ARIA Insights from the Donanemab Trials (P1-9.001).

Area of Science:

• Neurology
• Pharmacology
• Radiology

Background:

• Amyloid-related imaging abnormalities (ARIA) are a safety concern for amyloid-targeting therapies (ATTs).
• Identifying patient factors contributing to ARIA risk is crucial for clinical ATT use.
• This study characterizes ARIA risk with donanemab, an ATT.

Purpose of the Study:

• To characterize the risk of amyloid-related imaging abnormalities (ARIA) associated with donanemab.
• To identify patient characteristics, comorbidities, and medications linked to ARIA risk.

Main Methods:

• Post-hoc analysis of 2031 donanemab-exposed participants from TRAILBLAZER-ALZ and TRAILBLAZER-ALZ2 studies.
• Used penalized regression and decision trees to identify variables associated with ARIA with edema and effusions (ARIA-E).
• Evaluated participants with mild cognitive impairment or dementia due to Alzheimer's disease.

Main Results:

• ARIA-E occurred in 27.5% (TRAILBLAZER-ALZ), 24.0% (TRAILBLAZER-ALZ2), and 19.8% (addendum) of participants.
• Most ARIA-E events were transient and asymptomatic.
• Increased ARIA-E risk associated with APOE ɛ4/ɛ4 genotype, microhemorrhages, cortical superficial siderosis, higher mean arterial pressure, and amyloid burden. Antihypertensive use correlated with decreased ARIA-E.

Conclusions:

• Baseline factors like APOE ɛ4/ɛ4 genotype and MRI findings (microhemorrhages, siderosis) are key predictors of ARIA-E risk.
• Genotyping and baseline MRI are valuable for assessing ARIA risk.
• Findings are hypothesis-generating for future ATT validation and may identify modifiable risk factors.