PTC124 "Daily Pill for Duchenne" - Research summary

Promising results were published this week (23 April 2007) in the science journal “Nature” about the safety and efficacy of a drug which has the potential to develop into a treatment for 10-15% of boys with Duchenne muscular dystrophy. This summary provides an overview of that research and answers some key questions.

Contents:


An overview of the PTC124 research

The Nature article reports that the drug, called PTC124, was found to significantly restore the production of full-length dystrophin and muscle strength in a living organism. The article describes the results of experiments in which PTC124 was tested in human cell culture and an animal model for Duchenne muscular dystrophy.

A genetic condition can arise due to a mutation in a gene which carries the information needed for cells to produce a fully functioning protein. In the case of Duchenne muscular dystrophy the condition is caused by a number of different mutations in the dystrophin gene, one of which is called a “nonsense mutation”.

Nonsense mutations do not only occur in Duchenne muscular dystrophy, but are also found in other genetic conditions, like cystic fibrosis. These nonsense mutations prevent the cell’s production machinery from accessing all the required information stored in a gene. This results in the production of a shortened, non-functional protein – the production of the protein is stopped before it reaches its full length.

PTC124 binds to components in the cell’s production machinery called ribosomes and “convinces” them to ignore the early ‘stop’ signal, so that a complete, functional protein is produced. The drug will not repair the genetic error and therefore will need to be taken throughout the life of a person affected by the condition.

The article published in ‘Nature’ describes the results of experiments where PTC124 was given to mice carrying a nonsense mutation in the dystrophin gene. The researchers found that full-length dystrophin production was partly restored which was associated with increased muscle strength. The article also states that the drug has no effect on the production of other proteins in the body, which was an important safety issue.

About 10% to 15% of boys with Duchenne muscular dystrophy carry a nonsense mutation which changes the information in the DNA into a stop signal. For these boys the drug could present a potential treatment, but for the majority of boys with Duchenne muscular dystrophy, whose condition is caused by different mutations, the drug would not be suitable.

PTC Therapeutics, the drug company behind the technology, has also published results of phase-I clinical trials in which the safety of the drug was tested on 62 healthy volunteers. They found that the drug was generally well tolerated and was safe enough to be taken to the next stage. Currently a phase-II clinical trial is in progress in the United States and 22 boys with nonsense mutations aged between 5-12 years old are participating in this study. The clinical trial was designed to last eight weeks during which two different doses of PTC124 were tested. Muscle biopsies were analysed before and after the drug was given to evaluate the effect on dystrophin production in addition to further chemical and functional tests.

The results of this phase-II trial have not yet been published, but are expected shortly. If the results of the phase-II clinical trial are positive, a phase-III clinical trial will be performed to evaluate the effects of the drugs in a larger number of patients. The results of the phase-III trial must also be positive before the drug could be licensed as a treatment.


Quotes from researchers and clinicians about this research

“The findings described in the Nature article by Professor H. Lee Sweeney and colleagues are encouraging, particularly in the light of the clinical studies which are being carried out in the United States. This drug appears to have the potential to become a treatment in the longer term for some people with Duchenne muscular dystrophy. The Muscular Dystrophy Campaign is looking forward to the publication of the full results of these clinical trials so that we can see more clearly what the prospects and possible timescales are for treatment.
Dr. Marita Pohlschmidt, Director of Research, Muscular Dystrophy Campaign

"This is an incredibly exciting new drug, which has the potential to add decades to patients' lives. In Scotland, we have already increased life expectancy of patients from late teens to late 20s. This drug is one of many new treatments which could help us improve that even further."
Dr Douglas Wilcox, senior lecturer and honorary consultant in medical genetics at Glasgow University

"It will be very important to see if this exciting new drug can be used safely and effectively in the clinic. But PTC124 or similar products could only ever be a small part of the solution as the vast majority of cystic fibrosis patients have a different type of mutation from the rare nonsense mutation which is specifically targeted by this class of compounds."
Professor David Porteous at Edinburgh University, a researcher specialising in cystic fibrosis

Questions and answers

Q: When will a treatment be available?
A: This is a very difficult question to answer. The results of the preclinical and clinical studies published so far look encouraging and if PTC124 lives up to its promises then the drug could be licensed in the coming years. However, it is important to understand that a clinical trial is not a guarantee for a treatment, but rather a way to find out whether it works in a human being.

It is therefore important to find out exactly what the effects of PTC124 are on the production of full length dystrophin and the restoration of muscle strength in boys with Duchenne muscular dystrophy before one can make any predictions about the prospects and timescales for a treatment.

Q: Will all boys with Duchenne muscular dystrophy benefit from this new drug?
A: PTC124 would only be suitable for about 10-15% of boys with Duchenne muscular dystrophy. In the majority of cases the drug will not be effective. This is because it can only treat those boys who have a “nonsense” mutation which tells the cell’s protein-producing machinery to stop prematurely. Nonsense mutations can be found in other genetic diseases such as cystic fibrosis and in the case of Duchenne muscular dystrophy the machinery produces a shortened, non-functional dystrophin protein. In order to find out if an affected boy would benefit from taking PTC124, a genetic test is required to identify the specific genetic mutation.

Q: How can I get involved in clinical trials?
A: Clinical trials for PTC124 are currently performed in the United States and the charity is not aware of any immediate plans for clinical trials in the UK. A clinical trial is a series of studies designed to test the safety and efficacy of a drug or a treatment. A phase-I study in healthy volunteers has already been completed for PTC124 and the results indicate that it is safe for human beings to take the drug. The efficacy of the drug has also been tested in boys with Duchenne muscular dystrophy who carry nonsense mutations, but the results have not yet been published.

PTC Therapeutics (the company developing the drug) has indicated that the outcome of the phase-II study is promising, but it is important to understand the detailed results of this study before making any predictions about moving into the next phase. The next step, a phase-III study, will include more boys will be included, possibly also from countries outside the US.

To participate in a clinical study like this, it is important to know the specific genetic mutation which is causing the condition. Parent Project UK  has established a database which holds the genetic information of boys with Duchenne. The registry represents a source for enrolling boys into clinical trials and if you are willing to participate in a clinical trial it is advisable to put your name down. It is also important to let your clinician know that you are willing to take part in a clinical trial.



Update: 4 May 2007 - interim Phase 2 results in boys with Duchenne

Update: At the annual meeting of the American Academy of Neurology on 4 May 2007 PCT Therapeutics presented interim Phase 2 results of PCT124 in boys with Duchenne Muscular Dystrophy due to a nonsense mutation. The trial has been conducted at three different centres in the US and the company claims that overall the results are positive.
In this Phase 2 study three cohorts of boys have received three different dose levels of PCT124 over a period of 28 days. The two lower dosage groups (26 patients) have been analysed and the results show that treatment with PCT124 is associated with increased production of dystrophin in the muscle and a reduction of the creatinine kinase levels in the blood in at least 50% of evaluated boys. The analysis of the higher dose level is still ongoing. Several parents and teachers also reported that boys treated with PCT124 showed improvements in their activity level and increased endurance.

The MDC Research Team will continue to monitor developments and will provide updates when new information becomes available.


Further information and links

The magazine, 'Nature', (www.nature.com) is subscription only so the original article is not freely available. The article itself is written in medically technical language with no summary in layman's terms. You might like to take a look at news articles in The Times or BBC News.

About Duchenne muscular dystrophy
For more information about this condition, go to our information pages.

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We hope you found this information useful. The Muscular Dystrophy Campaign’s research department hopes to help the general public, particularly those living with muscle disease and their families, understand the implications of research into these conditions. If you have any comments about this summary, please click here to contact our research department.