FDA Approves Updated Label for Alzheimer Therapy Donanemab to Lower ARIA-E Risk

Brandy Matthews, MD, FAAN

According to a new announcement from Eli Lilly, the FDA has approved an updated label for donanemab (Kisulna), an FDA-approved therapy for early-stage Alzheimer disease (AD), to now include a new recommended titration dosing schedule, which may lead to lowered risk of amyloid-related imaging abnormalities (ARIA).¹

Donanemab, an amyloid-targeting treatment, was approved in 2024 for patients with mild dementia stage of early AD with confirmed amyloid pathology. At the time, the recommended dosage of the therapy was 700 mg administered intravenously over approximately 30 minutes every 4 weeks for the first 3 doses, followed by 1400 mg every 4 weeks. In the latest updated labeling, the new recommended dosing regimen involves a more gradual titration, while still preserving the drug’s effect on amyloid plaque removal and phosphorylated tau 217 (p-tau) reduction.

Findings from the TRAILBLAZER-ALZ 6 study (NCT05738486), a double-blind, ongoing phase 3b study comparing the standard donanemab dosing regimen to 3 alternative dosing arms, was the basis behind the updated labeling. In the study, the modified titration arm met its primary end point of ARIA-Edema (ARIA-E) relative risk reduction (RRR) at 24 weeks vs the standard, approved dosing arm. Overall, the ARIA-E frequency was 13.7% in the modified titration arm compared with 23.7% in the standard arm at that time point, which remained consistent out to 52 weeks.²

"We are confident that this label update for Kisunla will significantly aid healthcare professionals in evaluating appropriate treatment options for their patients," Brandy Matthews, MD, FAAN, vice president of Global & US Medical Affairs for Alzheimer’s Disease at Eli Lilly, said in a statement.¹ "This update underscores our unwavering commitment to patient safety and the advancement of Alzheimer's disease treatment by potentially mitigating the risk of ARIA-E."

In TRAILBLAZER-ALZ 6, the 4 treatment arms varied in donanemab dosage per infusion and frequency of dosing but the total donanemab exposure by week 16 was the same. Overall, the ARIA-E frequencies for standard (n = 208), modified titration (n = 212), dose skipping (n = 210), and C_max (n = 213) arms were 23.7%, 13.7%, 18.6%, and 18.3%, respectively, at 24 weeks and similar at 52 weeks: 24.2%, 15.6%, 18.6%, and 18.8%, respectively. Notably, only the modified titration arm met the primary objective with a posterior risk reduction and a 94.1% probability that the RRR was at least 20%.

The modified titration arm also met the secondary outcome of improved ARIA-E severity at 24 weeks. In the trial, radiographic severity of ARIA-E was significantly lower with modified titration (P = .011), with 86.3% of participants showing no ARIA-E by week 24 vs 76.3% in the standard arm, and no severe events observed.

READ MORE: Predicting Amyloid Positivity with CARM: Clinical Insights from James Galvin, MD, MPH

When the impact of apolipoprotein (APOE) ε4 genotypes was assessed, ARIA-E was numerically less frequent in the modified titration arm relative to the standard arm, regardless of genotype. The largest difference in ARIA-E frequency was observed in those homozygous for APOE ε4, with a 57.1% rate in the standard arm vs 19.0% in the modified arm. Overall, the frequency of symptomatic ARIA-E in homozygous, heterozygous, and non-carrier participants was 4.8%, 8.0%, and 0%, respectively, in the standard arm and 0%, 3.5%, and 2.7%, respectively in the modified titration arm.

"This updated dosing strategy is a meaningful advancement for patients and their care teams," Elly Lee, MD, chief medical officer and principal investigator at the Irvine Center for Clinical Research, said in a statement.¹ "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."

In TRAILBLAZER-ALZ 6, the modified titration arm remained effective in lowering amyloid plaque levels and plasma p-tau217. At 24 weeks, patients in the standard arm had an adjusted mean change of 58.8 CL for amyloid reduction vs 56.3 CL (SE, 1.7) in the modified titration regimen. Plasma p-tau217 levels significantly decreased from baseline at week 24 in both the standard (0.136 [±0.012]) and modified titration arms (0.145 [±0.012]; P <.0001), with similar reductions observed across groups.

Donanemab’s 2023 approval was based on findings from the phase 3 TRAILBLAZER-ALZ-2 trial (NCT04437511), a large-scale, double-blind, placebo-controlled trial of 1736 patients with early-stage AD who received donanemab or placebo every 4 weeks for up to 72 weeks. That study, which used the original approved donanemab dosing regimen, showed an ARIA-E frequency of 24% in patients on the drug, although most events were largely mild to moderate radiographically. In terms of timing, ARIA-E first occurred after receiving up to 3 donanemab infusions in most cases (58%).³

REFERENCES
1. FDA approves updated label for Lilly's Kisunla (donanemab-azbt) with new dosing in early symptomatic Alzheimer's disease. News release. Eli Lilly. July 9, 2025. Accessed July 9, 2025. https://investor.lilly.com/news-releases/news-release-details/fda-approves-updated-label-lillys-kisunla-donanemab-azbt-ne
2. Wang H, Serap E, Nery M, et al. Modified titration of donanemab reduces ARIA risk and maintains amyloid reduction. Alzheimer & Dement. Published online April 2, 2025. doi:10.1002/alz.70062
3. Sims JR, Zimmer JA, Evans CD, et al. Donanemab in early symptomatic Alzheimer disease: the TRAILBLAZER-ALZ 2 randomized clinical trial. JAMA. Published online July 17, 2023. doi:10.1001/jama.2023.13239