Department of Child Neurology, National Center Hospital, National Center of Neurology and Psychiatry, 4-1-1 Ogawahigashi-cho, Kodaira, Tokyo, 187-8551, Japan.
Department of Neurology, National Hospital Organization Higashisaitama Hospital, 4147 Kurohama, Hasuda, Saitama, 349-0196, Japan.
Orphanet J Rare Dis. 2018 Jun 15;13(1):93. doi: 10.1186/s13023-018-0834-2.
Exon 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.
A 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 Trials were identified by searching published and unpublished studies from electronically available databases and clinical trial registries through October 2017.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).
Five 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.
Current 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.
外显子跳跃已被认为是治疗杜氏肌营养不良症（DMD）的一种很有前途的治疗方法。依替膦酸酯于 2016 年在美国获得有条件批准。迄今为止，尚无关于外显子跳跃药物的随机对照试验（RCT）的系统评价或荟萃分析发表，以确定外显子跳跃治疗 DMD 的汇总估计值。
对比较依替膦酸酯和安慰剂治疗 DMD 的双盲 RCT 进行了系统评价和荟萃分析。通过检索已发表和未发表的研究，从电子可用数据库和临床试验注册处检索试验，检索时间截至 2017 年 10 月。主要结局是 6 分钟步行试验（6MWT）距离、北美之星动态评估（NSAA）评分和不良事件的变化。进行了随机效应荟萃分析和偏倚风险评估。本系统评价在 PROSPERO（CRD42016037504）上进行了注册。
纳入了 5 项研究，共 322 名参与者，其中 1 项研究涉及依替膦酸酯，4 项研究涉及 drisapersen。与安慰剂相比，外显子跳跃组在 24 周治疗后，6MWT 距离（平均差异 [MD] -9.16，95%置信区间 [CI] -21.94 至 3.62）或 NSAA 评分（MD 1.20，95%CI -2.35 至 4.75）无变化。drisapersen 每周 6mg/kg 注射的亚组分析显示 6MWT 有显著变化，24 周后 drisapersen 组更优（MD -20.24；95%CI -39.59 至 -0.89）。然而，drisapersen 导致注射部位反应显著增加（风险比 [RR] 3.67，95%CI 1.96 至 6.89，p<0.0001）和肾毒性（RR 1.81，95%CI 1.11 至 2.94，p=0.02）。五项研究中有两项研究（包括依替膦酸酯和一项 drisapersen 研究）的偏倚风险较高。
目前尚无证据表明外显子跳跃药物对 DMD 有效。尽管在特定剂量下可能有效，但 drisapersen 报告了严重的副作用。少数 RCT 且参与者数量相对较少，这表明难以进行充分有效的 DMD 研究。前瞻性计划的荟萃分析和实际数据的利用可能提供更准确的外显子跳跃治疗该病的效果估计值。
