Donanemab Label Update: What the Modified Titration Data Means for Clinicians: John Sims, MD

WATCH TIME: 3 minutes

"The modified titration reduced ARIA risk by 41% in the first six months—the window when most ARIA events happen. Importantly, we saw fewer symptoms, less severity, and even zero severe cases. That’s what really moves the needle in terms of patient care and confidence in prescribing."

In mid-2024, the FDA approved Eli Lilly’s donanemab (Kisulna) as the next amyloid-targeting therapy for patients with mild cognitive impairment as well as early-stage Alzheimer disease (AD) confirmed with amyloid pathology. With the approval, it became the first such medication to be stopped when amyloid plaques are removed, potentially resulting in lower therapy costs and fewer infusions. While its approval was notable, several in the field continued to have concerns with amyloid-related imaging abnormalities (ARIA), a serious adverse event of antiamyloid treatments that was found in 24% of treated patients in the phase 2 TRAILBLAZER-ALZ 2 trial (NCT04437511), the confirmatory study that led to the donanemab’s approval.¹

About a year after donanemab hit market, the FDA approved a new recommended titration dosing regimen for the therapy, with the potential to lower the risk of ARIA. Findings from the published TRAILBLAZER-ALZ 6 trial (NCT0573846), an ongoing phase 3b study comparing the standard donanemab dosing regimen to 3 alternative dosing arms, was the basis for the updated labeling. In the double-blind study, investigators observed an ARIA-E frequency of 13.7% in the modified titration arm compared with 23.7% in the standard arm at 24 weeks, with efficacy that remained consistent out to 52 weeks.^2,3

With regard to the latest news, NeurologyLive^® reached out to John Sims, MD, PhD, trial investigator for TRAILBLAZER-ALZ 6, to discuss the downstream impacts of this new titrated dosing regimen and what it means for clinicians who treat those with AD. Sims head of medical development for donanemab at Eli Lilly and Company, emphasized how these safety improvements could lead to more confident prescribing, enhanced physician-patient conversations around risk/benefit, and potentially improve early diagnosis and access to therapy for AD.

REFERENCES
1. 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
2. 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
3. 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