To characterize amyloid-related imaging abnormalities (ARIA) risk associated with donanemab, a novel amyloid-targeting therapy (ATT).

ARIA is an important safety concern associated with the class of ATTs. Identifying patient characteristics, comorbidities, concomitant medications, and modifiable factors potentially contributing to ARIA risk is paramount to inform use of ATTs in clinical practice. 

This post-hoc exploratory analysis evaluated data from 2031 donanemab-exposed participants in the phase 2 TRAILBLAZER-ALZ study (NCT03367403), the phase 3 TRAILBLAZER-ALZ2 study (NCT04437511), and the open-label TRAILBLAZER-ALZ2 addendum. TRAILBLAZER-ALZ and TRAILBLAZER-ALZ2 participants had mild cognitive impairment or mild dementia due to Alzheimer’s disease with amyloid and tau pathology (via PET). Addendum enrollment required PET evidence of amyloid, but participants without tau pathology were eligible. Participants received donanemab every 4 weeks for up to 72 weeks and stopped treatment if amyloid PET-based completion criteria were met. Hypothesis-generating penalized regression and decision tree-based models were employed to identify variables associated with ARIA−edema and effusions (ARIA-E).

In TRAILBLAZER-ALZ, TRAILBLAZER-ALZ2, and the addendum, respectively, ARIA-E occurred in 36/131 (27.5%), 205/853 (24.0%), and 207/1047 (19.8%) of donanemab-treated participants. Most events were transient and asymptomatic. Baseline factors most strongly and independently associated with increased ARIA-E frequency included APOE ε4/ε4 genetic presence, higher number of microhemorrhages, presence of cortical superficial siderosis, higher mean arterial pressure, and greater amyloid burden. Antihypertensive medication use was associated with decreased ARIA-E frequency. Within APOE ε4 genotypes (non-carrier, heterozygous, homozygous), ARIA-E frequency increased with higher number of microhemorrhages and presence of cortical superficial siderosis on baseline MRI.

Baseline variables associated with ARIA-E frequency were identified through post-hoc exploratory analysis of donanemab clinical datasets. Genotyping and baseline MRI may represent the most informative methods to assess potential ARIA risk in practice. This analysis is hypothesis-generating for future validation work across the class of ATTs and may yield modifiable factors.