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

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

Background: 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.

Design/methods: 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).

Results: 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 4/4 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 ɛ4 genotypes (non-carrier, heterozygous, homozygous), ARIA-E frequency increased with higher number of microhemorrhages and presence of cortical superficial siderosis on baseline MRI.

Conclusions: 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. Dr. Greenberg has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Eli Lilly. Dr. Greenberg has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Washington University/IQVIA. Dr. Greenberg has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Bayer. Dr. Greenberg has received research support from National Institutes of Health. Dr. Greenberg has received publishing royalties from a publication relating to health care. Dr. Battioui has received personal compensation for serving as an employee of Eli Lilly and Company. Dr. Battioui has stock in Eli Lilly. Ming Lu has received personal compensation for serving as an employee of Eli Lilly and Company. Ming Lu has received stock or an ownership interest from Eli Lilly and Company. Dr. Biffi has nothing to disclose. Paul Ardayfio has received personal compensation for serving as an employee of Eli Lilly and Co.. Paul Ardayfio has received stock or an ownership interest from Eli Lilly and Co.. Dr. Zimmer has received personal compensation for serving as an employee of Eli Lilly & Company. Dr. Zimmer has stock in Eli Lilly & Company. Dr. Evans has received personal compensation for serving as an employee of Eli Lilly & Company. Dr. Evans has received stock or an ownership interest from Eli Lilly & Company. Mrs. Wang has received personal compensation for serving as an employee of Eli Lilly and company. Dr. Monkul Nery has received personal compensation for serving as an employee of Eli Lilly And Company. An immediate family member of Dr. Monkul Nery has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Karuna Therapeutics. The institution of an immediate family member of Dr. Monkul Nery has received research support from Boehringer-Ingelheim. The institution of an immediate family member of Dr. Monkul Nery has received research support from Compass Therapeutics. The institution of an immediate family member of Dr. Monkul Nery has received research support from Recognify Life Sciences. The institution of an immediate family member of Dr. Monkul Nery has received research support from Neurocrin Biosciences. Scott W. Andersen, 19156 has received personal compensation for serving as an employee of Eli Lilly. Scott W. Andersen, 19156 has stock in Eli Lilly. Scott W. Andersen, 19156 has received personal compensation in the range of $100,000-$499,999 for serving as a Statistician with Eli Lilly. Dr. Collins has received personal compensation for serving as an employee of Eli Lilly and Company. Dr. Collins has stock in Eli Lilly and Company. An immediate family member of Dr. Brooks has received personal compensation for serving as an employee of Indiana Hospital Association. Dr. Brooks has received stock or an ownership interest from Eli Lilly and Company. Dr. Sims has received personal compensation for serving as an employee of Eli Lilly and Company. Dr. Sims has stock in Eli Lilly and Company.