Department of Neurology, Shengjing Hospital of China Medical University, Shenyang, 110000, Liaoning, China.
CNS Drugs. 2024 Mar;38(3):169-192. doi: 10.1007/s40263-024-01067-2. Epub 2024 Mar 1.
Recent clinical trials of anti-Aβ monoclonal antibodies (mAbs) in the treatment of early Alzheimer's disease (AD) have produced encouraging cognitive and clinical results. The purpose of this network meta-analysis (NMA) was to compare and rank mAb drugs according to their efficacy and safety.
PubMed, Embase, Web of Science, and the Cochrane Library were searched for randomized controlled trials testing various mAbs for the treatment of cognitive decline in patients with AD, up to March 31, 2023. R software (version 4.2.3) along with JAGS and STATA software (version 15.0) were used for statistical analysis. Odds ratio (OR) for binary variables, mean difference (MD) for continuous variables, and their 95% confidence intervals (CI) were utilized to estimate treatment effects and rank probabilities for each mAb in terms of safety and efficacy outcomes. We calculated the surface under the cumulative ranking area (SUCRA) to evaluate each mAb, with higher SUCRA values indicating better efficacy or lower likelihood of adverse events.
Thirty-three randomized controlled trials with a total of 21,087 patients were included in the current NMA, involving eight different mAbs. SUCRA values showed that aducanumab (87.01% and 99.37%, respectively) was the most likely to achieve the best therapeutic effect based on the changes of Mini-Mental State Examination (MMSE) and Clinical Dementia Rating scale Sum of Boxes (CDR-SB) scores. Donanemab (88.50% and 99.00%, respectively) performed better than other therapies for Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog) and Positron Emission Tomography-Standardized Uptake Value ratio (PET-SUVr). Lecanemab (87.24%) may be the most promising way to slow down the decrease of Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) score. In the analysis of the incidence of adverse events (subjects with any treatment-emergent adverse event), gantenerumab (89.12%) had the least potential for adverse events, while lecanemab (0.79%) may cause more adverse events. Solanezumab (95.75% and 80.38%, respectively) had the lowest incidence of amyloid-related imaging abnormalities characterized by edema and effusion (ARIA-E) and by cerebral microhemorrhages (ARIA-H) of the included immunotherapies. While SUCRA values provided a comprehensive measure of treatment efficacy, the inherent statistical uncertainty required careful analysis in clinical application.
Despite immunotherapies significantly increasing the risks of adverse events and ARIA, the data suggest that mAbs can effectively improve the cognitive function of patients with mild and moderate AD. According to the NMA, aducanumab was the most likely to achieve significant improvements in different cognitive and clinical assessments (statistically improved MMSE and CDR-SB), followed by donanemab (statistically improved ADAS-Cog, and PET-SUVr) and lecanemab (statistically improved ADCS-ADL).
最近针对早期阿尔茨海默病（AD）的抗 Aβ 单克隆抗体（mAb）的临床试验取得了令人鼓舞的认知和临床效果。本网络荟萃分析（NMA）的目的是比较和根据疗效和安全性对 mAb 药物进行排名。
检索 PubMed、Embase、Web of Science 和 Cochrane 图书馆中截至 2023 年 3 月 31 日的各种 mAb 治疗 AD 患者认知下降的随机对照试验。使用 R 软件（版本 4.2.3）和 JAGS 和 STATA 软件（版本 15.0）进行统计分析。二分类变量的比值比（OR）、连续变量的均数差（MD）及其 95%置信区间（CI）用于估计每种 mAb 的治疗效果，并根据安全性和疗效结局对每种 mAb 的排名概率进行排名。我们计算了累积排序区域下面积（SUCRA）以评估每种 mAb，较高的 SUCRA 值表示更好的疗效或不良反应的可能性较低。
目前的 NMA 纳入了 33 项随机对照试验，共 21087 名患者，涉及 8 种不同的 mAb。SUCRA 值显示，基于 Mini-Mental State Examination（MMSE）和 Clinical Dementia Rating scale Sum of Boxes（CDR-SB）评分变化，aducanumab（分别为 87.01%和 99.37%）最有可能达到最佳治疗效果。Donanemab（分别为 88.50%和 99.00%）在阿尔茨海默病评估量表认知子量表（ADAS-cog）和正电子发射断层扫描-标准化摄取比值（PET-SUVr）方面的表现优于其他疗法。Lecanemab（87.24%）可能是减缓阿尔茨海默病合作研究-日常生活活动（ADCS-ADL）评分下降的最有前途的方法。在不良事件发生率（出现任何治疗相关不良事件的受试者）分析中，gantenerumab（89.12%）发生不良事件的潜力最小，而 lecanemab（0.79%）可能导致更多的不良事件。Solanezumab（分别为 95.75%和 80.38%）在包括免疫疗法在内的淀粉样蛋白相关成像异常特征为水肿和渗出（ARIA-E）和脑微出血（ARIA-H）方面的发生率最低。虽然 SUCRA 值提供了治疗效果的综合衡量标准，但在临床应用中需要仔细分析其内在的统计不确定性。
尽管免疫疗法显著增加了不良事件和 ARIA 的风险，但数据表明 mAb 可有效改善轻度和中度 AD 患者的认知功能。根据 NMA，aducanumab 最有可能在不同的认知和临床评估中（统计学上改善 MMSE 和 CDR-SB）取得显著改善，其次是 donanemab（统计学上改善 ADAS-Cog 和 PET-SUVr）和 lecanemab（统计学上改善 ADCS-ADL）。
