Sarepta Therapeutics and Prosensa have both announced news from the clinical trials of exon skipping for Duchenne muscular dystrophy. The trials tested eteplirsen and drisapersen – drugs with the potential to treat around 13 percent of boys with Duchenne muscular dystrophy.

Sarepta released encouraging results from 120 weeks of eteplirsen treatment in their Phase 2b clinical trial. The results indicate that the walking ability of the 10 boys participating in the study is still being stabilised. The distance they can walk in six minutes has only decreased by five percent in almost two years which is a lot less than would be expected. The drug is also being well tolerated with no significant side effects. This announcement extends previously released results from 96 weeks of treatment. However, we need to remember that this is a very small study and the results will need to be confirmed in a larger study which is currently being planned. In the meantime, this clinical trial is still ongoing which will allow longer term evaluation of eteplirsen.

Since the announcement in September 2013 of the disappointing phase 3 results of drisapersen, GSK has ended its collaboration with Prosensa. This large phase 3 clinical trial which involved 186 boys unfortunately failed to prove that this drug, which has a slightly different chemical composition to eteplirsen, was effective. However, Prosensa says that they will continue their drug development program for Duchenne MD. They are currently reanalysing the results of the trial together with results obtained in earlier trials. Initial analysis shows that the treatment seemed to be effective in delaying the progression of the disease when administered for longer time periods in younger boys. As a result, Hans Schikan, Prosensa’s Chief Executive Officer said “[this data] encourages us to engage patient groups, clinical experts and regulators to explore a path forward for drisapersen, which includes the possibility of re-dosing”.

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) 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 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 including a research summary

Clinical trials – your questions answered

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