Effects of monoclonal antibodies against amyloid-β on clinical and biomarker outcomes and adverse event risks: A systematic review and meta-analysis of phase III RCTs in Alzheimer's disease

Abstract

Objective: To investigate the effects of monoclonal antibodies against Aβ on cognition, function, amyloid PET and other biomarkers, as well as risk for amyloid-related imaging abnormalities (ARIA) and other adverse events, in Alzheimer's disease (AD).

Methods: Pubmed, Web of Science, ClinicalTrials.gov and gray literature were searched for phase III RCTs and random-effects meta-analyses were performed.

Results: Seventeen studies (12,585 patients) were included. Antibodies statistically improved the cognitive outcomes ADAS-Cog {SMD = -0.06 [95 % CI (-0.10; -0.02), I² = 0%]} and MMSE {SMD = 0.05 [95 % CI (0.01; 0.09), I² = 0%]} by small effect sizes, but did not improve the cognitive/functional measure CDR-SOB {SMD = -0.03 [95 % CI (-0.07; 0.01), I² = 18 %]}. Moreover, antibodies decreased amyloid PET SUVR {SMD = -1.02 [95 % CI (-1.70; -0.34), I² = 95 %]} and CSF p181-tau {SMD = -0.87 [95 % CI (-1.32; -0.43), I² = 89 %]} by large effect sizes. They also increased risk for ARIA {RR = 4.30 [95 % CI (2.39; 7.77), I² = 86 %]} by a large effect size. Antibody effects on reducing amyloid PET SUVR were correlated with their effects on improving ADAS-Cog (r = +0.68, p = 0.02). In subgroup analyses by individual drug, Aducanumab improved ADAS-Cog, CDR-SOB, ADCS-ADL by small effect sizes and decreased amyloid PET SUVR and CSF p181-tau by large effect sizes. Solanezumab improved ADAS-Cog and MMSE by small effect sizes, and increased (improved) CSF Aβ_1-40 levels by a moderate effect size. Bapineuzumab, Gantenerumab and Crenezumab did not improve any clinical outcomes. Bapineuzumab and Gantenerumab decreased CSF p181-tau by a small and large effect size, respectively. All drugs except Solanezumab increased ARIA risk.

Conclusions: In this meta-analysis of phase III trials in AD, we found that monoclonal antibodies against Aβ induced clinical improvements of small effect sizes, biomarker improvements of large effect sizes, and increases in risk for the hallmark adverse event, ARIA, by a large effect size, when all drugs were pooled together. Among individual drugs, Aducanumab produced the most favorable effects followed by Solanezumab. These findings provide moderate support for the continuous development of anti-Aβ monoclonal antibodies as a treatment for AD.

Keywords: Alzheimer’s disease; Amyloid-beta; Meta-analysis; Monoclonal antibodies.

Figure 1.

Flow diagram of study selection process.

Figure 2.. Forest plots and funnel plots of meta-analyses of primary outcomes.

ADAS-Cog: Alzheimer disease assessment scale - Cognitive subscale; MMSE: Mini Mental State Examination; CDR-SOB: Clinical dementia rating scale – Sum of boxes; SMD: Standardized Mean Difference; Hedges’ g = SMD. Negative values for ADAS-Cog and CDR-SOB and positive values for MMSE indicate improvement.

Figure 3.. Forest and funnel/L’ Abbe plots of meta-analyses of secondary outcomes.

Amyloid PET SUVR: Amyloid PET Standardized uptake value ratio; CSF p-tau: Tyr₁₈₁-phosphorylated tau protein concentration in CSF; ARIA: amyloid related imaging abnormalities. SMD: Standardized Mean Difference; Hedges’ g = SMD

Figure 4.. Forest and funnel plots of meta-analyses of tertiary outcomes.

SMD: Standardized Mean Difference; Hedges’ g = SMD

Figure 5.. Correlations between amyloid PET SUVR and ADAS-Cog, CDR-SOB effect sizes.

Limitation: data for amyloid PET SUVR were reported only for sub-populations of the original studies. Each correlation relies on the assumption that effect sizes for PET in these sub-populations are representative of those for the entire populations.