Efficacy and safety of exon skipping therapies for Duchenne Muscular Dystrophy: A Systematic Review

Background Duchenne muscular dystrophy (DMD) is an X-linked recessive disorder characterized by progressive muscle weakness and muscle wasting. Exon skipping therapies have been approved as part of the therapeutic arsenal for DMD, however, there is contrasting evidence regarding their clinical benefits. The aim of this study was to determine the efficacy and safety of exon skipping therapies for DMD. Method ology: A systematic review was conducted in three databases including PubMed, ClinicalTrials.gov , and Cochrane-Ovid, based on the following question using PICO strategy: What is the efficacy of exon skipping therapies for DMD? Search was limited to randomized controlled trials (RCTs) and Open Label RCTs with reported results, published between January 2016 and December 2024, involving patients with DMD treated with any of the existing exon-skipping therapies, reporting efficacy measured by primary clinical and secondary molecular outcomes. Secondary safety outcomes were also registered. Eligible studies were assessed for risk of bias. A descriptive analysis was performed in subgroups according to variants amenable to exon 45, 51, or 53 skipping. Results A total of nine studies were left after the final filters were applied. Studies were conducted across centers in seven different countries. Four studies used viltolarsen (exon 53), three eteplirsen (exon 51), and two golodirsen (exon 53). Trial length was heterogeneous with an average length of 119.6 weeks (±78.5). Overall, studies with exon skipping medications reported improvement in the clinical outcomes including the 6-minute walking test, time to stand and the North Star Ambulatory Assessment. Biological measurements showed an increase in dystrophin expression and exon skipping percentage. Long term follow up evidenced stabilization of both clinical and molecular outcomes in DMD patients, compared to age and treatment-matched controls. Conclusion Exon skipping therapies have evidenced improved clinical and molecular outcomes. Longer follow-up extension studies are needed to further elucidate their effect in comparison to age-matched controls.