Donanemab treatment effect by baseline tau burden and disease severity: Observations from the TRAILBLAZER‐ALZ 2 trial

Abstract INTRODUCTION Clinical trials indicate that disease‐modifying therapies can slow clinical decline in Alzheimer's disease (AD), with earlier initiation associated with greater slowing. METHODS In the TRAILBLAZER‐ALZ 2 trial, the treatment effect of donanemab on the Clinical Dementia Rating Scale Sum of Boxes (CDR‐SB) score was assessed across disease stages defined by baseline tau PET, plasma P‐tau217 levels, or predicted disease progression. RESULTS Donanemab‐mediated slowing of disease progression occurred across baseline tau PET and plasma P‐tau217 levels. Participants with lower baseline tau PET and P‐tau217 showed greater slowing with donanemab versus placebo. Modeling CDR‐SB scores indicated that earlier treatment (at the 25 th percentile of baseline Predicted disease progression) delayed disease progression by 60% over 76 weeks, compared to 33% and 17% at the 50 th and 75 th percentiles. DISCUSSION Donanemab benefited participants with early symptomatic AD across clinical and pathological severities, with the greatest slowing in those treated earlier. ClinicalTrials.gov Identifier: NCT04437511