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