Posttreatment Amyloid Levels and Clinical Outcomes Following Donanemab for Early Symptomatic Alzheimer Disease: A Secondary Analysis of the TRAILBLAZER-ALZ 2 Randomized Clinical Trial.

Abstract

Importance Accumulation of amyloid plaque drives pathogenesis of Alzheimer disease (AD). Reduction of amyloid via amyloid-targeting therapies may result in clinical benefit. Objective To assess the correlation of posttreatment amyloid levels with clinical outcomes and biomarkers in AD. Design, Setting, and Participants This was a post hoc exploratory analysis from the randomized, placebo-controlled phase 3 trial, TRAILBLAZER-ALZ 2, conducted June 2020 through April 2023 at 277 medical research centers/hospitals in 8 countries. A total of 8240 participants aged 60 to 85 years with early symptomatic AD with amyloid and tau pathology based on positron emission tomography (PET) imaging were assessed for eligibility. Of these, 6504 participants were excluded predominantly due to inadequate amyloid or tau pathology. The current analysis included 1582 participants (766 in the donanemab group and 816 in the placebo group) with baseline and at least 1 posttreatment assessment. Data analysis took place from July 2024 to March 2025. Interventions Participants were randomized 1:1 to receive donanemab (700 mg for the first 3 doses and 1400 mg thereafter) or placebo intravenously every 4 weeks for up to 72 weeks, with outcomes assessed through 76 weeks. Main Outcomes and Measures Participants were categorized into 1 of 10 groups (deciles) based on their lowest amyloid value observed posttreatment. Clinical progression was assessed via changes in integrated Alzheimer's Disease Rating Scale (iADRS) and Clinical Dementia Rating-Sum of Boxes (CDR-SB) scores. Plasma biomarkers measured included phosphorylated tau 217 (p-tau217), p-tau181, glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL). Correlations between the median amyloid level in each decile were assessed with 76-week least-squares mean changes in each outcome and biomarker. Results Analyses included 1582 participants, including 766 treated with donanemab and 816 with placebo. The mean (SD) age was 72.9 (6.2) years, and 900 participants (56.9%) were female. Participants who received donanemab had lower posttreatment amyloid values than those in the placebo group. Across the trial population, lower posttreatment amyloid levels were correlated with slower clinical progression as measured by iADRS score (R2, 0.73 [95% CI, 0.37-0.97]) and CDR-SB score (R2, 0.87 [95% CI, 0.70-0.97]) and with decreases in p-tau217 (R2, 0.86 [95% CI, 0.73-0.97]), p-tau181 (R2, 0.88 [95% CI, 0.77-0.97]), and GFAP (R2, 0.87 [95% CI, 0.76-0.97]). There was no correlation between posttreatment amyloid value and NfL (R2, 0.03 [95% CI, 0.00-0.54]). Conclusions and Relevance The findings in this secondary analysis of a randomized clinical trial demonstrating a correlation between posttreatment amyloid plaque level and clinical benefit support amyloid plaque removal as the mechanism of action for donanemab treatment and the level of amyloid plaque as a potential surrogate biomarker in amyloid-targeting therapies. Trial Registration ClinicalTrials.gov Identifier: NCT04437511.