Aims

To evaluate the efficacy of aducanumab treatment in EMERGE and ENGAGE, Phase 3 studies of aducanumab in early Alzheimer’s disease.

Methods

EMERGE and ENGAGE were identically designed, randomized, double-blind, placebo-controlled, global Phase 3 studies that evaluated the efficacy and safety of aducanumab in patients aged 50-85 years with early Alzheimer’s disease (MCI due to AD or mild AD dementia, and confirmed amyloid pathology). Participants received high-dose aducanumab, low-dose aducanumab, or placebo, randomized 1:1:1, via intravenous injection monthly for 18 months. The primary endpoint was change from baseline on the CDR-SB at Week 78. Secondary endpoints included change from baseline on MMSE, ADAS-Cog13, and ADCS-ADL-MCI at Week 78. NPI-10 was a tertiary efficacy measure.

Results

In EMERGE, treatment with high-dose aducanumab resulted in a consistent and statistically significant reduction of clinical decline across both the primary and secondary endpoints. ENGAGE did not meet its primary endpoint; dose exposure, amongst other factors, contributed to the discordant results observed between the two studies in the high-dose aducanumab arm. In each study, aducanumab showed statistically significant and dose-dependent reduction in brain amyloid beta (Aβ) pathology. Effects on downstream biomarkers specific to Alzheimer disease (tau PET and CSF p-tau) and neurodegeneration (CSF t-tau) further support the clinical findings.

Conclusions

The results of the EMERGE trial indicate a beneficial effect of high-dose aducanumab in patients with early Alzheimer’s disease. The discordant results of the ENGAGE trial may be explained, at least in part, by lower exposure to the drug.