Subgroup analyses of the amyloid PET substudies from EMERGE and ENGAGE, phase 3 clinical trials evaluating aducanumab in patients with early Alzheimer’s disease

Abstract

AbstractBackgroundAducanumab, a human monoclonal antibody that selectively targets aggregated forms of beta amyloid (Aβ), is under investigation for the treatment of Alzheimer’s disease (AD). EMERGE and ENGAGE were 2 identically‐designed, randomized, double‐blind, placebo‐controlled Phase 3 trials that evaluated the efficacy and safety of aducanumab in participants with mild cognitive impairment (MCI) due to AD or mild AD dementia and confirmed amyloid pathology. These studies were initiated following the Phase 1b PRIME study in which aducanumab reduced amyloid burden and slowed decline on exploratory clinical endpoints. In both EMERGE and ENGAGE, dose‐ and time‐dependent reductions in amyloid positron emission tomography (PET) composite standard uptake value ratio (SUVR) were observed at Week 78 in the amyloid PET biomarker substudies.MethodParticipants were randomized (1:1:1) to receive high‐dose aducanumab, low‐dose aducanumab, or placebo via intravenous injection every 4 weeks for 18 months. Longitudinal amyloid PET imaging using 18F‐florbetapir was performed in a subset of patients (n=488 in EMERGE; n=585 in ENGAGE) at screening, Week 26, and Week 78.Subgroup analysis of amyloid PET SUVR for 6 prespecified factors including age (≤64, 65 to 74, or ≥75 years), sex (male or female), ApoE ε4 status (carrier or noncarrier), baseline clinical stage (MCI due to AD or mild AD dementia), baseline Mini‐Mental State Exam (≤26 or ≥27) and use of AD symptomatic medications at baseline (yes or no) for a total of 13 subgroups was conducted for each study.ResultAn advantage of high‐dose and low‐dose aducanumab over placebo was observed in the 13 subgroups, with time‐ and dose‐dependent Aβ reduction observed in each subgroup. These results were consistent with the overall results of the amyloid PET biomarker substudies in which aducanumab treatment was associated with robust dose‐dependent reduction in brain Aβ levels.ConclusionAmyloid PET SUVR subgroup analysis revealed a consistent dose‐ and time‐dependent advantage of high‐dose and low‐dose aducanumab over placebo in the prespecified subgroups.