Duchenne Muscular Dystrophy – the latest research and clinical trials
20 Nov 2012 by Evoluted New Media
Nick Catlin, Founder and Head of Research at charity Action Duchenne, explains the condition Duchenne Muscular Dystrophy and gives an update on the various research and clinical trials that are currently running
Duchenne Muscular Dystrophy (DMD) is an incurable muscle wasting disease affecting 1 in every 3500 male births in the UK. Duchenne is the most common and severe form of muscular dystrophy, and is the most common genetic childhood killer disease. It is caused by a genetic variation in the dystrophin gene. In every town and every city in the UK there will be at least one boy or young man living with Duchenne.
Since 2003 Action Duchenne has provided £4m for research projects and partnerships. The charity has worked with the MDEX consortium, Department of Health, and the Medical Research Council to deliver new clinical trials for Duchenne drugs. In addition, it has been instrumental in developing projects with biotech companies both in the UK and US including key projects with Sarepta (previously known as AVI Biopharma) and Summit.
There are high hopes for the upcoming market approval of small drugs that are able to provide a genetic treatment for DMD by introducing a functional dystrophin protein into muscle cells. Leading the field in terms of advanced clinical trials are Antisense Oligomers (AO) developed by GSK, Prosensa and Sarepta and with a novel drug Ataluren developed by PTC Therapeutics. These molecules aim to trick the RNA splicing mechanism to produce a functional dystrophin protein, using a technique known as exon skipping.
Action Duchenne’s skipDuchenne campaign (www.actionduchenne.org/skipduchenne) and funding programme will aim to ensure that the 83% of patients in the UK with DMD that can benefit will have immediate access to exon skipping drugs within the next 3-5 years.
For those young people who are unable to benefit from AOs, skipDuchenne proposes an alternative strategy using gene replacement delivered via vectors.
DMD is caused by mutations in the dystrophin gene that leads to a failure to produce a functional muscle protein called dystrophin. Dystrophin acts as a "coat hanger" for a number of proteins in a complex that provides stability and healthy cells. Cell instability and death will occur when this complex of proteins is misplaced or missing.
There have been many laboratory studies in DMD animal models over the last ten years that have shown that by using small molecules called antisense oligomers that target specific regions of the faulty gene a shortened dystrophin protein can be expressed in muscle cells. In the related condition Becker Muscular Dystrophy such a shortened protein can restore the dystrophin complex and muscle function to near normal levels in many cases.
Human studies are now underway targeting the exon 51 region of the gene and have shown to be safe and also to successfully express a shorter dystrophin protein.
GlaxoSmithKline and Prosensa are currently conducting extensive Phase 2b and Phase 3 trials for exon 51 in ambulant and non-ambulant patients and the full data set could be available for 2014. Prosensa has been developing further studies in other exons: Exon 44 Phase 1 study, Exon 45 and 53 to start in the next wave, 52 and 55 in another wave.
Sarepta is continuing with exon 51 human trials in the USA with an alternative AO chemistry that will build upon encouraging data already published by the UK MDEX consortium. Sarepta also has under consideration other exons 53, 45, 44 and 50. Further studies are planned with the new international exon skipping consortium.
It is therefore conceivable that if all continues to go well that within the next two years there will be sufficient data available to bring the first genetic treatment for DMD using exon skipping technology to the market.
Duchenne is the most common and severe form of muscular dystrophy, and is the most common genetic childhood killer disease.AOs can potentially restore the reading frame of 83% of Duchenne patients (Treat NMD 2009). Professor Steve Wilton has gone on to show that it is possible to sequence every single exon skip required to treat 83% of patients with a relevant AO. (Wilton et al 2007).
75% of patients have a deletion that occurs in the hotspot region between exon 43 and 55. Skipping the top 10 exons; 51, 45, 53, 44, 46, 52, 50, 43, 6 & 7 would restore dystrophic expression for >40% of all patients (Rus et al 2009).
Parents and patient organisations have so far backed the strategy for completing trials that will give compelling evidence for the use of one exon (exon 51).
[caption id="attachment_30920" align="alignleft" width="200" caption="Figure 2. Human studies are now underway targeting the exon 51 region of the gene"]
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PTC Therapeutics had announced recently that it is undertaking a Phase 3 study in a number of US and European Centres to further trial its drug Ataluren. This drug targets a small sub population of Duchenne patients that have single base pair gene variations in the gene. Even a single point variation can result in an out of frame mutation resulting in no dystrophin. It is proposed that Ataluren acts by skipping over this tiny mutation to produce functional dystrophin.
Other exon skipping programmes are also underway using other chemistries and while not yet at the human clinical trial stage offer real promise for near future application. These include conjugated AOs developed at Oxford and Cambridge. The Oxford and Cambridge teams have won grants from Wellcome and MRC to continue the work first established with Action Duchenne funding. PNA chemistries are under investigation and Action Duchenne has funded projects in the UK and China.
For those young people who are unable to benefit from antisense oligomers skipDuchenne proposes an alternative strategy using gene replacement delivered via vectors. There is animal data to show that this method of delivery using AAV vectors could replace the faulty gene with a gene that could either promote exon skipping (AAV U7), replace the gene with a mini gene or use a combination of vectors to restore the full gene at the membrane.
Action Duchenne is already funding research in this promising area of gene delivery with Royal Holloway University of London. The skipDuchenne research project will build upon this and other research and aims to bring a genetic treatment to those patients unable to benefit directly from AO exon skipping in the next five years.
Professor Kay Davies at University of Oxford has pioneered an approach to develop an effective therapy for DMD through increasing the amount of the dystrophin-related protein utrophin in muscle. Utrophin is a protein that is present in muscle cells at the junction where the nerve meets the muscle cell.
It has already been shown that utrophin can functionally replace dystrophin in the mouse and dog models of the disease. Up-regulation of utrophin has the advantage of being applicable to all patients as it is not mutation dependent. Furthermore, a small molecule, orally administered drug can be more easily delivered to all affected muscle types including heart and diaphragm, and would not require the use of an immunosuppressant.
The current clinical trial programme for assessing the efficacy and safety of exon skipping AOs follows the well-established pathway of development. This involves the familiar phases of trial development through preclinical, phase 1, 2 3 and 4 to drug marketisation. However, Action Duchenne, along with many others involved with the development of genetic medicines question if this framework is now fit for purpose for a rare disease like Duchenne?
Duchenne patients do not present as a homogenous group. Every child will have as a starting point a different dystrophin gene variation that has an impact on the clinical symptoms of the disease. Every Duchenne patient will have polymorphisms in all manner of other genes that may impact on the progression of the condition. Crucially every child will be exposed to a complex array of environmental, class and cultural factors including diet, housing, education, parental expectations and known medical interventions and support.
[caption id="attachment_30921" align="alignright" width="200" caption="Figure 3: Utrophin is a protein that is present in muscle cells at the junction where the nerve meets the muscle cell"]
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The slow and expensive clinical trial programmes for drug development for Duchenne are not just frustrating families, they are not giving us the data we need.
Rather than rejecting N=1 experiments, Action Duchenne believes that the answer lies in using as a starting point existing N=1 knowledge and patient data of every intervention and clinical assessment for the life of a single patient. New medicines can then be tested for safety and long term efficacy for an individual patient irrespective of their genome or current treatment regime. The research teams’ job would then be to data mine all patients taking that new drug over an extended period and begin to tease out patterns of medical interventions or genomic suitability that would seem to be working most effectively across the whole Duchenne community. We need to radically rethink clinical trial protocols for Duchenne and we need a database that holds the medical life history of a patient. The embryos of such databases do exist in the UK. The DMD Registry and North Star database have been great examples of beginning to collect this information for individual patients. Frustratingly in the UK we do not have a database in the NHS that could do this for every intervention for every patient despite massive expenditure on NHS IT infrastructure. However, this is an idea supported by clinicians such as Sir Gordon Duff in his Lancet article.
Clinical experiments therefore become integral to a patients treatment regime. Also by designing trials that start at Phase 3/4 or 4 in this way also offers the potential for biotech companies to gain conditional market approval for a medicine while under extensive trial. This could be a real incentive for smaller biotech companies to recoup R&D revenue and support further development. Such trials should be driven by risk management not a slavish adherence to existing phased protocols.
Clinical trials could be seen as part of the clinical management process of every Duchenne patient, and this would be a marked improvement over the current system.
The author: Nick Catlin
Nick is founder and Head of Research of charity Action Duchenne. The charity was set up by Nick and his partner Janet Hoskin and other Duchenne families in 2001 to support and promote innovative research into a cure and effective medicines for Duchenne Muscular Dystrophy. Nick and Janet have a son Saul, aged 11 who has Duchenne.
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