Mayopathy (institute of muscular dystrophy

Scoliosis (Non-ambulant patient with Duchenne muscular dystrophy )

Scoliosis is a frequent complication in the
untreated scoliosis is associated with multiple complications such as compromised seating and trunk balance, discomfort, pain and difficult attendant care, exacerbation of any underlying cardio- respiratory dysfunction.

non-ambulant patient with Duchenne muscular dystrophy (DMD). Weakness of the para spinal muscles leads to trunk and body positional changes facilitating the development of a progressive collapsing scoliosis.

Research suggests that up to 90% of boys would develop scoliosis without intervention. A physical therapist may be the best person to monitor the spine, as he or she is likely to see the child more often than his medical specialists and will be able to detect early change.
Parents can play an important role in protecting their son’s spine by carefully and routinely checking his posture in his chair. As a young man grows, changing the dimensions of his chair helps maintain the best upright posture without his having to lean.

What can be done?
The following are some management approaches that may be offered to slow down the progression of the scoliosis in your child:

#Standing and walking have a protective effect on the development of scoliosis. It will benefit children who are able to walk (supported or unsupported) to keep mobile and encourage symmetrical supported standing (for example with standing frames) in those who can stand for as long as possible.

Those children who walk well but who have an increasing scoliosis (an uncommon situation) may benefit from wearing a plastic spinal support called a brace.

For young children who are unable to walk, a spinal brace may be recommended to delay the progress of scoliosis until most of the growth of the spine is completed and allow optimal sitting position of your child.

If your child is sufficiently well grown, or if the curve is progressing quickly or the breathing or heart function deteriorates an operation to correct the scoliosis and stabilize the spine is likely to be the treatment of choice.

Modified seating arrangements for their electric wheelchairs might be an alternative solution for those children who are overweight or where surgery is declined or not an option in view of severe respiratory or cardiac problems.

Food and Drug Administration (FDA, the American drug regulator) say an application to licence eteplirsen would be premature

Tuesday 12 November 2013

Sarepta Therapeutics announced today that the Food and Drug Administration (FDA, the American drug regulator) in the USA considered the company's plans to file an application for eteplirsen to be licensed as premature. 

 The FDA is basing their decision partly on the results of the large phase 3 clinical trial carried out by GlaxoSmithKline and Prosensa that showed that drisapersen - a drug similar to eteplirsen - failed to show that boys who received the drug could walk further than those that received placebo (an inactive form of the potential drug). They also state that there are new findings regarding the natural progression of Duchenne muscular dystrophy, which suggests that the stabilisation observed during Sarepta's phase 2b extension trial might not be caused by the drug but could be due to the natural course of the condition. The trial involved only a small number of boys and a larger study will be needed to demonstrate that eteplirsen is an effective treatment.

The FDA also expressed doubts that dystrophin can be used as a biomarker in clinical trials. Biomarkers are biological substances found in blood, urine or other parts of the body that can be used as an indicator in clinical trials to see how well the body responds to a potential treatment. In the FDA's opinion, there is not sufficient knowledge about the levels of dystrophin that are needed in the muscle to assume that its levels can show whether a treatment will be effective.

Sarepta Therapeutics is committed to continuing with a phase 3 trial which they plan to start early next year. The trial will involve about 120 boys. As soon as we receive more details we will update this page to keep you informed.

Dr Marita Pohlschmidt, Director of research at Muscular Dystrophy Campaign, said:

   “The refusal of the FDA to grant Sarepta’s request for an opportunity to apply for a license for eteplirsen will be upsetting news for many families. The decision reflects concerns that the results of Sarepta’s Phase 2b clinical trial were based on a very small group of boys and that a Phase 3 trial is necessary to demonstrate that eteplirsen is an effective treatment for Duchenne muscular dystrophy. We welcome Sarepta’s commitment to pushing ahead with a Phase 3 trial, due to start early next year.”

Chris Garabedian, president and chief executive officer of Sarepta Therapeutics said:

We are very disappointed with the FDA's decision to reconsider their openness to a potential NDA filing based on our current data and the resultant impact this change may have on our efforts to achieve an earlier approval of eteplirsen. We strongly believe in the potential of eteplirsen to address a serious unmet medical need in DMD and we are committed to its development. Our team at Sarepta recognizes the urgency of families who are seeking new treatments, and we will continue to work with the FDA on an acceptable confirmatory study design and, in parallel, seek to address their concerns regarding a potential NDA filing based on our current dataset.

Sarepta Therapeutics eteplirsen results accepted for publication

Tuesday 6 August 2013

Sarepta Therapeutics eteplirsen results accepted for publication

The results of Sarepta Therapeutics' phase 2b clinical trial of eteplirsen - a potential exon  skipping drug (or molecular patch) - have been accepted for publication in a medical journal. The study focuses on the first 48 weeks of the trial. After boys with Duchenne muscular dystrophy received the potential drug, production of the dystrophin protein was restored in up to 50% of the muscle fibres that were examined. Researchers also noted that boys who took eteplirsen for 48 weeks were able to walk, on average, 67.3 metres further in six minutes than those who took a placebo (an inactive drug) for 24 weeks followed by eteplirsen for 24 weeks. Importantly, the results show that eteplirsen was safe, with no serious side effects observed in any boy in the trial.

Whilst these results are promising, but the trial was small, with only 12 boys in total. It is therefore possible that a larger trial will be required to confirm these results. Importantly, the company's paper has been accepted for publication in a scientific journal (called Annals of Neurology). This is the first time the results of the trial have been subjected to peer review. Peer review is a process of quality control for science which lets independent scientists (peers) examine the methods and results of a study to check that the conclusions reached are correct. The scientists can highlight inaccuracies or problems in the study which the authors must address before publication.

Dr Marita Pohlschmidt, Director of Research at the Muscular Dystrophy Campaign, said:

It is really encouraging that Sarepta Therapeutics has chosen to publish these results in a peer-reviewed journal. Peer review is 'quality control' for the scientific community. By publishing its results in this way Sarepta is allowing independent scientists to scrutinise the study and its conclusions.

What we need to see now is eteplirsen tested in a larger group - this trial included only twelve boys - to confirm these promising results.

Sarepta Therapeutics eteplirsen update...

Muscular Dystrophy Campaign
61A Great Suffolk Street
London
SE1 0BU 

Thursday 25 July 2013

Sarepta Therapeutics eteplirsen update

In a press release, Sarepta Therapeutics yesterday announced that they plan to submit a licensing application for eteplirsen early in 2014. If the application is successful, Sarepta could be given permission to market eteplirsen in the USA. The company has also announced further details of a phase 3 trial being planned for next year and given an update on the results of the phase 2b trial that is ongoing.

In a press release, Sarepta Therapeutics yesterday announced that they have held recent meetings with the Food and Drug Administration (FDA), the drug regulator in the USA, in which they presented the latest results from their ongoing phase 2b trial of eteplirsen. Eteplirsen is a potential exon skipping drug for boys with Duchenne muscular dystrophy. Following these meetings, the FDA has said they would be willing to consider a licensing application based on the current trial results. Sarepta now plans to submit the application early in 2014.

A licensing application means that the FDA will review the evidence from clinical trials and pre-clinical testing of eteplirsen. They will decide whether the potential drug is safe and effective and decide whether Sarepta should be given a licence to market eteplirsen in the USA. It must be noted that this announcement is not a guarantee that the licence will be granted - just that the FDA is willing to look at an application. Also, the application will only apply to the USA - a separate application will need to be made in Europe. Sarepta is now working towards producing the application and will continue to meet with the FDA to make sure the application is as complete as possible.

Along with planning a license application, the company has started to scale up production of eteplirsen, a process which is so far going according to plan. Although the scaling up process will require a lot of testing and careful quality control, Sarepta hopes that by the end of 2014 it could be in a position to supply eteplirsen to between half and all of the boys in the USA who could benefit from the potential drug. 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. This will aim to confirm the results of the current trial (see below for the latest results) and is likely to include approximately 50 boys each in a treatment and control group (who will not receive eteplirsen). The design of the trial is still being finalised and we will bring you more details when they become available. 

Recently, Sarepta also gave an update on the latest results of their ongoing phase 2b trial of eteplirsen. At a conference in Massachusetts, the company announced that the distance boys canwalk in six minutes is still stable after 84 weeks. Although this is encouraging, the trial includes only ten boys in total and so the results must be viewed with some caution. The company is still performing regular check-ups on all the boys in the trial to monitor the safety and effectiveness of the potential drug and plans to present results up to 96 weeks at a meeting of the World Muscle Society in October.

Drisapersen given breakthrough therapy status

Muscular Dystrophy Campaign
61A Great Suffolk Street
London
SE1 0BU 

Monday 1st July 2013.

Drisapersen given breakthrough therapy status          

Drisapersen, GlaxoSmithKline's (GSK) potential exon skipping drug for boys with Duchenne muscular dystrophy has been awarded 'Breakthrough Therapy' status in the USA. The status can be awarded by the United States Food and Drug Administration - the drug regulator in the USA - to potential therapies which show encouraging results in clinical trials. In this case, the regulator used the results of a 53-patient phase II clinical trial which were reported in April. The results showed that after 24 weeks, boys with Duchenne muscular dystrophy who were given drisapersen were able to walk 35 metres further in six minutes than those given a placebo (an inactive version of the drug).

Breakthrough status means that the company will now benefit from increased support from the FDA. This will ensure that drug development, and clinical trials can be handled as quickly and efficiently as possible.

Robert Meadowcroft, Chief Executive of the Muscular Dystrophy Campaign, said:  

"This is very encouraging news and we are one more step closer to delivering a potential treatment to some boys living with Duchenne muscular dystrophy. "

"We are also working closely with the All Party Parliamentary Group on muscular dystrophy who are conducting an Inquiry into access to potential treatments for conditions such as Duchenne muscular dystrophy. The Inquiry will look at the "Breakthrough Therapy" designation from the FDA and consider whether similar approaches could be used by regulators here in the UK."

exon skipping

What is exon skipping and how does it work?

In order to explain the concept of exon skipping, it is first necessary to explain how genes work and how mutations in the dystrophin gene can cause both Duchenne and Becker muscular dystrophy.

Contents:

• What are genes?
• What are exons?
• What happens in Becker muscular dystrophy?
• What impact does a Becker mutation have on the dystrophin protein?
• What happens in Duchenne muscular dystrophy?
• How can exon skipping help?
• Does this really work?
• Is there a clinical trial?
• Will it work for everyone with Duchenne muscular dystrophy?
• Will the same 'molecular patch' work for everyone? 
• Are ‘molecular patches' a cure?

What are genes?

DNA is an extremely long molecule which contains the instructions to create and maintain our bodies. A gene is a section of DNA that contains the instructions for the production of one specific protein. Proteins are essential parts of cells and play a role in every process occurring within the cell, as well as having structural or mechanical functions which help maintain the cells' shape. It is estimated that we have about 30,000 different genes.

What are exons?

Genes are divided into sections called exons and introns. Exons are the sections of DNA that code for the protein and they are interspersed with introns which are also sometimes called 'junk DNA'. The introns are cut out and discarded in the process of protein production, to leave just the exons. The dystrophin gene is our largest gene- it has 79 exons which are joined together like the pieces of a puzzle.

Exon structure of Dystrophin

What happens in Becker muscular dystrophy?

Let's zoom in on exons 68 to 75 to look at this a bit more closely:

Dystrophin exons 68-75

In Becker muscular dystrophy an exon is deleted, for example exon number 74 in the diagram:

Dystrophin exon 68-75 missing exon 74

Although a part of the gene is missing, exon 73 can join up with exon 75, and the puzzle can be completed to the end of the gene:

What impact does a Becker mutation have on the dystrophin protein?

The dystrophin protein normally sits in the membrane that surrounds muscle fibres like a skin, and protects the membrane from damage during muscle contraction. Without dystrophin the muscle fibre membranes become damaged and eventually the muscle fibres die.

Dystrophin is a very large protein with a section in the middle consisting of lots of repeated segments (in green below) and it is known that the protein can still work to some extent if some of these repeated segments are missing. Individuals with Becker muscular dystrophy have some of these repeated segments missing and have relatively mild symptoms- often being able to still walk into their 40s and 50s.

Diagram of the dystrophin protein

A man has even been known to be still walking at 61 years of age, despite having a deletion of 46% of the dystrophin gene!

Illustration of the dystrophin protein in Becker muscular dystrophy

What happens in Duchenne muscular dystrophy?

In Duchenne muscular dystrophy an exon, or exons are deleted which interfere with the rest of the gene being pieced together. In our example (using exons 50-57), exon 52 illustrates this:

Exon 51 can not join up with exon 53, which prevents the rest of the exons being assembled. For the dystrophin protein to work it must have both ends of the protein. Therefore, this mutation results in a completely non-functional dystrophin protein and the severe symptoms of Duchenne muscular dystrophy.

How can exon skipping help?

As the name suggests, the principle of exon skipping is to encourage the cellular machinery to 'skip over' an exon. Small pieces of DNA called antisense oligonucleotides (AOs) or 'molecular patches' are used to mask the exon that you want to skip, so that it is ignored during protein production. In our example, if we use a 'molecular patch' designed to mask exon 53: 

Exon 51 can now join up to exon 54 and continue to make the rest of the protein, with exons 52 and 53 missing in the middle:

Therefore, exon skipping may be able to reduce the symptoms of Duchenne muscular dystrophy, to those more like Becker muscular dystrophy.

Does this really work?

So far scientists have shown this technique to be effective in a mouse model of Duchenne muscular dystrophy (the mdx mouse) and in human Duchenne muscular dystrophy muscle cells grown in the laboratory.

Several clinical trials have now been conducted that show that injecting a molecular patch into the blood stream or under the skin results in the production of dystrophin in the muscles. No serious side-effects were observed. There are three companies involved in conducting clinical trials of exon skipping. The principal of exon skipping is the same for all of the clinical trials but the molecular patch being tested has a slightly different chemical formulation.

• The Dutch company Prosensa has formed a partnership with GSK to test a molecular patch to skip exon 51 .
• AVI Biopharma conducted a clinical trial in the UK of a exon 51 molecular patch developed by the MDEX consortium with funding from the Muscular Dystrophy Campaign. 

The next step is to find out if the increase in dystrophin in the muscles results in improved muscle function or at least slows the deterioration of the muscle. Clinical trials have been started to determine this and continue to monitor the safety of exon skipping.

Is there a clinical trial?

AVI Biopharma now plans to test higher doses of the molecular patch to try to gain a consistently strong response to the molecular patch. They are planning to conduct this trial in the US. 

GSK and Prosensa have started an international phase 3 clinical trial of exon 51 skipping. 

The challenge with all of these trials is to produce enough dystrophin in as many muscles as possible (including the heart) to prolong and improve the quality of life for boys with Duchenne muscular dystrophy.

Will it work for everyone with Duchenne muscular dystrophy?

It is thought that skipping one or two exons would be able to treat around 83% of the genetic errors causing Duchenne muscular dystrophy.

Will the same 'molecular patch' work for everyone?

No, the dystrophin gene is very large and the genetic errors associated with Duchenne muscular dystrophy occur in different places along this gene. There are however some common areas for mutations and initially 'molecular patches' will be made for these. The clinical trials are starting with exon 51 which would be applicable for around 13% of boys. Once the technology has been shown to be effective for a particular error it will be possible to design other 'patches'. A clinical trial has been started for a exon 44 molecular patch which is applicable to about 6 percent of boys. The companies have said that they have started preclinical research on patches for exon 50, 45, 52, 53 and 55.

Are 'molecular patches' a cure?

Scientists hope that this type of therapy will halt or even reverse the symptoms of Duchenne muscular dystrophy so that the symptoms are more like those of boys with Becker muscular dystrophy. It will not be a cure because if proven to be effective, this treatment would need to be repeated regularly- how often will become apparent during clinical trials.