Post-hoc analyses of amyloid reduction after one year of treatment with donanemab using clinical trial data: prediction of amyloid clearance and association with downstream measurements

Abstract Background Donanemab is an antibody designed to specifically target modified amyloid that is present only in plaques. An objective of this post hoc study was to identify baseline characteristics associated with 52-week amyloid clearance (AC) with donanemab treatment and to assess the association of AC with downstream biomarkers and clinical efficacy. Methods Data was utilized from TRAILBLAZER-ALZ 2 (placebo: N = 876; donanemab: N = 860), a Phase 3, double-blind, placebo-controlled study, and open-label addendum ( N = 1053) in participants with early symptomatic Alzheimer’s disease (AD). Donanemab-treated participants were split into two subgroups based on their 52-week amyloid level: AC W52 [< 24.1 Centiloids (CL)] and NAC W52 (≥ 24.1 CL). Machine learning and multiple linear regression analyses were utilized to assess baseline characteristics differentiating these subgroups. Placebo-treated participants were matched to AC W52 and NAC W52 participants by propensity score and compared using analysis of covariance or mixed models for repeated measures. Results On average, substantial 52-week amyloid reduction was observed in donanemab-treated participants in both the AC W52 ( N = 443) and NAC W52 ( N = 227) subgroups. Baseline amyloid [mean (SD): 95.8 (32.4) and 120.2 (34.0), respectively], was significantly correlated with 52-week amyloid levels [mean (SD): 4.8 CL (12.5) and 48.2 (22.5) CL, respectively ( p < 0.001)] and was inversely associated with probability of reaching 52-week AC ( p < 0.001). Of the baseline characteristics assessed, lower amyloid was the most important parameter differentiating AC W52 and NAC W52 subgroups, followed by older age, fewer APOE ε4 alleles, and lower body weight. These findings were replicated using open-label addendum data. The AC W52 subgroup, but not the NAC W52 subgroup, had significantly less 76-week tau accumulation than matched placebo (mPBO) ( p < 0.01). Although both subgroups showed significant plasma P-tau217 differences from the corresponding mPBO, the change from baseline was greater in the AC W52 subgroup. At 76 weeks, slowing of clinical progression for the AC W52 and NAC W52 subgroups versus mPBO, as measured by Clinical Dementia Rating Scale–Sum of Boxes, was 29.6% and 28.8%, respectively, and slowing by the integrated AD Rating Scale was 25.9% and 18.8%, respectively. Conclusions Donanemab-mediated 52-week amyloid clearance was associated with slower tau progression. Slowing of clinical progression was observed in both AC W52 and NAC W52 subgroups. Trial registration ClinicalTrials.gov Identifier: NCT04437511, June 2020.