FDA Approves Modified Titration Dosing for Donanemab-azbt to Reduce ARIA-E Incidence in Early AD
The US Food and Drug Administration (FDA) has approved a label update for donanemab-azbt (Kisunla), Eli Lilly and Company’s monthly intravenous amyloid-targeting therapy for adults with early symptomatic Alzheimer disease (AD), including patients with mild cognitive impairment (MCI) and mild dementia, with confirmed amyloid pathology. This update introduces a modified titration schedule intended to lower the incidence of amyloid-related imaging abnormalities with edema/effusion (ARIA-E), a known adverse effect of amyloid-targeting therapies.
"This updated dosing strategy is a meaningful advancement for patients and their care teams," said Elly Lee, MD, Chief Medical Officer and Principal Investigator, Irvine Center for Clinical Research in the news release. "By significantly reducing the risk of ARIA-E, we can offer patients and care teams greater confidence in the safety of Kisunla while preserving its ability to reduce amyloid."
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The FDA’s decision was based on results from the TRAILBLAZER-ALZ 6 study, a Phase 3b, double-blind, multicenter trial involving 843 participants aged 60–85 years. The modified dosing reduced ARIA-E incidence by 41% at 24 weeks and 35% at 52 weeks compared to the original schedule, while preserving efficacy in amyloid plaque and P-tau217 reduction. Amyloid PET imaging showed comparable plaque clearance at 24 weeks (67% vs. 69%).
The titration modification involves redistribution of the dosing vial from the first to the third infusion, maintaining the total dose delivered by week 24 while reducing initial exposure that may predispose patients to ARIA.
The updated label maintains the original boxed warning for ARIA. Though typically asymptomatic, ARIA can lead to headache, confusion, visual changes, seizures, or death, particularly in homozygous apolipoprotein E ε4 (APOE ε4/ε4) carriers and in patients concurrently receiving antithrombotics.
Both ARIA-E (vasogenic edema) and ARIA-H (microhemorrhages/hemosiderin deposition) were reported—29% combined incidence at 52 weeks. MRI monitoring remains essential prior to and during therapy.
Other adverse reactions included hypersensitivity and infusion-related events, necessitating post-infusion observation. No new safety signals emerged.
The once-monthly dosing with potential treatment discontinuation upon adequate amyloid clearance remains unchanged.
