Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Meta-Analysis
. 2018 Jun 15;13(1):93.
doi: 10.1186/s13023-018-0834-2.

Exon skipping for Duchenne muscular dystrophy: a systematic review and meta-analysis

Yuko Shimizu-Motohashi  1 , Terumi Murakami  2 , En Kimura  3 , Hirofumi Komaki  1 , Norio Watanabe  4
Affiliations
Meta-Analysis

Exon skipping for Duchenne muscular dystrophy: a systematic review and meta-analysis

Yuko Shimizu-Motohashi et al. Orphanet J Rare Dis. .

Abstract

Background: 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.

Methods: 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 Trials were identified by searching published and unpublished studies from electronically available databases and clinical trial registries through October 2017.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).

Results: 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.

Conclusions: 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.

Keywords: 6-min walk test; Drisapersen; Eteplirsen; Pooled estimates; Prospectively planned meta-analysis; Randomized controlled trial; Rare disease; Real-world data.

PubMed Disclaimer

Conflict of interest statement

Ethics approval and consent to participate

Not applicable.

Competing interests

YSM was sub-investigator of clinical trial for DMD sponsored by Taiho Pharma (Prostaglandin), and Dai-ichi Sankyo (exon skipping); clinical trial for Leigh encephalopathy sponsored by Sumitomo Dainippon Pharma (EPI-743). YSM is sub investigator of clinical trials for DMD sponsored by Pfizer (anti-myostatin antibody), Bristol-Myers Squibb (myostatin inhibitor); clinical trial for Pompe disease sponsored by Sanofi Genzyme (acid alpha-glucosidase). YSM has research funds from National Center of Neurology and Psychiatry, Intramural Research Grant for Neurological and Psychiatric Disorders (27–5, 29-waka4).

YSM has written manuscripts paid by Nippon Rinsho, Chugaiigakushya, and Nissoken.

TM has research funds from National Center of Neurology and Psychiatry Intramural Research Grant for Neurological and Psychiatric Disorders, and Japanese Ministry of Health Labour and Welfare, Health Labour Sciences Research Grant. She has also received Manuscript fee from Nihon Rinshosha, Igakushoin, NihonBunkaKgakusha, Elselvier Japan, during last 5 years.

EK has research funds from National Center of Neurology and Psychiatry, Intramural Research Grant for Neurological and Psychiatric Disorders (24–3, 26–7), Japan Society for the Promotion of Science, Grant-in-Aid for Scientific Research, Japanese Ministry of Health Labour and Welfare, Health Labour Sciences Research Grant, and Japan Agency for Medical Research and Development, and also received royalties from Chugai igakusha, Igakushoin, Medicaldo, Springer, and speaking fees and research funds from Hitachi, NHO Tokushima Hospital, NHO Suzuka Hospital, The Japan Muscular Dystrophy Association, The Japanese Society Gene Diagnosis and Therapy, The Japanese Society of Medical Networking for Intractable Diseases, Technical Information institute, Osaka Univ, Kyoto Univ, during last 5 years.

HK was and is the principal investigator of clinical trials for DMD sponsored by Bristol-Myers Squibb (myostatin inhibitor), Pfizer (anti-myostatin antibody), Taiho Pharma (Prostaglandin), Dai-ichi Sankyo (exon skipping), Nihon Shinyaku (exon skipping), Eli Lilly and Company (Tadalafil). HK is the principal investigator of clinical trial for Leigh encephalopathy sponsored by Dai-Nippon Sumitomo (EPI-743) and for Pompe disease sponsored by Sanofi Genzyme (acid alpha-glucosidase).

HK has research funds from National Center of Neurology and Psychiatry, Intramural Research Grant for Neurological and Psychiatric Disorders, Japanese Ministry of Health Labour and Welfare, Health Labour Sciences Research Grant, Japan Agency for Medical Research and Development, Taiho Pharma, Pfizer, Nihon Shinyaku, Bristol-Myers Squibb, Dai-ichi Sankyo, Eli Lilly and Company, GlaxoSmithKline, Dai-Nippon Sumitomo, Sanofi Genzyme.

HK has also received royalties for writing manuscripts from Medical Tribune, Shindan to Chiryoushya, Nihon Rinshyoshya, Tokyo Igakushya. HK has received speaking fees from Abbot, Genzyme Japan, Hiroshima Nanbyou Taisaku Center, Otsuka Pharmaceutical, Eisai, Japan Intractable Illness Nursing Society, Eli Lilly and Company, Mitsubishi Tanabe Pharma, Japan Blood Products Organization, Sumitomo Dainippon Pharma, Tohoku University Hospital, The Japan Muscular Dystrophy Association.

NW has research funds from the Japan Agency for Medical Research and Development, Japanese Ministry of Health Labor and Welfare, and the Japanese Ministry of Education, Science, and Technology. He has also received royalties from Sogensha, Paquet and Akatsuki during last 5 years.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

Fig. 1
Fig. 1
Flow diagram depicting the process of study selection
Fig. 2
Fig. 2
Risk of bias summary. A review of the authors’ judgment on each category of risk of bias for each of the five studies included is shown
Fig. 3
Fig. 3
Change in the 6MWT at week 24. Change from baseline (meters) in distance covered by the 6MWT measured after 24 weeks of treatment. In the figure, the mean difference of gain in distance is shown in negative numbers and loss in distance is shown in positive numbers, i.e., 64.25 indicates − 64.25 for actual measurement
Fig. 4
Fig. 4
Change in NSAA score at week 24. Change in NSAA score from baseline to after 24 weeks of treatment. In general, a higher score indicates better motor function. For the mean difference, gain of score is shown in negative numbers and loss of score in positive numbers in the figure, i.e., 4.15 indicates a negative score of − 4.15 in the actual measurement. As the trial by Voit2014 had only provided the adjusted mean difference versus placebo, SDs for each intervention group could not be calculated and were substituted with SDs reported in the NCT01462292 trial. There was no significant change in the NSAA scores between the treated and placebo groups. Subgroup analysis revealed a significant increase in the scores in the placebo groups compared with those in the eteplirsen group
Fig. 5
Fig. 5
Title: Adverse events, injection site reactions. There was no significant difference in the injection site reaction between the treated and placebo groups. Subgroup analysis revealed a significant increase in the drisapersen group, but not in the eteplirsen group, compared with that in the placebo groups
Fig. 6
Fig. 6
Adverse events, renal toxicity. Subgroup analysis showed a significant increase in the renal toxicity in the drisapersen group, but not in the eteplirsen group, compared with that in the placebo groups
See this image and copyright information in PMC

References

    1. Monaco AP, Neve RL, Colletti-Feener C, Bertelson CJ, Kurnit DM, Kunkel LM. Isolation of candidate cDNAs for portions of the Duchenne muscular dystrophy gene. Nature. 1986;323:646–650. doi: 10.1038/323646a0. - DOI - PubMed
    1. Mendell JR, Shilling C, Leslie ND, Flanigan KM, al-Dahhak R, Gastier-Foster J, et al. Evidence-based path to newborn screening for Duchenne muscular dystrophy. Ann Neurol. 2012;71:304–313. doi: 10.1002/ana.23528. - DOI - PubMed
    1. Moat SJ, Bradley DM, Salmon R, Clarke A, Hartley L. Newborn bloodspot screening for Duchenne muscular dystrophy: 21 years experience in Wales (UK) Eur J Hum Genet. 2013;21:1049–1053. doi: 10.1038/ejhg.2012.301. - DOI - PMC - PubMed
    1. Emery AE. Population frequencies of inherited neuromuscular diseases--a world survey. Neuromuscul Disord. 1991;1:19–29. doi: 10.1016/0960-8966(91)90039-U. - DOI - PubMed
    1. Bushby K, Finkel R, Birnkrant DJ, Case LE, Clemens PR, Cripe L, et al. Diagnosis and management of Duchenne muscular dystrophy, part 1: diagnosis, and pharmacological and psychosocial management. Lancet Neurol. 2010;9:77–93. doi: 10.1016/S1474-4422(09)70271-6. - DOI - PubMed

Publication types

MeSH terms