Safety and Efficacy of Disease-modifying Therapies in Spinal Muscular Atrophy: A Systematic Review and Network Meta-analysis
Mohamed Mamdouh1, Ahmed Fathallah2, Ibrahim Kamal3, Abdulrahman Hagrass4, Eid Ali Ismael4, Mohammed Elkholy5, Abdallah Kamal6, Anas Zakarya Nourelden3
1Faculty of Medicine, Beni-Suef University, Beni-Suef, Egypt, 2Faculty of Medicine, Minia University, Minia, Egypt, 3Faculty of Medicine, Al-Azhar University, Cairo, Egypt, 4Department of Neurology, Faculty of Medicine, Al-Azhar University, Cairo, Egypt, 5The Laboratory for Minimally Invasive Tumor Therapies, Department of Radiology, Deaconess Medical Center/Harvard Medical School, Boston, Massachusetts, United States of America., 6University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
Objective:
This study aims to examine the safety and efficacy of disease-modifying agents for spinal muscular atrophy (SMA) through a systematic review and a network meta-analysis.
Background:
SMA is a neurodegenerative disorder that leads to muscle weakness and atrophy due to the loss of motor neurons. The severity varies across five subtypes. Recent treatments include gene-targeted therapies like nusinersen, onasemnogene abeparvovec (OAX), and risdiplam, all designed to increase or replace the SMN protein, which is essential for motor neuron survival.
Design/Methods:
We retrieved relevant articles up to April 2024 from PubMed, Scopus, Web of Science, and the Cochrane Library. Two independent reviewers extracted data from eligible studies, including baseline characteristics. A network meta-analysis, conducted using the Netmeta R package, compared motor milestone response, overall survival, and adverse events. In addition, motor function changes after nusinersen therapy were evaluated through a double-arm analysis using RevMan v5.4.1.
Results:
We included 11 articles with a total of 966 SMA patients. The network analysis showed that both nusinersen and OAX significantly improved motor milestone response, with OAX being 30.36 times more likely [RR: 30.36, 95%CI: 1.4; 659.82] and nusinersen 3.79 times more likely [RR: 3.79, 95%CI: 1.16; 12.39] to help patients achieve milestones compared to controls. OAX also significantly increased survival [RR: 1.44, 95%CI: 1.2; 1.72], as did nusinersen [RR: 1.3, 95%CI: 1.07; 1.58]. Nusinersen improved motor function significantly in HFMSE [MD: 3.07], RULM [MD: 2.76], and HINE-2 [MD: 5.21] scales. Serious adverse events were lower for all drugs, but results were not statistically significant.
Conclusions:
Nusinersen and OAX significantly improve motor milestones and survival in SMA, while OAX achieves a higher response in motor milestones. Risdiplam elevates SMN protein levels but does affect survival.
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