Abstract
BackgroundExon skipping has been considered a promising therapeutic approach for Duchenne muscular dystrophy (DMD). Eteplirsen received conditional approval in the United States in 2016. To date, no systematic reviews or meta-analyses of randomized controlled trials (RCTs) of exon skipping drugs have been published to determine the pooled estimates for the effect of exon skipping in treating DMD.MethodsA systematic review and meta-analysis of double-blind RCTs comparing exon-skipping drugs with placebo in DMD was performed. Trials were identified by searching published and unpublished studies from electronically available databases and clinical trial registries through October 2017. The primary outcomes were changes in the 6-min walk test (6MWT) distance, North Star Ambulatory Assessment (NSAA) scores, and adverse events. Random-effects meta-analysis and assessment of risk of bias were performed. This systematic review was registered at PROSPERO (CRD42016037504).ResultsFive studies involving 322 participants were included, investigating eteplirsen in one and drisapersen in four studies. There were no changes in 6MWT distance (mean difference [MD] − 9.16, 95% confidence interval [CI] − 21.94 to 3.62) or NSAA scores (MD 1.20, 95% CI − 2.35 to 4.75) after 24 weeks of treatment in the exon-skipping group compared with placebo. Subgroup analysis for a 6 mg/kg weekly injection of drisapersen showed significant changes in the 6MWT, favoring drisapersen after 24 weeks (MD − 20.24; 95% CI − 39.59 to − 0.89). However, drisapersen resulted in a significant increase in injection site reactions (risk ratio [RR] 3.67, 95% CI 1.96 to 6.89, p < 0.0001) and renal toxicity (RR 1.81, 95% CI 1.11 to 2.94, p = 0.02). Risk of bias was high in two of the five studies, including the eteplirsen and one drisapersen study.ConclusionsCurrent available data do not show evidence that exon-skipping drugs are effective in DMD. Despite potential effectiveness when used at a specific dose, significant side effects were reported with drisapersen. The small number of RCTs with relatively small numbers of participants indicate the difficulty in conducting sufficiently powered studies of DMD. Prospectively planned meta-analysis and utilization of the real-world data may provide a more precise estimate of the effect of exon skipping in this disease.
Highlights
Exon skipping has been considered a promising therapeutic approach for Duchenne muscular dystrophy (DMD)
Participants were included in the reviewed studies if they were confirmed to have out-of-frame DMD mutations deemed by the authors as correctable by exon skipping
While our analysis showed no significant heterogeneity in the 6-min walk test (6MWT) results among the drisapersen-treated groups, results of both North Star Ambulatory Assessment (NSAA) and the time taken to walk 10 m had substantial or considerable heterogeneity, respectively
Summary
Exon skipping has been considered a promising therapeutic approach for Duchenne muscular dystrophy (DMD). It is estimated to affect one in 3500 to 6000 live male births [2,3,4]. Among several therapeutic approaches being investigated for this disorder is the exon skipping drug eteplirsen, for which the U.S Food and Drug Administration (FDA) announced accelerated approval in September 2016 [7]. Exon skipping is induced by antisense oligonucleotides (AOs). This approach is based on the rationale that converting the translational reading frame for the mutated dystrophin protein from out-of-frame to in-frame produces a shorter but functional dystrophin in place of the nonfunctioning dystrophin seen in DMD [8]
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