Jury still out on aducanumab role in Alzheimer’s disease
While aducanumab significantly reduced clinical decline in individuals with early Alzheimer's disease (AD) in one randomized trial, no changes were seen in another identical study — rendering the role of aducanumab in AD inconclusive.
Aducanumab is a human monoclonal antibody targeting the aggregated forms of β-amyloid, accumulation of which has been found in brains of AD patients and believed to be the cause of the disease.
However, various therapeutic attempts to block the formation amyloid plaques have been fraught with failures to show any significant improvement in AD. These previous studies have casted doubts on whether the hypothesis that β-amyloid is the cause of AD holds any water, and whether the presence of β-amyloid is a mere co-existence in the brains of AD patients.
Fuelled by the classical belief in the role of β-amyloid in AD and recent positive subgroup findings, two studies on aducanumab were revived in AD.
The double-blind, phase III, multinational EMERGE and ENGAGE trials were two identical studies with similar design. A total of 3,285 patients (mean age 70 years, 52 percent women) with early AD (MCI due to AD plus mild AD dementia) were randomized to received high-dose or low-dose aducanumab or placebo in both studies. [AAN 2020, abstract 46977]
In the EMERGE study, high-dose aducanumab led to significant decrease by 22 percent in the primary endpoint of Clinical Dementia Rating scale Sum of Boxes (CDR-SB) at 18 months compared with placebo (p=0.01).
Changes in secondary endpoints were also significant with high-dose aducanumab in the EMERGE study, as indicated by improvements in the MMSE (p=0.05), ADAS-Cog 13 (p=0.01), and ADCS-ADL-MCI scores (p=0.0006).
In contrast, there was no significant difference in CDR-SB scores (2 percent; p=0.83) between treatment groups in the ENGAGE study.
Increase in MMSE scores also did not reach significance in the high-dose aducanumab vs the placebo groups (3 percent; p=0.81) in the ENGAGE study, as opposed to the finding in EMERGE.
However, a post hoc analysis of a subset of patients who received high-dose aducanumab in the ENGAGE study showed positive findings in support of those observed in EMERGE.
Substudies of the CSF-disease related biomarkers showed significant reduction in phospho-tau levels with high-dose aducanumab in both EMERGE and ENGAGE trials, but not for total tau levels.
For both studies, there were no significant changes in CDR-SB or MMSE scores at week 78 from baseline with low-dose aducanumab.
The rates of adverse events (AEs) were similar across treatments groups: 92 percent in the high-dose group, 88 percent in the low-dose group, and 87 percent in the placebo for EMERGE; and 90 percent, 90 percent, and 86 percent, respectively in the ENGAGE study.
Headache, nasopharyngitis, and amyloid-related imaging abnormalities (ARIA; one related to oedema and the other to hemosiderosis) were the most common AEs reported.
“We are finalizing the details of a re-dosing study with the aim to offer access to aducanumab to eligible patients previously enrolled in the aducanumab clinical studies,” the researchers said.