Duchenne exon skipping trial results published

The results of Sarepta Therapeutics’ clinical trial of eteplirsen have been published in a reputable medical journal. Eteplirsen is a ‘molecular patch’ designed skip a portion of the dystrophin gene called ‘exon 51’. It has the potential to treat around 13 percent of boys with Duchenne muscular dystrophy – those with a mutation in the vicinity of exon 51.

The trial showed that considerable amounts of dystrophin protein were produced in the muscles after 48 weeks of treatment and this stabilized walking ability.

About the trial
Nationwide Children’s Hospital in Ohio USA began the phase 2b trial of eteplirsen in August 2011, enrolling 12 boys aged 7 to 13 years. They all had weekly IV infusions. Four of the boys received a lower dose of eteplirsen (30 mg/kg), four a higher dose (50 mg/kg) and four were in the placebo group and did not receive the active drug. The boys were randomly assigned to the groups and for the first 24 weeks of the study they did not know which group they were in, and neither did the clinicians treating them. Before the first treatment, and at weeks 12, 24 and 48 the boys had muscle biopsies and they performed six minute walk tests. After week 24 the four boys in the placebo group also received the active drug – two at the lower dose and two at the higher dose.

The results
After 48 weeks of treatment, the biopsies from the boys were examined under a microscope. Forty seven percent of the muscle fibres, on average, contained dystrophin. There was some variability between the boys – ranging from 30 to 60 percent of muscle fibres. There was little difference between the two doses given. The amount of dystrophin in the muscles built up over time and at least 12 weeks of treatment was needed before an effect was seen.

The walking ability of boys who took eteplirsen for 48 weeks was stabilized. By comparison the walking ability of those who received placebo for the first 24 weeks declined – they walked 67 metres less in 6 minutes. Importantly no serious side effects were observed.

What does this mean for patients?
These clinical trial results have been reported in various press releases and presented at scientific conferences since October 2012, but this is the first time that the full results have been publicly available for scrutiny. Publication in a medical journal means that independent scientists have reviewed the results and deemed that the study was well conducted and the conclusions reached accurate.

The results give a very promising indication that this may be an effective treatment for Duchenne MD, especially since all of the boys made considerable amounts of dystrophin in their muscle after 48 weeks of treatment. This dystrophin production was enough to stabilise the walking ability of the boys. The boys in the study are continuing to receive etiplersen and at a recent conference, the company announced that the six minute walk test results are still stable after 84 weeks.

However, we need to remember that this was a very small study involving only 12 boys, and in fact, two of the boy’s walk test results had to be excluded from the analysis because their walking ability deteriorated rapidly just after the study began. Therefore, the results will need to be confirmed in a larger study which is currently being planned.

Another consideration is that only one muscle in the arm or shoulder was examined for dystrophin production and it isn’t known if all of the muscles of the body will respond as well to exon skipping treatment. In particular, studies in mice have indicated that it may be the case that very little, if any, of the exon skipping drug will penetrate the heart, so an alternative strategy will need to be used to treat the heart. Researchers are working on the next generation of exon skipping drugs which are taken up more efficiently by all muscles of the body including the heart. These are yet to be tested in clinical trial.

What are the next steps?
This clinical trial is still ongoing which will allow longer term evaluation of the effectiveness and safety of etiplersen. Early next year Sarepta plans to submit an application to the Food and Drug Administration (FDA), the drug regulator in the USA, based on the results of this clinical trial. The FDA will decide whether Sarepta should be given a licence to market eteplirsen in the USA. If successful this could then be the basis to apply for a licence in other countries.

Sarepta has also started to scale up production of eteplirsen, which will be required to supply enough of the drug if it does obtain a licence. If a license is not granted by the FDA, the increased production will be used to support a larger phase 3 trial which Sarepta is currently planning.

An exon 51 skipping drug with a slightly different chemical formulation (called drisapersen) is also being trialed by the company Prosensa, in partnership with GSK. Drisapersen is currently in phase 3 clinical trial.

Further information
Read the Duchenne MD factsheet.
What is exon skipping and how does it work?

This research was published in the journal Annals of Neurology and is only available after paying a fee. The article is written in technical language with no summary in lay terms.

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