Summary

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• Aduhelm (aducanumab-avwa) is indicated for the treatment of Alzheimer’s disease. Treatment with Aduhelm should be initiated in patients with mild cognitive impairment or mild dementia stage of the disease, the population in which treatment was initiated in clinical trials. This indication is approved under accelerated approval based on the reduction in amyloid beta plaques observed in patients treated with Aduhelm. Continued approval for this indication may be contingent upon verification of clinical benefit in confirmatory trials.
• This summary is based on the review of 18 systematic review(s)/meta-analysis(es). ^[1-18]
• Network Meta-Analysis (NMA) Findings: Aducanumab demonstrated the highest likelihood of significant improvements in MMSE and CDR-SB; donanemab was more effective on ADAS-cog and PET-SUVr; lecanemab showed the most promise in slowing the decline of ADCS-ADL scores.
• Comparative Clinical Utility: Lithium significantly outperformed aducanumab on MMSE; donanemab and lecanemab were more effective than placebo on CDR-SB and ADAS-cog; high-dose aducanumab led to a 22% reduction in cognitive decline with improvements in CDR-SB and plasma p181-tau.
• Meta-Analysis of FDA-Approved mAbs: Statistically significant improvements were observed in CDR-SB, ADCS-ADL-MCI, ADCOMS, and ADAS-cog, along with biomarker changes, including increased CSF Aβ1-42 and plasma Aβ42/40 ratios, and decreased CSF P-Tau, T-Tau, and plasma p-tau181.
• Differences Among Populations/Subgroups: APOE4 carriers exhibited slightly better efficacy with amyloid-targeting therapies than non-carriers, though cognitive decline was similar or greater in non-carriers. Heterogeneity between trials indicated varying population responses.
• Adverse Events Incidence: Aducanumab had higher incidences of amyloid-related imaging abnormalities, specifically ARIA-E (6.5%) and ARIA-H (7.8%) compared to other monoclonal antibodies.
• Tolerability and Safety Concerns: Aducanumab, donanemab, and lecanemab were less well-tolerated compared to placebo, with aducanumab showing a higher incidence of serious adverse events, particularly in high-dose groups. Lithium demonstrated a better safety profile than aducanumab, lecanemab, and donanemab.
• Population Subgroup Differences: APOE4 carriers experienced higher, though not statistically significant, incidences of ARIA-E and ARIA-H, with symptomatic cases more frequent in high-dose treatment groups.
• Studies focused on patients with mild cognitive impairment due to AD and mild AD dementia, with older age and greater baseline cognitive impairment associated with disease progression; age and biomarkers (CSF/plasma p-tau, CSF t-tau, plasma neurofilament light) were significant for disease progression; APOE4 status predicted ARIA and influenced treatment efficacy.