drisapersen might work after all

At the end of 2013 devastating news was announced – the phase 3 clinical trial conducted by GlaxoSmithKline had failed to prove that the exon skipping drug ‘drisapersen’ improved muscle function in boys with Duchenne muscular dystrophy (MD). However, the drug’s original developer – Prosensa – has revealed that, based on more clinical trial results, it may work if boys are treated younger and for longer.

In addition to the large phase 3 trial which involved 186 boys, Prosensa conducted a smaller phase 2 trial of drisapersen which tested two different doses of the drug in 51 boys with Duchenne MD. The phase 2 trial showed that boys who received the higher dose of drisapersen (6 milligrams per kilogram of body weight once a week – the same dose as in the phase 3 trial) experienced stabilisation and even some improvement in their muscle function as measured by the six-minute walk test after 24 weeks. They maintained this stabilisation for another 24 weeks after treatment was stopped.

In the press release Prosensa said “Clinically meaningful improvement from the 24-week treatment period was maintained for 24 weeks after drisapersen administration ceased”. However, the number of boys treated was small and the results were not statistically significant. Therefore, further analysis of the results in combination with the results of the other clinical trials of drisapersen will be required.

Hans Schikan, CEO of Prosensa said “We are encouraged by these results, and are actively continuing with the analysis of the total drisapersen data set, which includes 300 patients and combined data representing 450 patient years to put these results into context”.

The boys in the phase 2 trial were on average younger than those in the phase 3 trial and Prosensa is speculating that this is the reason for the conflicting results. It is not known whether boys need to be younger for the treatment to work or if the way treatment success was measured – the six minute walk test – is only reliable in younger boys. Researchers around the world are continuing to assess alternative measures of muscle health in muscular dystrophy to find a more reliable test to be used in clinical trials in the future.

About drisapersen and 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 eteplirsen – the exon skipping drug being trialed by Sarepta
• Sarepta Therapeutics have a webpage called Skip Ahead with lots of useful information about exon skipping and how it works
• 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
• You can get regular updates by becoming a friend of the MDA Facebook page

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Updated 3 July 2018