Overviewing the Conduct and Rationale Behind Donanemab’s TRAILBLAZER-ALZ 6 Study: John Sims, MD

WATCH TIME: 3 minutes

"We debated sacrificing the standard arm for another experimental option, but keeping it gave us the cleanest comparison. In the end, the modified titration emerged as the most successful—reducing ARIA risk while maintaining efficacy."

Earlier this month, the FDA approved an updated label for donanemab (Kisulna; Eli Lilly), an antiamyloid medication for early-stage Alzheimer disease (AD), to include a new recommended titration dosing schedule. This new adjusted regimen involves a more gradual titration that is anticipated to lower the risk of amyloid-related imaging abnormalities (ARIA), a concern for antiamyloid-targeting treatments, while maintaining effect on amyloid plaque removal and phosphorylated tau 217 (p-tau) reduction.

Donanemab was the third approved agent in the antiamyloid class, following Biogen’s aducanumab (now removed) and Eisai’s lecanemab. It was originally approved in doses of 700 mg administered intravenously over approximately 30 minutes every 4 weeks for the first 3 doses, followed by 1400 mg every 4 weeks. The latest updated dosing regimen was based on findings from the published TRAILBLAZER-ALZ 6 trial (NCT05738486), a double-blind, phase 3 study testing standard donanemab dosing regimen to 3 alternative dosing arms.

In the study, the modified titration arm met its primary end point of ARIA-Edema relative risk reduction at 24 weeks vs the standard, approved dosing arm. Study investigators, including John Sims, MD, found an ARIA-E frequency of 13.7% in the modified titration arm vs 23.7% in the standard arm at 24 weeks, which remained consistent out to 52 weeks. Following the decision, Sims, head of medical development for donanemab at Eli Lilly and Company, sat down with NeurologyLive^® to give insights on TRAILBLAZER-ALZ 6 and the reasons to test a modified titration dosing regimen. In the conversation, Sims broke down the other 3 alternative dosing arms and why they were chosen, as well as their effects on specific genotypes of AD, such as those who are homozygous for apolipoprotein (APOE) e4.

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 21, 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