Laboratory of Clinical Investigation, Intramural Research Program, National Institute on Aging, NIH, Baltimore, MD 21224, USA.
Longitudinal Study Section, Intramural Research Program, National Institute on Aging, NIH, Baltimore, MD 21224, USA.
Ageing Res Rev. 2021 Jul;68:101339. doi: 10.1016/j.arr.2021.101339. Epub 2021 Apr 5.
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).
Pubmed, Web of Science, ClinicalTrials.gov and gray literature were searched for phase III RCTs and random-effects meta-analyses were performed.
Seventeen studies (12,585 patients) were included. Antibodies statistically improved the cognitive outcomes ADAS-Cog {SMD = -0.06 [95 % CI (-0.10; -0.02), I = 0%]} and MMSE {SMD = 0.05 [95 % CI (0.01; 0.09), I = 0%]} by small effect sizes, but did not improve the cognitive/functional measure CDR-SOB {SMD = -0.03 [95 % CI (-0.07; 0.01), I = 18 %]}. Moreover, antibodies decreased amyloid PET SUVR {SMD = -1.02 [95 % CI (-1.70; -0.34), I = 95 %]} and CSF p181-tau {SMD = -0.87 [95 % CI (-1.32; -0.43), I = 89 %]} by large effect sizes. They also increased risk for ARIA {RR = 4.30 [95 % CI (2.39; 7.77), I = 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 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.
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.
研究针对 Aβ 的单克隆抗体对阿尔茨海默病（AD）患者认知、功能、淀粉样 PET 及其他生物标志物的影响，以及对淀粉样相关成像异常（ARIA）和其他不良事件的影响。
检索 Pubmed、Web of Science、ClinicalTrials.gov 和灰色文献，以纳入 III 期 RCT 并进行随机效应荟萃分析。
纳入 17 项研究（12585 例患者）。抗体在统计学上改善了认知结局 ADAS-Cog（SMD = -0.06 [95%CI (-0.10; -0.02)，I = 0%]）和 MMSE（SMD = 0.05 [95%CI (0.01; 0.09)，I = 0%]），但未改善认知/功能测量 CDR-SOB（SMD = -0.03 [95%CI (-0.07; 0.01)，I = 18%]）。此外，抗体降低了淀粉样 PET SUVR（SMD = -1.02 [95%CI (-1.70; -0.34)，I = 95%]）和 CSF p181-tau（SMD = -0.87 [95%CI (-1.32; -0.43)，I = 89%]），这两个指标均为大效应量。抗体还增加了 ARIA 的风险（RR = 4.30 [95%CI (2.39; 7.77)，I = 86%]），这同样是一个大效应量。抗体降低淀粉样 PET SUVR 的效果与改善 ADAS-Cog 的效果相关（r = +0.68，p = 0.02）。在按单个药物的亚组分析中，Aducanumab 以小效应量改善 ADAS-Cog、CDR-SOB 和 ADCS-ADL，以大效应量降低淀粉样 PET SUVR 和 CSF p181-tau。Solanezumab 以小效应量改善 ADAS-Cog 和 MMSE，并以中等效应量增加（改善）CSF Aβ 水平。Bapineuzumab、Gantenerumab 和 Crenezumab 均未改善任何临床结局。Bapineuzumab 和 Gantenerumab 以小和大效应量分别降低了 CSF p181-tau。除 Solanezumab 外，所有药物均增加了 ARIA 的风险。
在这项 AD 三期临床试验的荟萃分析中，我们发现当所有药物汇总时，针对 Aβ 的单克隆抗体可诱导较小效应量的临床改善、较大效应量的生物标志物改善和 ARIA 这一标志性不良事件风险增加，后者为大效应量。在单个药物中，Aducanumab 的效果最好，其次是 Solanezumab。这些发现为继续开发抗 Aβ 单克隆抗体作为 AD 的治疗方法提供了中等程度的支持。
