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Introducing our new projects Research grants awarded

Target Research Issue 4 of 4 2013

Conditional approval How drugs are licensed

Biomarkers Non-invasive methods to measure and monitor disease progression

Also inside‌ read about all the latest research and clinical trial news from the UK and around the world


Glossary This glossary is intended to help with some of the scientific and technical terms used in this magazine. Words that are in the glossary are highlighted in italics in the text.

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Animal model – a laboratory animal such as a mouse or rat that is useful for medical research because it has specific characteristics that resemble a human disease or disorder.

The Muscular Dystrophy Campaign is the leading UK charity fighting muscle-wasting conditions.

Biomarker – A biological substance found in blood, urine or other parts of the body that can be used as an indicator of health or disease. A biomarker may be used to help clinicians diagnose a condition and monitor how it is progressing, but can also be used to see how well the body responds to a treatment. DNA – (deoxyribonucleic acid) is the molecule that contains the genetic instructions for the functioning of all known living organisms. DNA is divided into segments called genes. Dystrophin – The protein missing in people who have Duchenne muscular dystrophy and reduced in those who have Becker muscular dystrophy. 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. Exon – genes are divided into regions called exons and introns. Exons are the sections of DNA that code for the protein and are interspersed with introns, which are also sometimes called “junk DNA”. Exon skipping – a potential therapy currently in clinical trial for Duchenne muscular dystrophy. It involves ‘molecular patches’ or ‘antisense oligonucleotides’ which mask a portion (exon) of a gene and causes the body to ignore or skip-over that part of the gene. This restores production of the dystrophin protein, albeit with a piece missing in the middle. Gene – genes are made of DNA and each carries instructions for the production of a specific protein. Genes usually come in pairs, one inherited from each parent. They are passed on from one generation to the next, and are the basic units of inheritance. Any alterations in genes (mutations) can cause inherited disorders. In-vitro fertilisation (IVF) – a process by which the egg is fertilised by sperm outside the womb.

be used to mask errors in the genetic code, this is known as exon skipping and is in clinical trial for Duchenne muscular dystrophy. Certain types are also being investigated in the laboratory for their ability to completely switch off genes. Also called antisense oligonucleotides. Mutation – the alteration of a gene. Mutations can be passed on from generation to generation. Nonsense mutation – a change in the DNA which causes a premature stop signal to occur in a gene. When this happens protein is either not produced at all or does not function properly. Phase 1 clinical trial – a small study designed to assess the safety of a new treatment and how well it’s tolerated, often using healthy volunteers. Phase 2 clinical trial – studies which test the effectiveness of a potential treatment on a small group of patients and which find the most effective dose. Participants are usually divided into groups to receive different doses or a placebo. Phase 3 clinical trial – a study to test the effectiveness of a treatment on a larger number of patients. Participants are usually divided into groups to receive the potential treatment or a placebo. Placebo – an inactive substance designed to resemble the drug being tested. It is used to rule out any benefits a drug might exhibit because the recipients believe they are taking it. Protein – molecules required for the structure, function, and regulation of the body’s cells, tissues, and organs. Our bodies contain millions of different proteins, each with unique functions. The instructions for their construction are contained in our genes. Randomised controlled trial – a clinical trial where treatments and placebo are allocated randomly to participants rather than by conscious decisions of clinicians or patients. Utrophin – a very similar protein to dystrophin. Low levels of utrophin are present in everyone – including people with Duchenne muscular dystrophy – but in insufficient amounts to compensate for the loss of dystrophin.

Magnetic resonance imaging (MRI) – a non-invasive body imaging procedure that uses powerful magnets and radio waves to construct pictures of the internal structures of the body.

The Muscular Dystrophy Campaign’s medical research programme has an international reputation for excellence, investing more than £1m each year, which includes more than 25 live projects taking place at any one time. Our information, care and support services, support networks and advocacy programmes support more than 5,000 families across the UK each year. We have awarded more than 6,000 grants totalling more than £6m towards specialist equipment, such as powered wheelchairs.

References and further information Please contact us at if you would like any further information or a link to the original research article. The articles are written in technical language with no summary in layman’s terms; and some may require a payment before they can be viewed.

Disclaimer While every effort has been made to ensure the information contained within Target Research is accurate, the Muscular Dystrophy Campaign accepts no responsibility or liability where errors or omissions are made. The views expressed in this magazine are not necessarily those of the charity. ISSN 1663-4538

Muscular Dystrophy Campaign, 61A Great Suffolk Street, London SE1 0BU t: 0800 652 6352 e: w:

Micro-RNA – small RNA molecules which are usually used by cells to control how genes are turned on and off and to control the process of protein production. Molecular patch – a short piece of genetic material (DNA or RNA) which can bind to a specific gene and change how the code is read. They can

We are dedicated to beating muscular dystrophy and related neuromuscular conditions by finding treatments and cures and to improving the lives of everyone affected by them.

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Welcome to the final edition of Target Research for 2013. In this issue, we introduce the seven new research grants which we have awarded. The projects have all been assessed through our rigorous peer review system to ensure that we continue to fund only world class scientific research. The projects focus on Duchenne muscular dystrophy and will investigate several different approaches to developing new potential treatments. In the second feature article, we take a look at biomarkers, and how researchers and clinicians are working to find safe, easy and non-invasive ways to assess muscle damage and monitor disease progression. These will be important in future clinical trials as they will help clinicans to measure the effectiveness of trial treatments. I do hope you enjoy this edition of Target Research. If you have any questions please do get in touch.

Neil Bennett Editor, Target Research t: 020 7803 4813 e: tw:

Contents 4

Introducing our new research projects The new PhD studentships and project grants we are funding


Research news A round up of news stories from around the world

10 Conditional approval: accelerating access to new potential treatments What does this mean for you? 12 Biomarkers Non-invasive methods to measure and monitor disease progression 15 Ask a Scientist Your questions answered by leading UK researchers 15 Is this the end of Exon Skipping? Dr Marita Pohlschmidt, the Director of Research

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Introducing our

new research projects We are pleased to announce the funding of seven new research projects this year which will increase our understanding of Duchenne muscular dystrophy and pave the way to bring new treatments to clinical trials. The grants are jointly funded by the Duchenne forum – a funding partnership between six UK charities dedicated to beating Duchenne muscular dystrophy.

Small molecules to increase utrophin for Duchenne muscular dystrophy In this project Dr Angela Russell and her PhD student will study molecules showing therapeutic promise for Duchenne muscular dystrophy. They will use cutting-edge techniques to investigate how compounds that increase the levels of a protein called utrophin work. One way to compensate for the loss of dystrophin in Duchenne muscular dystrophy may be to increase levels of a protein called utrophin. Utrophin is produced in small amounts in adult muscle cells and is similar to dystrophin in structure and function. The potential effectiveness of the technique has been demonstrated in animal models of Duchenne muscular dystrophy (mdx mice) where muscle function was nearly as good as in healthy mice. Dr Russell has been working with Professor Kay Davies and her team to identify potential drugs that could increase levels of utrophin in the muscle and may be of therapeutic benefit. Although one potential drug (called SMT C1100) developed by the team is in clinical trials, the precise mechanism by which it might increase levels of utrophin is not known. This project will investigate the molecular mechanism of action of the most promising new lead compounds by studying the relationship between the structure and activity of drugs identified in a new, more sensitive drug screen. The researchers aim to identify the targets of the new molecules in cells, and investigate the pathways they affect using biological and chemical methods. This research will show how drugs that increase utrophin protein levels in muscles are working at a biological level. This may help researchers develop more drugs that act in a similar way and may identify molecules that can be used to monitor the progression of Duchenne muscular dystrophy (biomarkers).

GRANT INFO Project leader: Dr Angela Russell University of Oxford

Conditions: Duchenne muscular dystrophy

Duration: Four years, starting 2013

Total project cost: ÂŁ 110,700


Developing small molecules to target Duchenne muscular dystrophy In this project, Professor Kay Davies aims to use an improved drug screen to identify small molecules that can increase utrophin levels more effectively than the potential drug (SMT C1100) which is currently in clinical trials. Professor Davies has been working to identify potential drugs that can increase levels of utrophin in the muscle. The team has developed one potential drug – SMT C1100 – which a Phase I clinical trial showed was safe and distributed around the body. The next phase will test whether SMT C1100 increases utrophin levels in the muscles of boys with Duchenne muscular dystrophy and whether this could improve muscle function. There is a need for the search for new drugs to go on, and follow-on compounds need to be developed which are more effective than SMT C1100. Professor Davies and her colleagues have generated a new, more sensitive drug screen which has been used to identify new compounds. This project aims to continue the work to identify and characterise potential therapeutic compounds. These will be tested in a mouse model of Duchenne muscular dystrophy and successful candidates will be developed for clinical trials. An advantage of this approach is that it is applicable to everybody with Duchenne or Becker muscular dystrophy, regardless of mutation.

Gene therapy for Duchenne muscular dystrophy Professor Dickson and his team aim to develop a novel gene therapy approach that is aimed at delivering a functional, full-size dystrophin gene to muscle cells using a harmless virus. Gene therapy approaches offer the possibility to use a harmless virus to deliver a functional copy of the dystrophin gene to muscle cells to restore production of dystrophin protein. One of the challenges is that the dystrophin gene is too big for some viruses to carry - just like an envelope can only hold so many pieces of paper, a virus can only carry a certain amount of DNA. To address this challenge, researchers will cut the dystrophin gene into two, or even three pieces and insert each piece into an individual virus. If all the viruses infect a single cell, the parts of the dystrophin gene can be joined together to produce a full-length dystrophin protein. This is called transplicing technology (with dual- or triple-transplicing indicating whether the gene has been cut into two or three pieces). This project aims to optimise transplicing technology by increasing gene delivery to muscle cells and making the process inside the cell more efficient. The new technology will be tested in cells grown in the laboratory, and in mouse models of Duchenne muscular dystrophy. Although this project will focus on technology with the potential to treat Duchenne and Becker muscular dystrophies, this could be adapted for use in other muscular dystrophies and neuromuscular conditions.

Genome surgery for Duchenne muscular dystrophy This ground-breaking technique could have the potential to be the frst therapy to offer a permanent correction of the genetic mutation in a person’s own DNA. This project aims to develop and test the molecular tools required for the techique. Repairing the mutations in the dystrophin gene could restore production of dystrophin to the muscles which may prevent muscle damage and slow the decline in muscle function. Professor Dickson and his team are working on a strategy described as genome surgery, which has the potential to permanently correct a mutation in a person’s own DNA. This is done by using enzymes called endonucleases that act like ‘molecular scissors’ designed to cut out the precise part of the gene containing the mutation. Other molecular tools can then add in the correct DNA sequence and join the cut ends together. This would correct the genetic mutation and allow production of the full-size dystrophin protein. This PhD studentship, aims to generate the molecular tools required for the genome surgery technique and test them in cells grown in the laboratory and animal models of Duchenne muscular dystrophy. If effective, this therapy has the potential to permanently correct the mutation in all boys with Duchenne muscular dystrophy and may also be able to treat people with Becker muscular dystrophy.

GRANT INFO Project leader: Professor Dame Kay Davies University of Oxford

Conditions: Duchenne muscular dystrophy

Duration: Two years, starting 2013

Total project cost: £128,064

GRANT INFO Project leader: Professor George Dickson Royal Holloway University, London

Conditions: Duchenne muscular dystrophy; Becker muscular dystrophy

Duration: Three years, starting 2013

Total project cost: £ 180,306

GRANT INFO Project leader: Professor George Dickson Royal Holloway University, London

Conditions Duchenne muscular dystrophy; Becker muscular dystrophy

Duration: Three years, starting 2013

Total project cost: £ 79,704 leading the way forward


Investigating inflammation in Duchenne muscular dystrophy Dr Jennifer Pell will investigate the regulation of inflammation which is known to contribute to muscle-wasting and weakening in Duchenne muscular dystrophy. The project aims to understand the role of certain proteins produced by muscle stem cells in this process. Our immune system produces molecules that help to protect us from infections and drive the clear up of damaged cells, a process called inflammation. In Duchenne muscular dystrophy, the destruction of the muscle fibres can trigger inflammation which can further damage the muscles. This project will focus on a particular family of proteins that are released from muscle stem cells and are thought to be involved in regulating inflammation in the muscles. The researchers have found that members of the protein family can regulate many key molecules and growth factors required for muscle repair and also that the biological pathways these proteins are involved in are changed in people with Duchenne muscular dystrophy. The study will increase our understanding of the role of inflammation in Duchenne muscular dystrophy and could highlight new potential targets for therapeutic intervention. Although it could not address the underlying genetic defect, it could form part of a combination therapy by reducing the rate of the breakdown of the muscle and stimulating its repair and growth.

GRANT INFO Project leader: Dr Jennifer Pell University of Cambridge

Conditions: Duchenne muscular dystrophy

Duration: Two years, starting 2013

Total project cost: £124,408.40

Altering the muscle environment to influence stem cells In this project, Professor Morgan will use a mouse model of Duchenne muscular dystrophy to identify drugs and factors which could be developed to increase the ability of transplanted stem cells to repair damaged muscle. Satellite cells, the stem cells of skeletal muscle, are responsible for repairing and replacing damaged muscle. Satellite cells reside in a dormant state on the edges of muscle fibres. They are activated following muscle damage and migrate to the site of damage where they develop into new muscle cells. Researchers believe that satellite cell transplant (injecting healthy satellite cells into an individual) may one day offer a potential mechanism to treat neuromuscular conditions and Professor Morgan and her colleagues are researching ways to maximise the efficiency of the process in a mouse model of Duchenne muscular dystrophy. Using this mouse model, researchers have already discovered that treating a specific area of the muscle with radiation (like a very powerful x-ray) before transplant can improve the ability of the cells to repair the damaged muscle. However, the levels of radiation required are not safe for people with Duchenne muscular dystrophy. This PhD studentship will investigate the mechanism of how radiation improves the efficiency of stem cell transplants and aims to identify new drugs or factors that have the same effects, but without the harmful side effects. These molecules could then be used to improve the efficiency of stem cell transplants in the future.

GRANT INFO Project leader: Professor Jennifer Morgan Institute of Child Health, University College London

Conditions: Duchenne muscular dystrophy

Duration: Four years, starting 2014

Total project cost: £111,225

Identifying biomarkers for Duchenne muscular dystrophy This project aims to identify biomarkers for Duchenne muscular dystrophy. If successful, these could be used to improve diagnosis, measure the progression of the condition and assess the benefit of potential drugs in clinical trials. Biomarkers are small molecules that can be easily measured and whose levels change in line with the severity and progression of a condition. Biomarkers for Duchenne muscular dystrophy could be used to monitor the condition and measure people’s response to potential new treatments – for example in clinical trials – without painful muscle biopsies. In this project, Professor Wood and his student will examine three micro-RNAs involved in the formation of muscle tissue to see if they might be suitable biomarkers for Duchenne muscular dystrophy. Micro-RNAs are small pieces of RNA (a molecular copy of a gene) used by cells to control which genes are turned on or off. They can sometimes be found in the blood where their levels can be measured. Professor Wood believes the three micro-RNAs to be investigated are released from muscle fibres and are involved in repairing damaged muscle. This will be investigated in various models including muscle cells grown in the laboratory and animal models of Duchenne muscular dystrophy. If micro-RNA levels correlate with muscle repair, they could be suitable biomarkers for Duchenne muscular dystrophy, and possibly other neuromuscular conditions. Professor Wood and his PhD student will develop an improved laboratory method for detecting them, which could make the tests more readily available in the clinic.

GRANT INFO Project leader: Professor Matthew Wood Department of Anatomy, Oxford University

Duration: Four years, starting 2014

Total project cost: £ 110,231




The research team is always on the look-out for exciting developments in the fields of muscular dystrophies and related neuromuscular conditions. Here we bring you the latest research and clinical trial news from around the world.

Researchers find new genes which cause congenital muscular dystrophies An international team of scientists, which included Muscular Dystrophy Campaignfunded Professor Francesco Muntoni, have identified new genes that can cause congenital muscular dystrophy. This discovery will allow a precise genetic diagnosis for a greater number of people with the condition. Researchers have also started to investigate the function of these genes and these could help researchers to identify potential therapeutic avenues in the future. An international team of scientists led by Prof Muntoni in London has identified further genes that can cause congenital and limb girdle muscular dystrophies. The first new gene identified is called Guanosine diphosphate mannose pyrophosphorylase B (or GMPP for short) and carries the genetic blueprint for a protein with the same name. GMPP protein is an enzyme that forms part of the biological pathway which is needed to build a protein called dystroglycan which helps to maintain the structure of muscles. If GMPP is missing, dystroglycan cannot be built properly and cannot do its job. The researchers used a combination of techniques, including cutting-edge technology called next generation sequencing (which can read many genes quickly and cheaply) to identify mutations in the GMPP gene in eight people with congenital muscular dystrophy or limb girdle muscular dystrophy. To confirm that mutations in the GMPP gene were causing the condition and were not just a harmless “spelling mistake” in the DNA code, the team used a zebrafish animal model. When the zebrafish GMPP gene was turned off, symptoms similar to those in people with congenital muscular dystrophy were observed, including muscle damage and reduced mobility. Prof Muntoni and Muscular Dystrophy Campaign-funded PhD student Tamieka Whyte were also involved in a second recent study that identified a second gene called SGK196. Working with researchers based in Iowa and Los Angeles in the USA, they also looked in more detail at the biological pathways involved in this and mutations in two other genes (called B3GALNT and GTDC2). They found that the genes all carry the genetic blueprint for proteins that play a role in the same biological pathway that is responsible for building the dystroglycan protein. The mutations stop these proteins working properly which in turn stops dystroglycan being assembled correctly. This can cause congenital muscular dystrophies and limb girdle muscular dystrophies. The identification of these genes means that more people with a congenital muscular dystrophy will receive a precise genetic diagnosis. This is vital for individuals and families to understand their condition and to plan for the future. It may also allow families to consider the option of using new technology when planning to have children. Knowing the genetic diagnosis will allow clinicians to gather more precise information on how the conditions progress so affected individuals can gain access to appropriate care. In the longer term, this research could result in a greater understanding of the biological pathways that are involved in the conditions. Knowing more about the gene functions, and that several genes which play a role in a single biological pathway can cause the condition, may help researchers to identify potential therapies in the future.

Government to produce draft regulations for mitochondrial transfer IVF The government’s Chief Medical Officer has announced plans to draft new regulations that would move mitochondrial transfer IVF – a technique developed by Muscular Dystrophy Campaign-funded researchers – one step closer to the clinic. In a press conference in London, the Government’s Chief Medical Officer announced that the Government plans to draft regulations that would allow researchers to apply for licences from the Human Fertilisation and Embryology Authority (HFEA) to use mitochondrial transfer IVF techniques to give women with severe mitochondrial disease the choice to have healthy children. The techniques may have the potential to stop mitochondrial disease being passed on from a mother to her children. In March, a consultation showed that the public was broadly supportive of the new techniques being made available to women affected by mitochondrial diseases, and this announcement signals that the next step is being taken. The regulations being drafted will eventually allow researchers to apply for licences from the HFEA to use the technique in the clinic. Each case will require an individual licence and the Government expects up to 10 people each year to benefit from the technique. We will keep you

updated on this topic as and when we find out more. leading the way forward


Questions asked about how ataluren works An international team led by researchers from Scotland has today published a study that suggests the methods used by PTC Therapeutics to identify ataluren in their original studies were flawed. While this may reduce our understanding of the mechanism behind ataluren, the paper does not alter the encouraging results observed in clinical trials of the potential drug – where a low dose of ataluren increased the distance boys with Duchenne muscular dystrophy could walk in six minutes. Originally, ataluren was identified using a drug screen – a technique which allowed researchers to test the activity of many potential drugs quickly and easily. The drug screen identified that ataluren was able to help cells grown in the laboratory to ignore the stop signals caused by nonsense mutations. Researchers believed that this ability meant that ataluren could have the potential to treat boys with Duchenne muscular dystrophy caused by these mutations. In the new study, researchers repeated the tests of ataluren and demonstrated that the system did not work how PTC Therapeutics expected and that ataluren is not able to help cells to ignore stop signals in a gene. The researchers tested ataluren in several different ways, and in no test did it demonstrate the ability to help cells ignore stop signals in a gene. While this may reduce our understanding of ataluren and how it works, the flaw in the method used to identify ataluren does not alter the encouraging results that have been observed in tests in animal models or in clinical trials of the potential drug. In an international phase 2b clinical trial, boys with Duchenne muscular dystrophy, caused by a nonsense mutation, who received a low dose of ataluren were able to walk almost 30m further in six minutes than those who received a placebo (an inactive drug). Currently, ataluren is being tested in a larger phase 3 clinical trial which PTC Therapeutics believes will confirm the results they observed in the phase 2b trial.

Call for GNE myopathy/ HIBM patients in the UK A GNE myopathy natural history study is open for recruitment in the UK. GNE myopathy (which is also known as hereditary Inclusion body myopathy) is a rare, severe and progressive genetic muscle disease resulting from mutations in the GNE gene. Other names for the same condition are Nonaka disease, Quadriceps-sparing myopathy or distal myopathy with rimmed vacuoles. GNE myopathy leads to weakness and wasting of muscles in the legs and arms. First symptoms usually occur in young adults. Initially, increased tripping and a steppage gait are often noted because of foot drop. The condition gets worse slowly, and also leads to weakness of proximal leg muscles with difficulties climbing stairs or getting up from sitting, and weakness of the hands and shoulder muscles. However, the severity and rate of progression are highly variable even within families, but GNE myopathy often leads to disability and loss of ambulation. The team, at Newcastle University, are recruiting patients with genetically confirmed GNE myopathy over 18 years of age and residing in the UK. In this study they will assess quality of life, perform various muscle tests and analyse serum biomarkers to assess the natural progression of the disease. Participants will undertake an initial visit, with follow-ups after six and 12 months and yearly after that. Normally, the first (or baseline) visit would last for approximately two and a half to three hours. No new potential treatments (e.g. medications) or experimental treatments will be administered to any patients as part of the study. The GNE myopathy study is a part of the “GNE myopathy Disease monitoring program: A Registry and Prospective Observational Natural History Study to Assess GNE myopathy (GNE-M DMP)” which is being sponsored by Ultragenyx Pharmaceutical Inc. To find out more about the study and the eligibility criteria please contact: Professor Hanns Lochmüller ( and Dr Oksana Pogoryelova (, phone +44 (0) 191 241 86040 or you can visit the study’s website at

Using MRI to monitor progression of limb girdle muscular dystrophy 2I A team of researchers from Newcastle University has published a study which investigated the potential of magnetic resonance imaging (MRI) to monitor disease progression in people with limb girdle muscular dystrophy type 2I. Thirty-two participants with limb girdle muscular dystrophy type 2I were assessed using both MRI imaging and functional tests. These included tests of muscle function and strength as well as a six-minute walk test. By taking two sets of measurements 12 months apart, researchers were able to test how well the different tests measured disease progression. The researchers took MRI images of 14 different muscles and found that in nine of them, they could detect muscle-wasting – with muscle tissue being replaced by fat. However, the distance people could walk in six minutes did not change. This suggests that MRI may give researchers and clinicians a sensitive measure of disease progression, although it may need to be combined with functional tests to ensure that what is being measured is relevant to patients. Using MRI could potentially also give clinicians a less invasive method of examining muscle-wasting than taking muscle biopsies and could let researchers examine whole muscles, and several muscles at once – rather than a small snapshot that is seen on a biopsy. Having accurate ways of measuring disease progression is important for clinical trials, where well defined outcome measures are needed. These are signs and symptoms of the disease that if reduced by the treatment being tested, would demonstrate its effectiveness. They are often things that measurably worsen as the disease progresses. This study will increase understanding of how muscle structure changes over time in people with limb girdle 2I. This will allow researchers and clinicians to develop better ways to assess potential treatments being tested in future clinical trials.


Research news

in brief 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 published in a medical journal. After boys with Duchenne muscular dystrophy received the potential drug, production of the dystrophin protein was restored in up to 50 percent 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. The results show that eteplirsen was safe, with no serious side-effects observed in any boy in the trial. Importantly, the company’s paper has been published 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.

SMA Information Hub launched The development of a new information hub, designed to improve healthcare for hundreds of people living with a rare neuromuscular condition and to pave the way for clinical trials into potential treatments, is now underway. SMA REACH UK (SMA Research and Clinical Hub UK), backed by £300,000 from The SMA Trust, will link clinical centres across the UK focusing on Spinal Muscular Atrophy (SMA). The hub will combine and build on information held in Newcastle University’s SMA Patient Registry, funded by the Jennifer Trust and Treat-NMD, and the SMArtNet database backed by the Jennifer Trust and the Muscular Dystrophy Campaign. It will allow scientists and health professionals to share the results of scientific research, knowledge of clinical practice, symptoms and disease progression and details of patients wishing to take part in clinical trials.

Access to rare disease drugs – new campaign report launched A new campaign report was presented to Health Minister Norman Lamb MP in September by the All Party Parliamentary Group (APPG) for Muscular Dystrophy warning that people with muscle-wasting conditions could be denied cutting-edge therapies owing to drastic changes to the way drugs are funded and assessed for rare diseases. Following the APPG’s six month inquiry supported by the Muscular Dystrophy Campaign the hard-hitting report, Access to high-cost drugs for rare diseases, reveals that while potential treatments for Duchenne muscular dystrophy are in clinical trials, parents fear that treatment maybe delayed by unnecessary funding issues and bureaucracy. The MPs were particularly concerned that funds previously earmarked for rare disease drugs, have now been merged into the overall budget for NHS services commissioned across England. This leaves expensive therapies for rare conditions competing for funds with medications for more common conditions, such as diabetes or heart disease. The MPs also reported serious concerns over the approval process for new drugs used by the National Institute for Clinical Excellence (NICE), which they fear may delay cutting-edge therapies or prevent them reaching children and young people entirely.

Hello from Target MD Hello from Target MD, where our last edition of 2013 reflects some of our activities for this time of year – shopping, Christmas carol concerts, meeting up with friends and reflecting on the year gone by. Going out and doing many everyday activities on the high street often present barriers for disabled people, in the form of lack of access or, indeed, poor attitudes or discrimination. Our high street focus is close to the heart of many Trailblazers, who will be publishing a high street report early in the New Year. Read about the wonderful Christmas fare we have on offer from our online shop, including tickets for our popular Spirit of Christmas concerts all around the country. Do join us and usher in the festive season at a beautiful concert venue near you. You’ll also meet Amanda Hayes, affected by the rare condition, myasthenia gravis, who tells of the support she received from our charity to get the benefits she was entitled to. On behalf of the Target MD team, I’d like to wish you and yours a Merry Christmas and every good blessing for 2014. Thank you to all of you who fundraise, take part in fundraising events or volunteer for us in any way. We depend upon the support of people like you to fight musclewasting conditions.

Ruth Martin Editor, Target MD t: 020 7803 4836 e: tw: @RuthWriter Target MD is also available to read online: leading the way forward


Accelerating access to promising new therapies in the EU ajt/istock

Conditional approval is a new regualtory mechanism in the EU which may help pharmaceutical companies to speed up access to promising treatments for rare diseases by approximately two to three years. In this article, we find out more about the process.

Orphan therapies are defined as medicinal products intended to prevent or treat rare disorders. In 2011 alone, a record five new orphan treatments for rare diseases were approved by the European Medicines Agency (or EMA - the European drug regulator) and ten in the United States by the Food and Drug Administartion (or FDA). A number of promising orphan drugs for rare neuromuscular conditions, including Duchenne muscular dystrophy are now in the final stages of the clinical trial process and, if it can be demonstrated that the treatments are safe and effective, close to potentially applying to be licensed for use by patients in the clinic. While funding for scientific research is a crucial first step in the development of new treatments, pharmaceutical and biotech companies are required to complete a series of broad tests of safety and effectiveness for potential treatments before they can be used in the clinic, from identifying potential drug candidates, to conducting pre-clinical studies (for example in animal models) and clinical trials, the research and development process for new therapies is lengthy and complex. Once clinical trials suggest that a drug appears to be safe and effective, the pharmaceutical company must apply for marketing authorisation – another lengthy process. The lack of treatments for rare diseases has led to the setting up of new regulatory mechanisms to support accelerated patient access to potential drugs and treatments, which appear, on preliminary evidence, to be safe and well-tolerated by patients. One such regulatory mechanism in the EU is called ‘conditional approval’ which can speed up access to potential treatments by two to three years. In order to explain how the process works, it is helpful to review the research and development process that is

necessary to bring a drug or treatment to the clinic: i) after pre-clinical tests are completed in the laboratory, Phase 1 trials can begin, usually in healthy volunteers and focuses on the safety of a potential treatment, as well as something called pharmacokinetics – how drugs are handled by the body. ii) phase 2 trials test the safety and effectiveness of a potential treatment in patients with a certain condition. The trials are designed to find the correct dose to treat that condition. iii) one or more larger phase 3 trials would normally be performed to confirm the results in a large patient population and to provide further information about the effectiveness and safety of the treatment. At this stage, a pharmaceutical company could file a ‘Market Authorisation Application’ for full approval by the EMA. For potential drugs or treatments to be given ‘conditional approval’ in the EU, certain criteria must be met. There must be preliminary evidence that suggests the drug is safe and effective, a very high unmet medical need, clear benefit to public health from making the treatment available in the clinic, and a commitment by the pharmaceutical company to provide confirmatory clinical data within a reasonable time period. If the results of the phase 2 trials meet these criteria a company can apply for ‘conditional approval’ by submitting a ‘conditional marketing authorisation application’ to the EMA. Following a detailed assessment of all the results available (including pre-clinical studies and clinical trial data) the European Comission can grant a ‘conditional approval’ which enables patient access to the treatment immediately. Conditional


Conditional approval Drug on market

The routes to market for drugs for rare diseases

Makers of orphan drugs which show effectiveness and safety in early trials can apply for conditional approval if they believe they will be able to generate the data required for a full licence in the future. Conditional approval means the drug will be available on the market for a fixed length of time (between one and five years) whilst the further data is gathered. If the data confirms the drug’s effectiveness and safety, conditional approval is converted into full approval




Drug on market

Full licence

Exceptional circumstances

With treatments designed for only small groups of patients, in some cases a company would never be able to collect enough data to apply for a full licence. In these cases, drug makers can apply through exceptional circumstances. Exceptional circumstances allows the drug to be placed on the market, but an annual assessment of safety and effectiveness is made to ensure that the drug works as expected.

approval is granted for one year, with the provision for yearly renewal and the pharmaceutical company must continue to monitor the safety and effectiveness of the treatment.The EMA will also require the pharmaceutical company to commit to provide additioal study data. This is usually in the form of a completed phase 3 trial that confirms the results of previous trials. If this trial is successful, ‘conditional approval’ could be converted to a full marketing authorisation. In allowing a company to make its product available before the full clinical research programme is complete, the regulatory authorities accept the risk that further studies may show the treatment is not sufficiently effective or that there is a safety concern that was not demonstrated in the relatively small numbers of subjects and patients that characterise phase 1 and phase 2 clinical trials. Granting ‘conditional approval’ is therefore a difficult decision and is only taken if the preliminary evidence suggesting that the treatment is safe and effective is deemed to be acceptable, and if the consequences of delay in patients being able to be treated with the new medicine are serious. If conditional approval is not granted after phase 2 clinical trials, it may take two to three years or longer to complete the phase 3 trial and additional regulatory review. Families and individuals who are living with progressive and rare conditions such as neuromuscular conditions are understandably concerned about the time it takes to research, develop and approve treatments. If everything goes to plan, it typically takes 12 to 16 years to complete the various steps for treatment development and licensing in the EU. In enabling access to a medicine or treatment that appears to be safe and well-tolerated by patients approximately three years earlier,

With drugs designed to treat rare diseases it is often difficult for companies to collect enough data to apply for a full license. Large trials in many different population groups would be required – something difficult to achieve when the number of patients is limited.

the EU ‘conditional approval’ process offers a pragmatic and responsible option for individuals living with neuromuscular conditions and for their families. One example of a pharmaceutical company that is trying to accelerate patient access via the ‘conditional approval’ mechanism in the EU is PTC Therapeutics Inc. PTC submitted a ‘marketing authorisation application’ to the EMA at the end of 2012 for a potential drug called ataluren, which is being evaluated for the treatment of Duchenne muscular dystrophy caused by nonsense mutations. These mutations are spelling mistakes in the genetic code that stop dystrophin production. This type of mutation causes approximately 13 percent of cases of Duchenne muscular dystrophy. The PTC application to the EMA is based on the results of phase 2a and 2b clinical trials which included approximately 200 participants. The application is currently under review, and an EMA decision is expected before the end of this year. ‘Conditional approval’ would lead to boys with Duchenne muscular dystrophy caused by nonsense mutations in the EU having access to a promising a therapy approximately three years earlier than if patients and their families were forced to wait for the results of a standard approval process. PTC Therapeutics Inc and other pharmaceutical companies are working in cooperation with regulatory authorities and patient organisations, such as the Muscular Dystrophy Campaign, to accelerate access to promising therapies so that more people can benefit from access as soon as possible . The basis for this article was provided by PTC Therapeutics Inc following a request from the Muscular Dystrophy Campaign. leading the way forward



Andrew Johnson/istock

Biomarkers, or biological markers, are molecules or characteristics which can be easily measured and whose level is affected by a disease or condition. In the field of neuromuscular conditions biomarkers could be used to monitor the progression of a condition and to test how well an individual responds to a potential treatment, for example in a clinical trial. In this article we find out about the research aiming to identify biomarkers.


Non-invasive monitoring 1. Molecules are released by damaged muscles and enter the bloodstream. 2. The molecules circulate around the body. 3. By taking a blood sample, clinicians can measure the amount of the molecule in the blood. 4. The molecules may be removed from the blood by the kidneys and can then be detected in urine.

What are biomarkers The term biomarker is defined by the American National Institutes of Health as “a characteristic that can be objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes, or pharmacological responses to a therapeutic intervention”. But what is behind this complicated definition? Biomarkers are molecules or compounds, whose levels can be accurately measured and which reflects the severity or progression of a condition, or a response to a treatment. For biomarkers to be useful in monitoring the progression of a condition or a response to treatment they must be easy to access – ideally in a body fluid (blood or urine for example) which can be taken from the body in a non-invasive way and tests that can accurately measure the level of the biomarker in a reliable and reproducible way must be available. Although biomarkers must be easy to measure, the search for a biomarker is often not straightforward. Cutting-edge technology is now available that can identify proteins or molecules whose levels vary between people with a certain condition and healthy individuals. However, the levels of these molecules can vary in response to activity level and time after eating. To show that the level of a molecule is consistently changed, biomarkers must be validated. This involves comparing the levels of a biomarker in large numbers of people with or without a condition or in people with more or less severe symptoms of a condition. For instance a biomarker for muscle damage may need to be measured alongside clinical outcome measures to prove that the levels of the biomarker really do relate to the symptoms being monitored. Biomarkers are already widely used in some branches of medicine. For example, after a heart attack a number of different biomarkers can be measured to determine exactly when an attack occurred and how severe it was which can help clinicians offer the best treatment possible. Infections can also be monitored with biomarkers. For example, levels of a protein called C-Reactive Protein in the blood rise quickly at the start of an infection and fall as the infection is resolved or cleared. By measuring the level of C-Reactive Protein, clinicians can monitor the severity and stage of an infection by taking blood tests for routine tests in a laboratory.

Biomarkers in neuromusulcar conditions There are currently no biomarkers for neuromuscular conditions that have been properly validated for use in the clinic or to assess responses to potential treatments in clinical trials. Current clinical trials rely on clinical measures like the six minute walk test and muscle biopsies. However, not all clinicians agree that the methods are ideal. The results of functional muscle tests can depend on the state of mind of an individual and it requires time and effort to standardise the tests in different centres. A particular muscle function test may only be applicable to people at certain stages of a condition – for instance a walking test is clearly not suitable for people who use a wheelchair. If treatments were to become available, then new tests would be required to test them in these individuals. Muscle biopsies involve removal of a sample of muscle with a needle. This is invasive and painful, and taking repeated muscle biopsies should be avoided. The small muscle sample is a snapshot, and doesn’t represent what is happening elsewhere in the body. Researchers and clinicians believe that biomarkers could overcome these limitations and provide a more accurate method to monitor the responses to potential treatments in clinical trials as well to improve diagnosis and monitoring of progression neuromuscular conditions. Much research is therfore being undertaken to identify and validate biomarkers for use in neuromuscular conditions.

Using RNA as a biomarker You may have read about the new project in Professor Wood’s laboratory which aims to find out whether molecules called micro-RNAs could be used as biomarkers for Duchenne muscular dystrophy. RNA molecules are used in cells to carry the genetic messages from the genes in the nucleus to the cytoplasm where proteins are made. The molecules are a copy of the gene’s DNA and are made up of a sequence of letters corresponding to that DNA. As their name suggests, micro-RNA molecules are small versions of these RNA molecules. They are too small to carry genetic messages, but if the sequence of a micro-RNA matches part of a full-size RNA the two can bind or stick together. This can mask the sequence of the full-length RNA from the cell’s biological machinery and stop protein being produced. Regulating protein production in this way is the key function of micro-RNAs. Because the sequence of the micro-RNA must match the RNA that it regulates, each micro-RNA can only regulate a limited number of genes. To carry out their functions, different types of cells turn on a different set of genes. To regulate these genes different cell types use specific groups of micro-RNAs, which means researchers can start off by looking at micro-RNAs which may be relevant to a certain type of cell. leading the way forward


The search for biomarkers The number of biomarker studies is increasing quickly. Many natural history studies and clinical trials now ask participants for blood or urine samples which are used to identify and validate biomarkers. These samples are assessed using cutting-edge tools, which let researchers measure the levels of thousands of proteins or RNAs at once. This process generates large amounts of data, and potential biomarkers are selected by cross referencing this with the clinical trial or natural history data. Since there are so many clinical traials ongoing, the search for biomarkers has recently focused on Duchenne muscular dystrophy, and dystrophin itself. However, in healthy individuals, dystrophin is produced in varying amounts in different muscle of the body so identifying the best muscle use to test the level of dystrphin is not easy. Using dystrophin as a biomarker may also require muscle biopsies to be taken, although researchers are also testing whether certain skin cells, which produce dystrophin, could be used instead. Biomarkers that reflect the amount of utrophin levels are also being searched for. A recent trial showed that a potential drug (called SMT-C1100) which aims to increase utrophin levels in people with Duchenne or Becker muscular dystrophies was safe and well-tolerated. Further trials will test whether the drug increases utrophin production in the muscles and having biomarkers which can accurately measure this could reduce the number of biopsies needed. In spinal muscular atrophy (SMA), researchers are searching for biomarkers which could also be used to diagnose the condition before the onset of symptoms. Work in mouse models suggests that treatments for the more serious forms of SMA may need to be started early in life and, if treatments become available, these biomarkers could one day help to identify individuals where this is necessary. Research examining whether the SMN protein (which is reduced in individuals with the condition) could be used as a biomarker is ongoing, and in a recent study, researchers including Muscular Dystrophy Campaign-funded Professor Thomas Gillingwater have identified two further proteins whose levels correlate with the severity of disease in different mouse models of SMA. With biomarker searches underway, the next step will be to validate them. If this can be achieved, clinicians may one day be able to diagnose and monitor neuromuscular conditions without using invasive, painful procedures like muscle biopsies.

The Bio-NMD project, which finished earlier this year, was a European project in which twelve partners from around Europe worked together to conduct research into biomarkers for neuromuscular conditions. The project focused on three conditions where the mutations responsible are well understood – Becker muscular dystrophy, Collagen-VI-related myopathies (which include Bethlem myopathy and Ullrich congenital muscular dystrophy) and Duchenne muscular dystrophy.


Over three years, researchers taking part in the project collected and shared more than 1,000 samples from patients. These were used to identify molecules with the potential to be developed for use as biomarkers. The levels of one protein called matrix metalloproteinase-9 (or MMP9) appear to be related to progression of Duchenne muscular dystrophy and researchers are now aiming to validate this in further studies. Researchers also found a skin cell which produces dystrophin protein and hope this could be developed to monitor restoration of dystrophin expression in clinical trials. In Collagen VI disorders (which result from a lack of correctly constructed collagen protein), researchers identified a white blood cell which normally produces collagen. The level of collagen produced by these cells was related to that observed in muscle biopsies, and this suggests that blood tests could one day replace some muscle biopsies. Although the Bio-NMD project has now ended, researchers involved in the project will continue to investigate the most promising biomarker candidates, and aim to produce validated biomarkers that can be used to diagnosis and monitor these conditions and in testing the effectiveness of potential new treatments in clinical trials.


The second key property of micro-RNAs that make them suitable for use as biomarkers is the recent discovery that the molecules can be found in the blood. Researchers do not fully understand how the molecules reach the blood or what their function is: one option is that they leak out of damaged cells, but another theory is that they are released by healthy cells as messengers which can control the proteins being produced by other cells. In this new project, Prof Wood aims to investigate three micro-RNAs that are thought to regulate protein production in muscle cells. The micro-RNAs can be found in the blood of mdx mice (an animal model for Duchenne muscular dystrophy) and the researchers will now test whether levels of the micro-RNAs correlate with the progression of the condition. If this is the case, the next step would be to confirm the micro-RNAs behave in a similar way in humans. If micro-RNA biomarkers can be identified and validated, one of the major challenges for clinicians will be the accurate quantification of the levels of the molecules. Currently, this is not a standard test in hospital laboratories and requires specialised equipment. As part of the research project in Oxford, new technology and methods to measure micro-RNAs will be developed, which will be suitable for use in diagnostic laboratories or as part of clinical trials.


Prosensa and GlaxoSmithKline announce results of exon skipping trial Prosensa and GlaxoSmithKline have issued a press release about the preliminary results of their phase III clinical trial of drisapersen – a molecular patch designed to skip exon 51 of the dystrophin gene. The trial failed to prove that boys who received drisapersen could walk further than those who received a placebo. The companies will now carry out a full analysis of all their drisapesen data to try fully understand the safety and effectiveness of the potential treatment. In a press release issued in September, GlaxoSmithkline (GSK) and Prosensa announced preliminary results of their phase 3 trial of drisapersen – a molecular patch designed to skip exon 51 of the dystrophin gene - which failed to prove that the drug is effective. After 48 weeks, boys who received drisapersen could walk approximately 10m further in 6 minutes than those who received a placebo control. However, because the effects of Duchenne muscular dystrophy can vary widely between individuals, it is important to use statistics to confirm whether a small difference in the distance boys can walk is caused by the drug or by chance. Unfortunately, in this case, the statistical tests could not confirm that the difference was caused by the drug. The researchers also used other tests to measure the effectiveness of drisapersen including the NorthStar assessment (which itself includes many muscle function tests) and a 10m running test. These measures found that boys who received drisapersen performed no better than those who received the placebo. Together, the companies will now carry out an in depth analysis of all the data from all the drisapersen trials to understand the results. Whilst this is done, boys in the ongoing trials of drisapersen have stopped receiving the molecular patch, although this may be restarted if clinicians can identify individuals or small groups of boys who may benefit. Whilst news of these trial results will be disappointing for individuals and families affected by Duchenne muscular dystrophy, it is important to note that these results are not the end of exon skipping technology and only affect drisapersen. Because molecular patches are designed to target individual exons, the results as such, are not necessarily relevant to molecular patches designed to skip other exons. However, as the researchers examine all the data they have collected, they may be able to apply some of the things they learn in future clinical trials of exon skipping. Hans Schikan, the Chief Executive Officer of Prosensa, has said that the company remains committed to their exon skipping programme and whilst the data of the various drisapersen studies is analysed in more detail, the Prosensa trials testing molecular patches for other exons will continue. It should also be noted that Sarepta Therapeutics is also developing a molecular patch to exon 51, called eteplirsen, which is currently in a phase 2 clinical trial. The results of the drisapersen trial are not directly applicable to Sarepta’s work because eteplirsen is based on a different ‘chemistry’. Molecular patches are small pieces of DNA, and since DNA is quickly degraded in our bodies, it must be chemically altered to protect it from degradation. Sarepta and Prosensa use different chemical alterations (or chemistries) to provide this protection and it is not clear which will be most effective. The Muscular Dystrophy Campaign funds a broad range of research projects investigating several different technologies and techniques with the potential to treat Duchenne muscular dystrophy. Because not all clinical trials are successful, it is important to explore all potential treatments and not to focus or rely on any single avenue to treatment. By funding a broad range of research projects we can maximise the chance of developing treatments that are both safe and effective.

Is this the end of Exon Skipping? The press release that announced that the phase III clinical trial of drisapersen had failed to prove that boys who received the drug could walk further than those who received a placebo came as a real blow to the families who saw their hopes shattered. The results of the previous phase 2 study had been encouraging and there was an expectation that this next phase would confirm the data. In our communications I had always been cautious in the interpretations of results from previous clinical phases – sometimes I even wondered whether I was being overcautious. However, there is logic in the way clinical trials are designed. From a very small phase 1 study aimed at testing a drug for its safety until the phase 3 trial designed to assess its effectiveness in a large patient population, every step is essential to obtain the data that the regulatory bodies require to give market approval. Until this process is completed it is very difficult to give assurance to our families that an efficient treatment will be available. But is this the end of exon skipping? In my opinion this is not the case. The technology behind this potential treatment is sophisticated and complex and although this sad news is certainly a setback the pharmaceutical industry and the scientific community will work hard to improve exon skipping to fully explore its potential to treat this devastating condition. We welcome their commitment and the charity will continue to support research into this therapeutic avenue in the coming years.

Dr Marita Pohlschmidt Director of Research, Muscular Dystrophy Campaign. leading the way forward

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Target Research 2013 (4 of 4)  

In the latest edition of Target Research (issue 4 of 4, 2013) you'll read about our new research projects, which have all been assessed thro...

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