Research Update 2014 – DMD & Becker MD

We will be publishing summaries of the progress made this year towards treatments for muscular dystrophies and related neuromuscular conditions. First up are Duchenne and Becker MDs which are trailblazing the way forward.

Utrophin drug moving forward
Summit, a UK drug company, started a phase 1b clinical trial in December 2013 to test SMT C1100 in 12 boys with Duchenne MD. SMT C1100 is an oral drug designed to increase the amount of a protein called utrophin in the body. It is thought that utrophin might be able to substitute for the dystrophin that is missing in boys with DMD because the two proteins are very similar. Clinical trials of this approach have been eagerly awaited because it has the advantage that it could be used to treat all boys with Duchenne MD, no matter what their genetic mutation is. In addition, if it proves to be effective it may also be applicable to individuals with Becker MD.

Results of the trial, which were presented at a conference in July 2014, showed that SMT C1100 was safe and well-tolerated at all dose levels tested. Encouragingly, levels of enzymes in the blood such as creatine kinase (CK) (a marker of damaged muscle fibres) were reduced. However, this will need to be confirmed in future clinical trials because CK levels are known to fluctuate during the course of the disease, there were only a small number of participants and it wasn’t a placebo controlled trial.

Of concern was the observation that levels of the drug in the blood stream were very variable between the trial participants. Only two boys had amounts in their blood comparable to the levels achieved in the healthy adults in the phase 1 trial; levels were lower in the other ten. The company speculates that diet or other disease related factors may be the cause. Summit plans to start another trial before the end of this year to monitor dietary impact on SMT C1100 uptake. This will then lead into a phase 2 trial next year.

UPDATE 11/12/14: Summit has received the go-ahead from UK authorities to start a modified diet clinical trial of SMT C1100 in 12 boys with DMD between the ages of 5 and 13. The trial aims to find out if specific diets can improve the absorption of the drug into the blood stream. The trial will also evaluate the potential impact that SMT C1100 is having on enzyme markers of muscle health. Preliminary results from the trial are expected to be reported in mid-2015. The Phase 1b modified diet trial will be conducted at four UK hospitals and if it is successful, it will be followed by a Phase 2 trial that will assess the drug’s safety and effectiveness over a longer time period.

Exon skipping
Sarepta Therapeutics and Prosensa have both made significant progress this year in the clinical trials of exon skipping for Duchenne MD. The trials tested eteplirsen and drisapersen which are drugs with the potential to treat around 13 percent of boys with Duchenne MD – those with a mutation near exon 51 of the dystrophin gene.

Eteplirsen still looking good
In July Sarepta released encouraging results from 144 weeks of eteplirsen treatment in their Phase 2b clinical trial. The results indicated that the walking ability of 10 of the boys participating in the study, who were 12 years old on average, was still being stabilised. The distance they could walk in six minutes had 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.

In October Sarepta Therapeutics started recruiting for its phase 3 clinical trial of eteplirsen in the USA. 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.

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.

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 and in October they added the proviso that some additional data would need to be provided with the application. Sarepta hopes file the application by the middle of 2015. 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. 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.

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. On November 12 the first of these trials started in the USA in boys between the ages of seven and 21 who are no longer able to walk. Read more about this non-ambulant eteplirsen trial. The other trials are expected to start in the near future.

Drisapersen works after all
In September 2013 disappointing results from the phase 3 clinical trial of exon skipping drug drisapersen were reported. The trial conducted by GlaxoSmithKline (GSK) failed to prove that drisapersen improved muscle function in boys with Duchenne 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 some smaller trials of drisapersen. Many of the boys who participated in the drisapersen trials were also enrolled into an extension study. Recent analysis of these extra results suggests that boys who were younger and were treated for longer experienced stabilisation and even some improvement in their muscle function. In particular boys of seven years or younger, given two years of continuous drisapersen treatment, improved in the six minute walk test by eight meters on average compared with a 29 meter decline for those who received a placebo or delayed treatment with drisapersen. A “clinically meaningful improvement” was also reported for the older, more severely affected boys, but this improvement was more subtle and took longer to emerge.

It is not known whether boys need to be younger for the treatment to work optimally 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 look for more reliable measures of muscle health to be used in clinical trials in the future.

The drisapersen studies were stopped in March this year after the results of the GSK trial were released but based on these new results Prosensa has started giving boys involved in the previous clinical trials access to drisapersen in the USA, Canada, Belgium and Sweden and other countries will follow.

Prosensa has been given the go ahead by the FDA in the USA to file an application for accelerated approval for drisapersen and they started the submission process in October. After this application is completed they will apply for approval in Europe. Prosensa has said that too early to outline their regulatory plans for drisapersen in Australia and other countries. As a first step though, drisapersen already has an orphan drug designation in Australia which should make it cheaper to gain regulatory approval.

Prosensa are also running clinical trials for exon skipping drugs designed to skip other parts of the dystrophin gene – exons 44, 45 and 53 which together may able to treat a further 22 percent of boys with Duchenne MD.

For help understanding exon skipping please contact us or take a look at this website:

Increasing blood flow may be of benefit
Results from a small clinical trial have shown that drugs that are usually prescribed for erectile dysfunction — sildenafil (Viagra) and tadalafil (Cialis) — might be able to reduce some of the symptoms of Duchenne MD.

Studies in mice have indicated that in Duchenne MD blood vessels supplying muscles do not adequately dilate during exercise, resulting in muscle fatigue and weakness. In mice this can be reversed with drugs such as sildenafil and tadalafil.

The results of a small clinical trial involving 10 boys with Duchenne MD were published in May. The boys aged between 8 and 13 years had the blood flow in their forearm muscles measured as they carried out handgrip exercises. Their blood flow was compared with 10 similarly aged healthy boys, which confirmed that those with Duchenne MD had reduced blood flow. It was found that after a single dose of either sildenafil or tadalafil they had the same blood flow response as the healthy boys during exercise. A similar result was obtained in a previous clinical trial of tadalafil for Becker MD.

Although the team’s findings are encouraging, a lot more research needs to be done before these types of drug can be recommended for individuals with Duchenne and Becker MD. Crucially it is not known if increasing blood flow improves muscle strength and slows disease progression and if long-term use of this type of drug is safe. In order to address these questions a phase 3 clinical trial of tadalafil for Duchenne MD has started recruiting participants. The trial aims to recruit over 300 boys with Duchenne MD in 16 countries (not Australia) and will include functional tests like the 6 minute walk test.

It will be interesting to see if this large trial gets different results to a small trial in Denmark which was published in October this year. This trial tested sildenafil on 16 individuals with Becker MD and showed that muscle and heart function was not changed by the treatment. Of more concern is that a trial of sildenafil for Duchenne and Becker MD was started in 2010 to investigate whether it could treat the heart problems associated with these conditions. Unfortunately it was suspended in 2013 due to a negative impact on heart function. As a result, future studies will need to carefully monitor the impact of this type of drug on the heart.

First drug specifically for Duchenne MD approved in Europe
Ataluren has become the first ever drug licenced to treat the underlying genetic cause of Duchenne MD. In August the European Commission granted conditional approval for Ataluren, which will now be known by the name “Translarna”. The drug developed by PTC Therapeutics is designed to overcome a specific change in the DNA called a “nonsense mutation” which causes 10 to 15 percent of cases of Duchenne MD. Clinical trials have indicated that it may be able to slow down the progression of muscle weakness.

Conditional approval is granted to medicines that, based on available evidence, would give positive public health benefits which outweigh the risks. It can only be granted for medicines to treat serious conditions that have no readily available treatment, and it is therefore important that patients have early access to the medicine. PTC Therapeutics will now be able to market Translarna in Europe (the 28 countries that are Member States of the European Union, as well as European Economic Area members Iceland, Liechtenstein and Norway) while it conducts its Phase 3 clinical trial, which is expected to deliver results in 2015.

Approval for Translarna in Australia will require a separate application to the Australian Therapeutic Goods Administration (TGA), and no plans to do so have been announced. However, the phase 3 clinical trial will be recruiting patients in Melbourne and Sydney.

*Please read this additional Translarna information or contact us for a detailed explanation of the significance of conditional approval and what a nonsense mutation is.

Boosting muscle growth
Another strategy for the development of a treatment for MD is to boost muscle growth. One way to do this is to interfere with the mechanisms naturally present in the muscle that put the brakes on muscle growth so that muscles remain within the normal size range. The brakes are a protein called myostatin and blocking this protein could result in increased muscle growth and strength.

Researchers in the USA are aiming to inhibit myostatin using a form of gene therapy. It involves increasing levels of a protein called follistatin which is a natural inhibitor of myostatin. A harmless virus is used to deliver the follistatin gene inside muscle cells and these instructions are used to make the follistatin protein.

The results of a phase 1 trial involving six Becker MD patients have recently been published. The participants had the virus containing the follistatin gene injected into their quadriceps muscles. Four of the six participants showed an improvement in the distance they could walk in six minutes, while the other two had no change. Encouragingly the muscles showed signs of improved health when examined under a microscope. However, this was a very small trial with no placebo control so further research will be required to determine if the treatment is safe and effective.

On that back of these positive results the researchers have received funding to conduct another trial of the same gene therapy in boys with Duchenne MD.

Breathing easy – Catena clinical trial results
Santhera, a Swiss pharmaceutical company has released preliminary results of their phase 3 trial of Catena (also known as Raxone or idebenone) in boys with Duchenne MD. Catena is a synthetic drug similar to the naturally occurring antioxidant Coenzyme Q10. The results of the trial show that Catena is able to slow the decline in breathing ability. More detailed results are anticipated in the near future and Santhera are engaging in talks with drug regulators regarding the licencing of this medicine.

Clinical study currently recruiting
Clinicians at the Royal Children’s Hospital are embarking on a new clinical study which aims to find a way to diagnose breathing problems in boys with Duchenne MD earlier so that they can be promptly treated. If you are interested in finding out more and potentially taking part in this research please contact the study coordinator: Mary Roberts ( or contact A/Prof Monique Ryan ( or +61 3 9345 5661).

News from the lab
Although the news from the current clinical trials is encouraging, scientists are still working hard in the laboratory to find more effective treatments that are applicable to a wider range of Duchenne MD patients. Below are just a few of this year’s highlights.

US scientists have discovered a way in which it might be possible to treat the approximately six percent of boys with Duchenne MD who have a mutation in the first four exons (or segments) of the dystrophin gene, including duplication mutations. There are currently no exon skipping drugs being developed for these boys, but this new research showed that it may be possible to use a ‘one size fits all’ exon skipping drug for these patients which encourages the cell to use an alternative start point further down the gene. This would result in a shorter dystrophin protein being made but it is known that people who naturally produce this shortened protein have relatively mild symptoms.

French researchers have demonstrated in dogs that have Duchenne MD that it may be possible to deliver exon skipping drugs to the muscles using a virus. The study showed that this was a highly effective way of getting the drug into muscle cells. There was also a prolonged effect, meaning that injections would be infrequent, whereas current exon skipping treatment requires weekly infusions. This research paves the way for a clinical trial that is being planned for 2015 which will involve treating the arms of boys with Duchenne MD who are no longer able to walk.

Researchers in the USA and Japan have proven the potential of a technique called ‘genome surgery’ or ‘CRISPR’. The Americans were able to treat mice with a condition similar to Duchenne MD. The technique permanently repairs mistakes in the DNA which would essentially cure the condition, and could be applied to a wide range of genetic conditions. However, the research was done in early mouse embryos of only a few cells, and even then only a proportion of the cells in the resulting adult mouse were repaired and able to produce dystrophin. So there is still a big challenge facing scientists to work out how to use this technology to treat the billions of cells in a person’s body.

One possibility is that genome surgery may be used in conjunction with stem cell therapy, and this is what the Japanese scientists have reported. They took skin cells from a patient with Duchenne MD and converted them into immature cells, known as ‘induced pluripotent stem (iPS)’ cells. Under the right conditions these cells can become a range of other cell types. They used the genome editing technique to correct the mutation in these immature cells. The scientists were then able to mature these cells into dystrophin-producing muscle cells in the petri dish. Although it would be too difficult to treat the whole body with these cells it is thought that these cells could be injected locally into the muscles that most need a boost – for example the diaphragm for breathing or muscles used for chewing and swallowing – and improve quality of life. However, this is early stage research and the safety and viability of these stem cells is still unknown and requires further research.

Further information
• The Duchenne and Becker MD factsheets contain more information about the conditions and include a research summary
Clinical trials – your questions answered
• For any terms you are unfamiliar with please take a look at our glossary

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Updated 18 November 2014