Comparative Efficacy and Safety of Monoclonal Antibodies for Cognitive Decline in Patients with Alzheimer's Disease: A Systematic Review and Network Meta-Analysis.

BACKGROUND: Recent clinical trials of anti-Aß 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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).

Safety and Efficacy of Nusinersen and Risdiplam for Spinal Muscular Atrophy: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

OBJECTIVE: We performed a systematic review and meta-analysis of the efficacy and safety of nusinersen and risdiplam in the treatment of spinal muscular disease (SMA). METHODS: We screened the literature published in Pubmed, Web of Science, Embase, and Cochrane before July 2023 to conduct randomized controlled trials to test the treatment of SMA patients with nusinersen and risdiplam. The data were analyzed using Review Manager 5.4 software and Stata version 15.0 software. RESULTS: A total of six randomized controlled trials were included, involving 728 SMA patients, to synthesize evidence. It is reported that nusinersen treatment was beneficial for increasing the score of the Hammersmith Functional Motor Scale-Expanded (HFMSE) (WMD: 4.90; 95% CI: 3.17, 6.63; p < 0.00001), Revised Upper Limb Module (RULM) (WMD: 3.70; 95% CI: 3.30, 4.10; p < 0.00001), and Hammersmith Infant Neurological Evaluation Section 2 (HINE-2) (WMD: 5.21; 95% CI: 4.83, 5.60; p < 0.00001). In addition, the risdiplam treatment group also showed statistically significant improvements in the HFMSE score (WMD:0.87; 95% CI: 0.05, 1.68; p = 0.04), the 32-item Motor Function Measure (MFM32) (WMD:1.48; 95% CI: 0.58, 2.38; p = 0.001), and (WMD: 1.29; 95% CI: 0.57, 2.01; p = 0.0005). Nusinersen and risdiplam did not cause a statistically significant increase in the RULM score for adverse events (OR: 0.93; 95% CI: 0.51, 1.7; p = 0.82) and for severe adverse events (OR: 0.77; 95% CI: 0.47, 1.27; p = 0.31). CONCLUSION: Our analysis found that nusinersen and risdiplam treatment showed clinically meaningful improvement in motor function and a similar incidence rate of adverse events compared with the placebo. Further research should be carried out to provide a direct comparison between the two drugs in terms of safety and efficacy.

Safety and efficacy of lecanemab for Alzheimer's disease: a systematic review and meta-analysis of randomized clinical trials.

Objective: We performed a systematic review and meta-analysis of the cognitive effectiveness and safety of lecanemab on subjects with Alzheimer's disease (AD). Methods: We screened the literature published before February 2023 in PubMed, Embase, Web of Science, and Cochrane that were searched for randomized controlled trials testing lecanemab for the treatment of cognitive decline in patients with MCI or AD. Outcomes measured were CDR Sum of Boxes (CDR-SB), Alzheimer's Disease Composite Score (ADCOMS), AD Assessment Scale-Cognitive Subscale (ADAS-Cog), Clinical Dementia Rating (CDR), amyloid PET Standardized Uptake Volume Ratio (SUVr), amyloid burden on PET, and risks for adverse events. Results: A total of four randomized controlled trials were included, involving 3,108 AD patients (1,695 lecanemab groups and 1,413 placebo groups) to synthesize evidence. Baseline characteristics of the two groups were similar in all outcomes except that ApoE 4 status and higher MMSE score were observed in the lecanemab group. It is reported that lecanemab was beneficial to stabilize or slow down the decrease in CDR-SB (WMD: -0.45; 95% CI: -0.64, -0.25; p < 0.00001), ADCOMS (WMD: -0.05; 95% CI: -0.07, -0.03; p < 0.00001), ADAS-cog (WMD: -1.11; 95% CI: -1.64, -0.57; p < 0.0001), amyloid PET SUVr (WMD: -0.15; 95% CI: -0.48, 0.19; p = 0.38), amyloid burden on PET (WMD:-35.44; 95% CI: -65.22,-5.67; p = 0.02), adverse events (subjects with any TEAE) (OR: 0.73; 95% CI: 0.25, 2.15; p = 0.57), ARIA-E (OR:8.95; 95% CI: 5.36, 14.95; p < 0.00001), and ARIA-H (OR:2.00; 95% CI: 1.53, 2.62; p < 0.00001) in early AD patients. Conclusion: Our analysis found that lecanemab showed significant positive statistical efficacy with respect to cognition, function, and behavior in patients with early AD though the actual clinical significance is yet to be established. Systematic review registration: https://www.crd.york.ac.uk/PROSPERO/#recordDetails, identifier: CRD42023393393.