Reference: J Prev Alzheimers Dis 2022;9:197
Alzheimer’s disease (AD) is a progressive, irreversible neurodegenerative disorder that affects up to 50% of adults by age 85. Accumulation of amyloid beta peptide in the brain is thought to play a key role, and has been a target of clinical development for more than 25 years. The apolipoprotein E 4 (APOE4) gene is thought to increase the accumulation of amyloid and be a risk factor for late onset AD. The difficult and fatal course of AD, paired with limited efficacy of available treatments, breeds high hopes for a miracle drug. Aducanumab, a human monoclonal antibody directed against amyloid beta, was granted accelerated FDA approval in June 2021. On the heels of a phase 1b study (PRIME) that suggested slowing of clinical decline, investigators at Biogen designed two identical trials to investigate the efficacy and safety of aducanumab.
Investigators enrolled 1,647 (ENGAGE) and 1,638 (EMERGE) participants aged 50-85 years old with AD implied by amyloid deposits seen on PET scans in two identically designed randomized phase 3 clinical trials. Participants were randomized 1:1:1 to receive high-dose aducanumab (6-10 mg/kg), low-dose aducanumab (3-6 mg/kg), or placebo, all administered IV every 4 weeks for 76 weeks. Because of concerns for amyloid-related imaging abnormalities (ARIA) that can occur at high doses of aducanumab and in APOE4 carriers, participants identified as APOE4 carriers received dosages at the lower end of the ranges for both high- and low-dose aducanumab (6 and 3 mg/kg, respectively). ARIA can manifest clinically as headaches, vomiting, confusion, and gait disturbance. The primary endpoint was change from baseline to week 78 in the Clinical Dementia Rating Sum of Boxes (CDR-SB) score. This 0-18 point scale assesses both cognition and function, with higher scores indicating more severe impairment. Secondary endpoints included change from baseline on several other clinical scales, adverse events, and CSF biomarkers. Brain MRIs were planned for all participants to assess for ARIA at screening and at 7 additional time points (26,280 total MRIs!). There were a number of protocol amendments due to failure of lower doses of other agents and recognition of a relatively benign course in most ARIA cases. Amendments included an increase in the target aducanumab dose from 6 to 10 mg/kg for APOE4 carriers in the high-dose aducanumab group and more leniency around continued dose titration in participants who developed ARIA. Both trials were stopped early due to prespecified futility criteria being met at a planned interim analysis, at which point 53% of EMERGE participants and 57% of ENGAGE participants had completed the study.
Results from the two identically designed trials were discordant. For patients who had received high-dose aducanumab compared to placebo, data from the EMERGE trial demonstrated a small but significant reduction in CDR-SB score (-0.39 points [95% CI -0.69 to -0.09]), but the ENGAGE trial demonstrated a nonsignificant increase in CDR-SB score (0.03 points, 95% CI -0.26 to +0.33). Neither trial found significant differences in the primary or secondary clinical outcomes comparing low-dose aducanumab to placebo. However, both trials found a dose-dependent increase in adverse events, with ARIA-edema in 43% (42%) of APOE4 carriers receiving high-dose aducanumab, 30% (29%) of those receiving low-dose, and 2% (2%) of those receiving placebo in the EMERGE and (ENGAGE) trials, respectively.
The bottom line here is that a promising new treatment for Alzheimer’s disease had a disappointing show in two expensive clinical trials. The effort spent on extensive post hoc exploratory analyses trying to explain the lack of statistical significance and discordance between trials does not offer us much confidence that there is efficacy to be found for aducanumab. What’s clear, however, is that higher doses result in higher risk of harm. The investigators (and Biogen) wanted this drug to work- we all do. But unless we have reason to believe that at some higher dose the dose-response curve for benefit will suddenly accelerate and outpace the dose-response curve for harm, further trials could be considered unethical. Unfortunately, it seems that we have a futile attempt at a new treatment for a disease that could desperately use a miracle.
For more information, see the EBSCO Health Notes blog post on aducanumab.
DynaMed EBM Focus Editorial Team
This EBM Focus was written by Katharine DeGeorge, MD, MS, Deputy Editor at DynaMed and Associate Professor of Family Medicine at the University of Virginia. Edited by Alan Ehrlich, MD, Executive Editor at DynaMed and Associate Professor in Family Medicine at the University of Massachusetts Medical School; Dan Randall, MD, Deputy Editor at DynaMed; Carina Brown, MD, Assistant Professor at Cone Health Family Medicine Residency; Nicole Jensen, MD, Family Physician at WholeHealth Medical; Vincent Lemaitre, PhD, Senior Medical Writer at DynaMed; and Sarah Hill, MSc, Associate Editor at DynaMed.