Donanemab Treatment Linked to Increase Risk of Serious ARIA in Alzheimer Disease

Treatment with donanemab (Kisunla; Eli Lilly) significantly increases the risk of amyloid-related imaging abnormalities (ARIA) in patients with early symptomatic Alzheimer's disease, according to a secondary analysis of clinical trial data published online March 10, in JAMA Neurology.

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While most ARIA events were mild to moderate and asymptomatic, some were serious or fatal, underscoring the need for careful patient selection and regular monitoring during treatment, study authors said.

In phase 2 and 3 trials from the TRAILBLAZER development program, involving nearly 2,000 participants, ARIA occurrence was more pronounced among those treated with donanemab compared with those in the placebo group, at 37.0% and 14.2%, respectively, according to the findings. In an open-label extension with approximately 1,000 participants receiving donanemab, the frequency of ARIA was 32%. The study, led by John Sims, MD, of Eli Lilly and Company, revealed that ARIA with edema or effusions (ARIA-E) occurred in 24.4% of donanemab recipients in the placebo-controlled trials and 19.8% in the open-label extension. Sims and colleagues reported ARIA with microhemorrhages or hemosiderin deposits (ARIA-H) in 31.3% and 27.2% of participants, respectively. They found the frequency of isolated ARIA-H (11.7%-12.5%) and macrohemorrhage (0.2%-0.4%) similar across all groups.

Elevated risk in early treatment. Most ARIA events presented within the first 6 infusions, with 58.3% of ARIA-E cases appearing as early as the third infusion, according to the findings. The symptoms most frequently associated with ARIA were confusion and headache. The researchers reported that the risk of ARIA correlated with participant baseline APOE4 status and findings on baseline imaging. Specifically, risk increased with a higher number of APOE4 alleles, with more microhemorrhages, in the presence of cortical superficial siderosis, with greater amyloid plaque burden, and with elevated mean arterial pressure. They also noted that use of antihypertensive medications appeared to reduce the risk.

Participants across the studies had a mean age of 73.7 years and approximately half (55.6%) were women. All had early symptomatic Alzheimer’s with elevated amyloid levels recorded at baseline. Participants received donanemab or placebo intravenously every 4 weeks for up to 72 weeks. Outcomes were assessed at 76 weeks.

ARIA fatalities. Sims et al reported that although most of the documented ARIA events were transient, some did lead to severe complications and to death. In the placebo-controlled trials, 17 deaths occurred in the donanemab groups vs 12 in the placebo groups. Three deaths in the phase 3 trial were documented as directly linked to serious ARIA. Additionally, in the long-term extension of the phase 3 trial, a participant heterozygous for APOE4 died from ARIA-E after the fifth donanemab dose. Another patient suffered a fatal intracranial hemorrhage following thrombolytic therapy for suspected stroke-like symptoms. A subsequent MRI revealed severe ARIA-E.

Most ARIA events presented within the first 6 infusions, with 58.3% of ARIA-E cases appearing as early as the third infusion, with the most common symptoms reported as confusion and headache. The risk of ARIA correlated with participant baseline APOE4 status and findings on baseline imaging.

Most ARIA events presented within the first 6 infusions, with 58.3% of ARIA-E cases appearing as early as the third infusion, according to the findings. The symptoms most frequently associated with ARIA were confusion and headache. Most ARIA events presented within the first 6 infusions, with 58.3% of ARIA-E cases appearing as early as the third infusion, according to the findings. The symptoms most frequently associated with ARIA were confusion and headache.

Boxed warning. Donanemab, the first amyloid-directed antibody to receive FDA approval (2024) for Alzheimer’s treatment, carries a boxed warning for ARIA-E and ARIA-H. The label highlights that ARIA is often asymptomatic but can mimic ischemic stroke and lead to serious intracerebral hemorrhages. The language also warns that APOE4 homozygotes face an increased risk of ARIA with amyloid-targeting therapies.

TRAILBLAZER program. The secondary analysis included data from the phase 2 TRAILBLAZER-ALZ and phase 3 TRAILBLAZER-ALZ 2 trials, which were conducted from 2017 to 2023, as well as an open-label addendum. The dataset for the pooled analysis included 257 participants from TRAILBLAZER-ALZ, 1,736 from TRAILBLAZER-ALZ 2, and 1,053 from the addendum.

Sims and colleagues acknowledged the dearth of long-term data on patients who experienced ARIA and the need to build that knowledge base. They suggested that a modified dose titration strategy may help mitigate ARIA risk, as was observed in TRAILBLAZER-ALZ 2 following amendment of the study protocol and has also been reported in preliminary results from the phase 3b TRAILBLAZER-6 study.

The investigators also noted implementation of a 4-week MRI evaluation to the TRAILBLAZER-ALZ 2 study, a tactic that they said reduced the risk of symptomatic ARIA-E by approximately 36% and a statistically nonsignificant 23.9% reduction in risk of serious ARIA.  

Use with caution. "While ARIA-E events were typically transient and asymptomatic, ARIA can be serious, life threatening, or fatal; therefore, safety monitoring is necessary with donanemab as with other amyloid-targeting therapies used in slowing disease progression in early symptomatic Alzheimer's disease," Sims and colleagues wrote in conclusion. They added that prediction or prevention of ARIA can also be improved by identifying independent baseline risks before initiating therapy.