Monday 28 March 2011
Prosensa publishes encouraging Duchenne exon skipping trial results
Prosensa has published results of their phase 1/2 clinical trial of exon skipping for Duchenne muscular dystrophy. The trial tested a drug which could potentially be used to treat the 13% of boys with Duchenne muscular dystrophy who have a mutation in the region of exon 51 of the dystrophin gene. The drug was generally well tolerated, even after 12 weeks of continuous treatment. Most of the boys produced new dystrophin protein in their muscles after the initial five weeks of treatment and there was a small increase in their average walking ability after the 12 week extension study. However, the results of such a small study need to be interpreted with caution. These results are encouraging and bode well for the phase 3 trial that is already underway to more thoroughly test the effectiveness of this drug in more boys with Duchenne muscular dystrophy.
Exon skipping involves short strands of DNA, known as "antisense oligonucleotides" (AOs) or "molecular patches" which can restore production of the protein dystrophin (which is missing in Duchenne muscular dystrophy). Read more about how exon skipping works.
A molecular patch, called PRO-051, has been developed by Dutch pharmaceutical company Prosensa. This drug is designed to bind to a particular section of the dystrophin gene (exon 51) and could potentially be used to treat the 13% of boys with Duchenne who have a mutation close to this section of the gene. Prosensa conducted the initial clinical trials of PRO-051, starting in 2006 in Europe. This new paper reports on the results of the most recent of these trials which involved body wide treatment with PRO-051 by injection under the skin. These results were used as the basis for the phase 3 trial that is now underway, but they have only just become publically available.
- What happened during the trial?
- What were the results of the trial?
- What does this mean for patients?
Twelve boys with Duchenne muscular dystrophy in the Netherlands, Belgium and Sweden between the ages of five and 16 participated in the study. They were divided into four groups of three, with each group receiving a different dose of the drug. They received the injections once a week under the skin on their abdomen for five weeks. It was a dose escalation study which means that the lowest dose was given to the first group of boys; if this was safe they started treating the group receiving the next highest dose and so on up to the highest dose.
The study then went into an extension phase where all of the 12 boys received the highest dose of the drug for 12 weeks.
The main aim of the study was to assess the safety of PRO-051. No serious side effects were reported during the trial, with the most common reactions being mild to moderate irritation at the injection site. Tests on the boy's urine indicated that the drug may be slightly affecting kidney function.
Muscle biopsies were taken two and seven weeks after the initial five-week dose escalation study. Analysis of these biopsies found that new dystrophin protein was produced in 10 out of the 12 boys. The most dystrophin was made by those receiving the highest doses.
The distance the boys could walk in six minutes was used to measure any improvement in muscle function by the end of the 12 week extension study. Before the trial, the boys could walk on average 384 metres and by the end of the trial this average had increased by 35 metres to 419 metres.
The results of this clinical trial are encouraging and bode well for the phase 3 trial that has already begun. Importantly, even with 12 weeks of continuous treatment the drug was generally well tolerated, and none of the 12 boys withdrew from the study. There was some indication that the drug may be slightly affecting kidney function, so this will need to be closely monitored in the phase 3 trial.
There was a small increase in the average distance the boys could walk in six minutes after the 12 week extension study. This is encouraging because the walking ability of boys of this age with Duchenne muscular dystrophy would normally decline. However, the results need to be interpreted with caution because of the small number of participants in the study and it was not placebo controlled.
The pharmaceutical company GSK has now bought a license to PRO-051 from Prosensa to allow them to develop and market it. They renamed it GSK2402968 and have started three clinical trials, including a large international phase 3 trial (please see further information and links below).
The phase 3 trial will test the drug in more boys for a longer period of time - they aim to treat 180 boys for 48 weeks. This trial is placebo controlled - participants will be randomly assigned to either the treatment group or the placebo group and neither the participants nor the clinicians will know who is receiving the placebo. This trial will give more concrete evidence of the effectiveness of exon skipping and if successful GSK will be able to apply to the regulatory authorities to make the drug widely available.
Exon skipping has the potential to treat over 80% of boys with Duchenne muscular dystrophy and molecular patches to treat mutations other than those around exon 51 are now being developed. Skipping of exon 51 is also being trialled by the company AVI Biopharma using a chemical formulation of molecular patch that differs slightly from that used by Prosensa. Read about the AVI Biopharma preliminary clinical trial results.
Comment or ask questions about this research in the TalkMD forum
Clinical trial summaries for exon skipping:
- Phase 3 study of the effect of a drug to skip exon 51 (GSK2402968)
- Testing the safety of a drug to skip exon 51 (GSK2402968) in boys who are unable to walk
- Investigating two doses of a drug to skip exon 51 (GSK2402968)
- Phase 1/2 study investigating the skipping of exon 44
The full original paper was published in the New England Journal of Medicine and is available to read online. It is written in technical language with no summary in lay terms:
- Goemans NM et al. Systemic administration of PRO051 in Duchenne's muscular dystrophy. New England Journal of Medicine. 2011 Mar 23.
Read about the exon skipping research we fund:
- Dr Matthew Wood - Improving exon-skipping for Duchenne muscular dystrophy
- Prof. Kay Davies - Optimization of "molecular patches" to restore dystrophin production in boys with Duchenne muscular dystrophy
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