Summary
Background
A hallmark of Alzheimer’s disease is the accumulation of β-amyloid (Aβ) peptide. Donanemab, an antibody that targets a modified form of deposited Aβ, is being investigated for the treatment of early Alzheimer’s disease.
Methods
We conducted a phase 2 clinical trial with donanemab in patients with early symptomatic Alzheimer’s disease who had deposition of tau and amyloid on positron emission tomography (PET). Patients were randomly assigned a 1: 1 ratio to receive donanemab (700 mg for the first three doses and 1400 mg thereafter) or placebo intravenously every 4 weeks for up to 72 weeks. The primary outcome was a change from the baseline in the Integrated Alzheimer’s Disease Assessment Scale (iADRS; range 0 to 144, with lower scores indicating greater cognitive and functional impairment) in 76 weeks. Secondary outcomes included the change in scores on the Clinical Dementia Assessment Scale – Sum of Boxes (CDR-SB), the 13-item cognitive subscale of the Alzheimer’s Disease Assessment Scale (ADAS-Cog13), the Cooperative Study of Alzheimer’s Disease – Inventory of Instrumental Activities of Daily Living (ADCS-iADL) and the Mini Mental State Examination (MMSE), as well as the change in amyloid and tau load in PET.
Results of
A total of 257 patients were enrolled; 131 were assigned to receive donanemab and 126 to receive placebo. The initial iADRS score was 106 in both groups. The change from baseline in the iADRS score at 76 weeks was −6.86 with donanemab and −10.06 with placebo (difference, 3.20; 95% confidence interval, 0.12 to 6.27; P = 0.04). The results of most secondary outcomes did not show substantial differences. At 76 weeks, the reductions in the level of amyloid plaque and in the overall load of tau were 85.06 centiloids and 0.01 greater, respectively, with donanemab than with placebo. Amyloid-related brain edema or strokes (mostly asymptomatic) occurred with donanemab.
Conclusions
In patients with early Alzheimer’s disease, donanemab resulted in a better composite score for cognition and the ability to perform activities of daily living than placebo at 76 weeks, although the results for secondary outcomes were mixed. Longer and larger trials are needed to study the efficacy and safety of donanemab in Alzheimer’s disease. (Funded by Eli Lilly; TRAILBLAZER-ALZ ClinicalTrials.gov number, NCT03367403.)