Donanemab in early symptomatic Alzheimer's disease: results from the TRAILBLAZER-ALZ 2 long-term extension

Abstract

Background: Donanemab significantly slowed clinical progression in participants with early symptomatic Alzheimer's disease (AD) during the 76-week placebo-controlled period of TRAILBLAZER-ALZ 2.

Methods: Participants who completed the placebo-controlled period were eligible for the 78-week, double-blind, long-term extension (LTE). Early-start participants were randomized to donanemab in the placebo-controlled period. Delayed-start participants (randomized to placebo) started donanemab in the LTE. Participants who met amyloid treatment course completion criteria were switched to placebo. An external control cohort comprised participants from the AD Neuroimaging Initiative (ADNI).

Results: At 3 years, donanemab slowed disease progression on the Clinical Dementia Rating Scale (CDR)-Sum of Boxes (CDR-SB) in early-start participants versus a weighted ADNI control (-1.2 points; 95 % confidence interval [CI], -1.7, -0.7). Seventy-six weeks after initiating donanemab, delayed-start participants also demonstrated slower CDR-SB progression versus a weighted ADNI control (-0.8 points; 95 % CI, -1.3, -0.3). Participants who completed treatment by 52 weeks demonstrated similar slowing of CDR-SB progression at 3 years. Compared with delayed-start participants, early-start participants demonstrated a significantly lower risk of disease progression on the CDR-Global over 3 years (hazard ratio=0.73; p < 0.001). In both groups, >75 % of participants assessed by positron emission tomography 76 weeks after starting donanemab achieved amyloid clearance (<24.1 Centiloids). The addition of LTE data to prior modeling predicted a median reaccumulation rate of 2.4 Centiloids/year. No new safety signals were observed compared to the established donanemab safety profile.

Conclusions: Over 3 years, donanemab-treated participants with early symptomatic AD demonstrated increasing clinical benefits and a consistent safety profile, with limited-duration dosing.

Trial registration: ClinicalTrials.gov identifier NCT04437511.

Keywords: Clinical benefit; Donanemab; Early symptomatic Alzheimer’s disease; Long-term extension data; TRAILBLAZER-ALZ 2.

Graphical abstract

Fig. 1

TRAILBLAZER-ALZ 2 overview: (a) study design and (b) study dosing. (a) The study design of TRAILBLAZER-ALZ 2 allowed for participants receiving donanemab to switch to blinded placebo infusions at 24, 52, 76, 102, or 130 weeks if they met treatment course completion criteria based on amyloid PET. (b) The percentage of donanemab infusions in participants randomized to donanemab (ie, early-start group) continued to decline as treatment course completion criteria based on amyloid PET were met. A similar trend was observed among participants randomized to placebo (ie, delayed-start group) who switched to donanemab during the LTE period. ^a Donanemab was administered intravenously at 700 mg Q4W for the first three doses and 1400 mg Q4W thereafter; ^b Number of participants receiving at least one infusion in the LTE period; ^c Participants randomized to donanemab during the PC period who did not meet the treatment course completion criteria by 76 weeks continued receiving donanemab Q4W; ^d Participants who met prespecified treatment course completion criteria based on amyloid PET were switched in a blinded fashion to placebo Q4W (saline infusion); ^e Participants randomized to placebo Q4W during the PC period were assigned to receive donanemab Q4W starting 78 weeks after randomization and followed the same dose-titration schedule as participants during the PC period. LTE: long-term extension; MRI: magnetic resonance imaging; N: number of participants; PC: placebo-controlled; PET: positron emission tomography; Q4W: every 4 weeks. Copyright © 2025 Eli Lilly and Company. All rights reserved. Permission for any use should be sought from Eli Lilly and Company.

Fig. 2

Clinical efficacy measured by change from baseline in the CDR-SB score. Efficacy was measured by change from baseline in the CDR-SB score versus the external weighted ADNI control cohort for participants in the (a) early-start group, (b) delayed-start group, and (c) early-start group who met treatment course completion criteria based on amyloid positron emission tomography by 52 weeks of the placebo-controlled period. Propensity score weights were estimated for the ADNI cohort with the average treatment effect among the treated estimand using the inverse probability weighting method from the generalized linear model. Change from baseline in the CDR-SB score was estimated using a mixed model for repeated measures using ADNI weights. ^a Includes only participants in the early-start group who met treatment course completion criteria by 52 weeks. ADNI: Alzheimer’s Disease Neuroimaging Initiative; CDR-SB: Clinical Dementia Rating Scale–Sum of Boxes; CI: confidence interval; ESS: effective sample size; LS: least-squares; N: number of participants; SE: standard error. Copyright © 2025 Eli Lilly and Company. All rights reserved. Permission for any use should be sought from Eli Lilly and Company.

Fig. 3

CDR-G hazard progression: early-start vs delayed-start treatment with donanemab. Early-start participants showed a 27 % reduced risk of progressing to the next clinical stage of the disease versus delayed-start participants. ^a Hazard ratio, 95 % CI, and p value were calculated using a Cox proportional hazards model. The model was stratified by pooled investigator and baseline tau level and included baseline covariates of age, CDR-G score, and acetylcholinesterase inhibitor/memantine use. CDR-G: Clinical Dementia Rating Scale–Global; CI: confidence interval. Copyright © 2025 Eli Lilly and Company. All rights reserved. Permission for any use should be sought from Eli Lilly and Company.

Fig. 4

Brain amyloid plaque. The effect of donanemab on amyloid plaque was demonstrated by (a) mean reduction in amyloid over time between early-start and delayed-start treatment, (b) amyloid clearance in participants in the early-start and delayed-start groups at 24, 52, and 76 weeks after donanemab initiation, and (c) amyloid reaccumulation among participants in the early-start group who met treatment course completion criteria by 52 weeks of the placebo-controlled period. ***p < 0.001 vs delayed-start treatment; ^†24 weeks from the start of donanemab treatment; ^‡52 weeks from the start of donanemab treatment. CL: Centiloids; LTE: long-term extension; LS: least-squares; PC: placebo-controlled; SD: standard deviation; SE: standard error. Copyright © 2025 Eli Lilly and Company. All rights reserved. Permission for any use should be sought from Eli Lilly and Company.