Donanemab Showed Sustained Cognitive Benefit Over 3 Years in Early Alzheimer Disease

New 3-year data from the long-term extension (LTE) of the phase 3 TRAILBLAZER-ALZ 2 trial showed that treatment with donanemab-azbt (Kisunla) continued to provide cognitive and functional benefit in individuals with early symptomatic Alzheimer disease (AD).1

The findings were presented during a late-breaking session at the 2025 Alzheimer’s Association International Conference (AAIC), being held July 27-31, 2025, in Toronto, Canada.

The TRAILBLAZER- ALZ 2 LTE study was a double-blind extension of the original TRAILBLAZER-ALZ-2 clinical trial, evaluating the efficacy and safety of donanemab in individuals with early symptomatic Alzheimer disease. In the original study, 1736 participants aged 60-85 years received donanemab (n = 860) or placebo (n = 876) administered intravenously every 4 weeks for up to 72 weeks. Results showed up to a 35% reduction in cognitive and functional decline in patients with less advanced disease over 18 months compared with placebo. Donanemab also reduced progression to the next clinical disease stage by 37%.2

The LTE study enrolled 1207 participants who had completed the 76-week TRAILBLAZER-ALZ-2 (core) study. Participants in the extension study were grouped based on original assignment and followed for an additional 78 weeks. Those who received donanemab (n=550) either continued therapy or were switched to placebo after reaching PET-confirmed amyloid clearance thresholds. Participants initially assigned to placebo (n=657) were crossed over to donanemab at LTE entry and followed under the same dosing and stopping criteria.1

The primary efficacy outcome was the change from baseline in the Clinical Dementia Rating–Sum of Boxes (CDR-SB), with additional assessments including the Clinical Dementia Rating–Global Score (CDR-G) and amyloid plaque burden by positron emission tomography (PET).1

At 36 months, the donanemab-treated group had a –1.2 point difference in CDR-SB compared to a matched untreated external cohort from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). This benefit grew from a –0.6 point difference at 18 months, indicating continued slowing of cognitive and functional decline over time. In analyses of disease progression, early initiation of donanemab was associated with a 27% lower risk of progressing to the next stage of AD, based on CDR-G scoring, compared with delayed treatment initiation.1

Amyloid plaque reduction was robust. More than 75% of participants who received donanemab achieved PET-confirmed amyloid clearance within 76 weeks of treatment. Among participants who had stopped therapy and were followed for up to 2.5 years, amyloid reaccumulation occurred at a slow rate of approximately 2.4 Centiloids per year—consistent with previous modeling.1

The long-term safety profile of donanemab remained consistent with earlier findings. Amyloid-related imaging abnormalities with edema/effusion (ARIA-E) occurred in <5% of participants and were mostly radiographically mild. No new safety signals were identified. Headache and infusion-related reactions remained among the most common adverse events.1

"The TRAILBLAZER-ALZ 2 long-term extension reaffirms that Kisunla delivered sustained clinical benefit that continued to increase over three years and a consistent safety profile," Mark Mintun, MD, group vice president, Neuroscience Research & Development, Eli Lilly and Company, said in a press release. "Participants continued to show meaningful outcomes, reinforcing the long-term value of early intervention." 1

Donanemab is administered via intravenous infusion every 4 weeks. Treatment is discontinued once patients meet prespecified amyloid clearance criteria. The TRAILBLAZER-ALZ clinical program also includes TRAILBLAZER-ALZ 3, evaluating donanemab in preclinical AD; TRAILBLAZER-ALZ 5, a registration trial in Asian populations; and TRAILBLAZER-ALZ 6, a completed study that tested a modified titration regimen to reduce ARIA risk.1 Findings from TRAILBLAZER-ALZ 6 supported the US FDA’s updated prescribing information for donanemab.3

References:

1. Lilly's Kisunla (donanemab-azbt) showed growing benefit over three years in early symptomatic Alzheimer's disease. News release. Eli Lilly and Company. July 30, 2025. Accessed July 30, 2025. https://investor.lilly.com/news-releases/news-release-details/lillys-kisunla-donanemab-azbt-showed-growing-benefit-over-three
2. Halsey G. Donanemab Significantly Slows Cognitive, Functional Decline in Early Alzheimer Disease. Patient Care. May 4, 2023. https://www.patientcareonline.com/view/donanemab-significantly-slows-cognitive-functional-decline-in-early-alzheimer-disease
3. Jennings S. Donanemab Label Revised: New Dosing Schedule Approved for Early Alzheimer’s Treatment. Patient Care. July 9, 2025. https://www.patientcareonline.com/view/donanemab-label-revised-new-dosing-schedule-approved-for-early-alzheimer-s-treatment