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

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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.

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