Utrophin drug shows promise for Duchenne and Becker muscular dystrophies

Published Date
Kristina Elvidge

Research part-funded by the Muscular Dystrophy Campaign has shown the ability of a drug to dramatically reduce muscle weakness in mice with Duchenne muscular dystrophy. The drug – SMT C1100 – increases the amount of a protein called “utrophin” in the muscles. This protein may be able to substitute for the dystrophin that is missing in boys with Duchenne muscular dystrophy. This is the first time that detailed evidence of the potential of this drug has been released. A phase 1 clinical trial of SMT C1100 has already been conducted and unfortunately it was not efficiently absorbed into the bloodstream. Summit plc is currently working to reformulate the drug so that it can be tested in another clinical trial.

Duchenne muscular dystrophy is caused by mutations in the dystrophin gene. This gene contains the instructions for making dystrophin protein which acts as a shock absorber to prevent damage when the muscle contracts. It is thought that utrophin, a protein naturally present in our body in small amounts, may be able to compensate for the lack of dystrophin in boys with Duchenne muscular dystrophy since both proteins are structurally similar and appear to have very similar functions.

Prof. Dame Kay Davies’ laboratory at the University of Oxford has been researching utrophin for more than 20 years. In recent years, in collaboration with Oxford biotechnology company Summit plc, they have been searching for drugs that can increase levels of utrophin in muscle. This new paper presents the results of testing the most promising drug candidate so far – SMT C1100 – in three independent laboratories in Oxford, Italy and the USA.


What did this research show?

The first hurdle was to prove that the drug was capable of increasing the levels of utrophin in muscle. SMT C1100 was shown to effectively increase the levels of utrophin in muscle cells from a boy with Duchenne muscular dystrophy grown in a Petri-dish in the laboratory. A mouse model of Duchenne muscular dystrophy was also treated with the drug orally once per day. The mice had significantly increased utrophin levels in their muscles. Importantly, the drug was also active in the heart – a muscle that is notoriously difficult to treat by other methods such as exon skipping.

The next challenge was to prove that the increased levels of utrophin were of benefit to the mice. The mice were treated with SMT C1100 for four weeks and the health of their muscles compared to untreated mice. The muscles appeared to be healthier when viewed under a microscope, with less inflammation and scar tissue (fibrosis). The amount of creatine kinase in the blood was also reduced.

Importantly, the treated mice also had stronger muscles that didn’t tire as easily. After treatment with SMT C1100 the mice were able to run about 50 percent further before they got tired, for example 150 metres compared to 100 metres. This was a similar improvement to that seen when the mice were treated with prednisolone, the steroid commonly taken by boys with Duchenne muscular dystrophy. Remarkably, when the mice were treated with both SMT C1100 and prednisolone, fatigue was almost completely prevented and the mice were able to run 3.5 times further than with no treatment at all, for example 350 compared to 100 metres.

What does this mean for patients?

Increasing levels of utrophin could potentially be a treatment applicable to all boys with Duchenne and Becker muscular dystrophy, regardless of their type of mutation. This research, verified by three independent laboratories, shows the potential benefits that SMT C1100 could have for the muscles.

Importantly, the drug was also active in the heart, which has proven to be a difficult organ to treat with other strategies such as exon skipping. It is essential that the heart is treated because as boys with Duchenne muscular dystrophy get older serious heart problems develop.

SMT C1100 has already been tested in a phase 1 clinical trial by pharmaceutical company BioMarin. They tested the drug in a small number of healthy volunteers and there were no safety concerns. However, the results of the trial – announced in August 2010 – were disappointing because it was concluded that insufficient amounts of the drug were being absorbed into the bloodstream and reaching the muscles. However, this isn’t an unusual result for a phase 1 trial and drugs often need further development before they can continue in clinical trials. Summit plc is currently working to reformulate the drug so that it can be tested again in clinical trial.

Professor Dame Kay Davies of Oxford University, who led the research said:

These are the most stringent tests we have and mean that there is more chance of achieving the same benefits in humans. We’ve shown that the drug can dramatically reduce muscle weakness in mice. These results give us everything we need to go forward into initial clinical trials in humans.

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

The Muscular Dystrophy Campaign has supported this line of research in Professor Davies’ lab from the start and it is fantastic that it is now coming to fruition. Many of the treatments currently being developed are very personalised and can only be used for a subset of patients. However, this approach of raising the activity of the utrophin gene could potentially be of significant benefit to all individuals with Duchenne and Becker muscular dystrophy. This would be a huge advantage and we look forward to hearing how well an improved formulation of the SMT C1100 drug does in the next clinical trial.



Background information

Research on utrophin by Prof. Dame Kay Davies at the University of Oxford, has been funded by the Muscular Dystrophy Campaign for more than 20 years. They discovered the utrophin gene in 1989 and the team then developed a mouse model to study utrophin function and understand how the gene is controlled.

The knowledge gained from these studies on the utrophin gene was used to search thousands of chemicals for those that would increase the levels of utrophin in muscle cells (in collaboration with Oxford biotechnology company Summit plc). At Summit plc these chemicals were modified and improved until a final candidate – SMT C1100 (now also known as BMN 195), was chosen for further testing and eventual use in clinical trials.

Summit plc signed a multi-million dollar deal with US pharmaceutical company BioMarin in July 2008 to take this chemical to clinical trials. In August 2010 BioMarin announced disappointing results from the Phase I clinical trial of “BMN-195” and halted development of the compound. BioMarin are now pursuing alternative drug candidates which may be ready for clinical trial in the near future. Meanwhile Summit plc is working on reformulating SMT C1100 so that it is better absorbed into the bloodstream.

Further information and links

The Muscular Dystrophy Campaign continues to fund this important work on utrophin. Read about the utrophin upregulation project.

More information about Duchenne muscular dystrophy.

Comment or ask a question about this research on TalkMD forum.

Read the coverage on the BBC website.

Watch a video of Prof. Dame Kay Davies talking about her research on YouTube.

The full original paper published in the free access journal PLoS One. The article is written in technical language with no summary in layman’s terms. The reference for the paper is:

Tinsley J.M. et al. Daily treatment with SMTC1100, a novel small molecule utrophin upregulator, dramatically reduces the dystrophic symptoms in the mdx mouse. PLoS One, 4 May 2011.

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