Sarepta Therapeutics has started recruiting for its phase 3 clinical trial of exon skipping drug ‘eteplirsen’ in the USA. This drug has the potential to treat around 13 percent of boys with Duchenne muscular dystrophy (MD) — those with a particular genetic change (or mutation). It is designed to correct mutations located near exon 51 of the dystrophin gene (see ‘What is exon skipping’ below for further explanation).

The trial aims to test eteplirsen in 80 boys with Duchenne MD at 39 study locations throughout the USA to provide further evidence of its effectiveness. It has previously only been trialed in 12 boys with Duchenne MD (see results update below).

The trial participants will receive the study drug once a week for 48 weeks by IV infusion. They will visit the clinic regularly to have functional tests such as the six minute walk test and lung function tests. Biopsies will be taken at least twice during the trial to allow the amount of dystrophin in the muscles to be measured.

Eighty more boys with Duchenne MD will be recruited to the study – all of which will have mutations elsewhere in the dystrophin gene so would not be treatable with eteplirsen. These boys will have no treatment or biopsies but the results of their muscle function tests will be compared to the treated boys to determine if eteplirsen is working.

Trial results update
In July Sarepta released encouraging results from 144 weeks of eteplirsen treatment in their Phase 2b clinical trial. The results indicate that the walking ability of 10 of the boys participating in the study, who are now 12 years old on average, is still being stabilised. The distance they can walk in six minutes has only decreased by an average of 8.5 percent in almost three years which is a lot less than would be expected. Importantly lung function has remained stable and the drug is also being well tolerated with no significant side effects.

Regulatory update
There has been a lot of discussion over whether eteplirsen might be eligible for accelerated, conditional approval by the Food and Drug Administration (FDA) in the USA. Accelerated approval is usually granted to drugs that treat a serious disease with no treatment options, based on initial trial data. This would mean that the drug is made available in the USA prior to the completion of further clinical trials.

In April 2014 it was announced that the FDA had agreed to consider an application for accelerated approval, so Sarepta will file the application this year. This does not guarantee approval but it is encouraging that the FDA is agreeing to look at the application. Full approval by the FDA would depend on the outcome of further trials and if the results of further trials are unconvincing the drug would be withdrawn from the market.

The FDA also provided guidance to Sarepta on the design of further exon skipping clinical trials, including the phase 3 trial that has just started. Other studies that were also discussed include those to test the drug in boys that are too young or too old to participate in this study and trials of other exon skipping drugs which are designed for boys with mutations in other parts of the dystrophin gene. These are expected to start in the near future.

An application would need to be made to the Australian Therapeutic Drugs Administration (TGA) before eteplirsen was made available here and as yet, Sarepta have not yet announced plans to do so.

What is exon skipping?
Duchenne muscular dystrophy is caused by errors in the DNA code of the dystrophin gene. This gene contains the instructions for the production of dystrophin protein which gives strength to the muscle structure, and without this protein the muscles are damaged and deteriorate.

The dystrophin gene is made up of 79 pieces called exons. In most cases of Duchenne MD an exon, or exons are deleted which interferes with the rest of the gene’s exons being pieced together, like the pieces of a jigsaw puzzle. Exon skipping drugs tell the cell’s DNA reading machinery to ignore an additional piece of the gene so that the remaining exons can be pieced together, albeit in a shortened form. It is hoped that this will reduce the symptoms of Duchenne MD to a severity similar to that experienced by people with Becker MD.

Exon skipping drugs are sometimes called ‘molecular patches’ or referred to by their technical name ‘antisense oligonucleotides’ or ‘AONs’. They are small pieces of genetic material, similar to DNA, that attach themselves to a specific location in a gene. As such, molecular patches are not universally applicable to all boys with Duchenne MD because they must be specific for a patient’s particular genetic error.

Initially molecular patches are being developed that work on the parts of the gene that most often contain mutations. The first molecular patches in clinical trial (eteplirsen and drisapersen which are being developed by pharmaceutical companies Sarepta and Prosensa respectively) work in the vicinity of exon 51 which applies to about 13 percent of boys with Duchenne MD. Six other molecular patches are currently in the drug development pipeline which could be applied to a further 32 percent of boys. In total it is thought that approximately 83 percent of boys with Duchenne MD may be able to be treated by exon skipping but this will require the development of more than 100 different molecular patches which could take some time.

Further information
• Read the phase 3 clinical trial summary on
• Read about the research MDA funds which aims to reduce inflammation in the muscles and improve muscle regeneration
• The Duchenne muscular dystrophy factsheet contains more information about the condition and includes a research summary
Clinical trials – your questions answered
• You can get regular updates by becoming a friend of the MDA Facebook page

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Updated 7 October 2014