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Case study: The UK’s expertise in Advanced Therapies showcased in successful GOSH DMD trial

A drug that ‘skips over’ a genetic fault responsible for the fatal muscle-wasting condition Duchenne muscular dystrophy has shown promising results in an international trial led by Great Ormond Street Hospital and supported by its associated NIHR Biomedical Research Centre. 

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The trial

Duchenne muscular dystrophy (DMD) is the most common and lethal form of muscle-wasting disease affecting boys in the UK. Around 100 boys are born with the condition each year.

“Children with DMD experience muscle loss over time,” says Professor Francesco Muntoni, Director of the Dubowitz Neuromuscular Centre at Great Ormond Street Hospital. “Most will need to use a wheelchair by their teenage years and sadly, with no cure, most do not live past their early thirties. When I joined GOSH in 2008, there were no clinical trials or therapies for DMD. But a decade later things are very different. We’re involved in dozens of trials, and life expectancy for these patients is increasing.”

DMD is caused by a gene fault which results in an inability to produce dystrophin, which is a protein that protects muscles from damage. An RNA-targeted exon skipping approach designed to lead to the production of dystrophin, a vital muscle-protecting protein, may slow progression of the disease.

Golodirsen was given to children and young people with DMD aged 6-15 years at centres in London, Newcastle, Paris and Rome, including eight children treated in the GOSH NIHR Clinical Research Facility (CRF).

25 patients treated with golodirsen all had an increase in exon 53 skipping and the group showed an average increase in dystrophin of approximately 16-fold over baseline as measured by western blot at Week 48. DMD patients cannot normally produce dystrophin.

The golodirsen study was funded by the European Union (SKIP-NMD Grant Proposal 305370-2, FP7-Health-2012-Innovation-1) and by Sarepta Therapeutics, Inc. This research also received support from the National Institute of Health Research Great Ormond Street Hospital Biomedical Research Centre (BRC), GOSH Charity, patient advocacy groups, the MRC Centre for Neuromuscular Diseases, the DMD-HUB and Muscular Dystrophy UK.

UK strengths

Advanced therapies, of which exon skipping is one example, are of strategic importance to the UK and have been incorporated into the country’s Life Sciences Industrial Strategy 2017 and the Life Sciences Sector Deal 2 2018.

The UK’s government and the Life Science sector have invested significantly in the development of world-leading infrastructure and expertise to support industry in the development and manufacture of Advanced Therapies. This is evidenced by the increasing number of Advanced Therapy clinical trials occurring in the UK year-on-year.

The NIHR invests significantly in people, centres of excellence, collaborations, services and facilities to support health and care research in England. Collectively these form the NIHR infrastructure. The NIHR’s research infrastructure includes collaborations between world-leading universities and NHS organisations in the form of BRCs, as well as purpose-built CRFs.

The GOSH BRC is a leading centre for gene therapy and has first-class experts in advanced therapies.

How the NIHR supported this trial

Golodirsen was developed and trialled by an EU-funded consortium known as SKIP-NMD, led by Professor Muntoni (lead researcher and GOSH Paediatric Neurologist).

  • The GOSH BRC supports the Research Biobank for Rare and Neuromuscular Diseases at the UCL Great Ormond Street Institute for Child Health which contains muscle cells of children affected by DMD. This was instrumental for the selection of the candidate personalised medicine used in the study of the response to different exon skipping drugs in cells from boys with DMD. This was the first step for the selection of golodirsen as the lead candidate.
  • With the help of the BRC biobank, in which tissue from DMD boys is stored with the appropriate consent, a novel technique for the assessment of dystrophin in muscle biopsies was developed1.
  • In collaboration with Newcastle BRC and CRF, a YouTube video was made to explain the study for the first time in a child-friendly way to ease the assent process. The concept of using visual material for recruiting children into clinical trials is now used in a number of studies, with positive user feedback.
  • Through supporting the GOSH MRI department, the GOSH BRC was able to use non-invasive muscle MRI to study patient response to the golodirsen therapy.
  • Recruitment of DMD boys in London and Newcastle was made possible via the UK North Star network, supported by the Muscular Dystrophy UK, and partially by NIHR.


GOSH’s long-lasting investment in research for Duchenne muscular dystrophy and commitment to the Duchenne community is unparalleled. The design and execution of this landmark, multi-site European clinical trial that led to the advancement of a treatment for Duchenne patients amenable to exon 53 skipping was made possible through excellent collaboration with GOSH’s BRC and CRF, Prof. Francesco Muntoni and the esteemed SKIP-NMD consortium members – investigators, researchers and advocates alike. Sarepta will continue to partner with GOSH, the Duchenne community, and our global scientific partners to tackle Duchenne using multiple approaches as we work towards our goal of finding treatments that will serve the entire patient community.

Ashish Dugar, VP of Medical Affairs, Sarepta Therapeutics, Inc.

The results

25 patients treated with golodirsen all had an increase in exon 53 skipping and the group showed an average increase in dystrophin of approximately 16-fold over baseline as measured by western blot at Week 48. “The success of this study is a significant step towards an effective treatment for children with DMD,” says Professor Muntoni. “Golodirsen appears to restore dystrophin production in patients with a particular type of genetic mistake, to levels that we think could noticeably slow muscle damage. We must now gather more evidence, but these findings will bolster the application for the drug’s approval in Europe when the time comes.”

The results also indicate that golodirsen is safe and well-tolerated by young patients. This new, personalised approach is suitable for these patients with DMD that are amenable to exon 53 skipping, which amounts to ~8% of affected children.

Based on the study’s findings and an urgent need for effective treatments, the US Food and Drug Administration (FDA) granted accelerated approval of golodirsen in late 2019.

Further data is now being gathered through a parallel two-year study funded by Sarepta Therapeutics. This study, called ‘ESSENCE’, is designed to measure dystrophin production and functional outcomes (both ambulatory and pulmonary) to confirm the effects of golodirsen. This evidence will be needed in order to achieve EMA approval.

UK patients that were treated in the SKIP-NMD trial will continue to have access to the drug, which is given via a weekly infusion. Others are receiving the treatment through the parallel ESSENCE trial.

 

 

1) Sardone et al. (2018) A novel high-throughput immunofluorescence analysis method for quantifying dystrophin intensity in entire transverse sections of Duchenne muscular dystrophy muscle biopsy samples; PLOS ONE; https://doi.org/10.1371/journal.pone.0194540