency, radiographic severity, symptoms, and timing in individuals treated with Kisunla (n=2031) vs placebo (n=999). Researchers utilized a post hoc machine learning model and regression analysis to assess independent association between ARIA-E and baseline variables.

Results showed that ARIA-E (edema/effusions) and ARIA-H (microhemorrhages/hemosiderin deposition) occurred more frequently in individuals treated with Kisunla:

• 24.4% of Kisunla-treated patients in the placebo-controlled trials and 19.8% in the open-label addendum experienced ARIA-E, compared to 1.9% for placebo.
• 31.3% of Kisunla-treated patients in the placebo-controlled trials and 27.2% in the open-label addendum experienced ARIA-H, compared to 13.0% for placebo.

Results also showed that most ARIA-E events (58.3%) occurred by the third monthly Kisunla infusion, and that most cases were mild to moderate. Serious and symptomatic (primarily headache or confusional state) ARIA-E occurred in 1.5% and 5.8% of Kisunla-treated patients, respectively.

Results demonstrated independent associations between ARIA-E and the following 6 baseline variables:

• Increased risk with APOE ε4 allele number
• Greater number of microhemorrhages
• Presence of cortical superficial siderosis
• Higher amyloid plaque
• Elevated mean arterial pressure
• Decreased risk with antihypertensive use

These results demonstrate that ARIA is a common and sometimes severe adverse event associated with Kisunla treatment. The authors of this study recommend individualized risk assessments and early, intensive MRI monitoring to mitigate serious outcomes in individuals with early symptomatic AD.

Source: 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. 2025;82(5):461–469. https://doi.org/10.1001/jamaneurol.2025.0065