High-clearance anti-amyloid immunotherapies in Alzheimer's disease. Part 1: Meta-analysis and review of efficacy and safety data, and medico-economical aspects.
Level 1 - systematic review of randomized trials
Meta-analysis of randomized controlled trials
PubMed 36184326 · doi:10.1016/j.neurol.2022.06.012
What was done
The authors conducted frequentist and Bayesian meta-analyses and a review of clinical efficacy, safety, and medico-economical data for high-clearance anti-amyloid-β immunotherapies in early Alzheimer's disease. They pooled highest-dose data from four trials: two phase 3 trials of aducanumab, one phase 2 trial of donanemab, and one phase 2 trial of lecanemab.
What was found
High-dose immunotherapy showed a statistically significant reduction in cognitive decline at 18 months on the CDR-SB versus placebo (mean difference = -0.24 points, P=0.04, frequentist random-effects model), with ADAS-Cog showing the most robust statistical signal; however, this effect remained below established minimal clinically relevant thresholds. Immunotherapies significantly increased amyloid-related imaging abnormalities: ARIA-edema (risk ratio = 13.39, P<0.0001), ARIA-hemorrhage (risk ratio = 2.78, P=0.0002), and symptomatic/serious ARIA (0.53% [7/1,321] in high-dose arms vs. 0% [0/1,446] in placebo; risk ratio = 6.44, P=0.04). Medico-economical analysis indicated aducanumab's US pricing was not aligned with its clinical benefit.
Why it matters
This synthesis demonstrates that although high-clearance amyloid immunotherapies modestly slow cognitive decline over 18 months, the effect size is below established thresholds of clinical meaningfulness and carries substantial risks of brain edema and hemorrhage.
Limits
The meta-analysis was limited to four trials, half of which were phase 2 studies, and only evaluated highest-dose groups. Outcomes were restricted to 18 months of follow-up, leaving long-term efficacy and safety unmeasured, and responder subgroup analyses were not definitive.
Cited by
- supports Drugs developed to remove beta-amyloid from the brain successfully clear beta-amyloid plaques, yet treated Alzheimer's patients continue to clinically decline.