Dr Jeremy Chataway is a consultant neurologist at the National Hospital for Neurology and Neurosurgery in London and has been involved in MS research for many years, most recently into the effects of simvastatin on progressive MS. He’s now leading on the MS-SMART trial, looking at the effects of three drugs which are already used for other conditions on people with secondary progressive MS. The trial is recruiting throughout 2015. Dr Chataway spoke to Open Door about the state of progressive MS research, and the promise of his current research
At a recent MS conference, Dr Robert Fox said that within 10 years he thinks we will be able to treat progressive MS in the same way we can now treat relapsing MS.Do you agree?
I certainly think it’s a golden time. Over the years, the MS community has achieved a number of drugs that control relapse rate, ultimately quite effectively. That has allowed everyone’s attention to fully move onto what was always the major problem: progressive MS, in whichever form that progression is. And we have a developing pipeline of drugs which I hope will come through and will hopefully prove themselves in final phase trials. I would say that it’s a different time from previously.
Why has there been so little research into progressive MS until relatively recently?
I think there are a number of reasons. The relapsing phase is the inflammatory phase, which has always responded to steroids. So we knew roughly what type of drug we’d need to control the relapse rate or the inflammatory state. Our dozen or so drugs are, if you like, more advanced derivatives of that. The fundamental biology and mechanism of the inflammatory stage is much better known. Whereas in progression it’s still fairly rudimentary, and I think a major piece of work does have to be done. As we understand the biology more, that will allow us to obtain more and more drugs that have an effect on the progressive phase.
Why are you choosing to look at drugs that are already available?
A big piece of work was done, primarily by the Edinburgh group, looking at all reports of all drugs that could have a role in progressive MS, but which also could have some synergistic effects on other degenerative conditions – for example, Alzheimer’s or Parkinson’s or motor neurone disease. A big sweep was carried out, and it boiled down ultimately to about seven drugs. It just so happens that a number of these drugs are what we could call ‘repurposed’, that is, they’ve been used in other conditions but we think they have a common pathway or mechanism which will allow them to be helpful in progressive MS. And the advantage of these sorts of drugs is that we know a huge amount about them.They have been tried in normal medical practice in millions and millions of people, so their safety profile is very well understood. So that’s how it came to be that we are trialling three repurposed drugs.
What makes you think they might be effective in MS?
Research into small groups of people, particularly following detailed MRI scans, have shown that there’s a good signal or hint of effect. The MS-SMART trial allows us to ramp up the number of people taking the drugs by a factor of 10. This means we can look in a much more detailed way at scans, other investigations and also the effect of the drug on the actual person. For example, amiloride, which has been looked at extensively by the Oxford group, seems to block a particular calcium channel in the brain, and we think that this could be helpful at this stage of the disease. When they did their work they showed that applying that drug to a group of people with progressive MS reduced the rate of brain shrinkage in particular parts of the brain. That’s the primary effect we’re after. Can we reduce the rate of brain shrinkage, or atrophy, which occurs in MS a little bit more than normal? We know that that’s related ultimately to disability or how the person is.
What are the advantages of trialling three drugs in parallel?
We spent a huge amount of time over a five year period working with a variety of experienced statisticians, trying to develop more efficient trial designs. Because unfortunately if you do it one by one by one we’ll be here for a long time. So what we’re trying to here is have three bites of the cherry. There are three active drugs: A, B and C and a dummy drug. And a person is ‘randomised’ as they call it, to one of those four arms. So in this way we can look at three drugs simultaneously and see if there’s an advantage over the dummy drug.
This model has been used very successfully in oncology. It’s quite a standard approach in cancer work, and of course they’ve been immensely successful. So we’re trying to borrow from a successful model and apply it into neurological science, into a very difficult part of the arena. We hope this will be the first of many attempts to do this kind of work.
How long will recruitment last?
Recruitment will take place through 2015. So we have 440 places in the trial, and they will be recruited from 10-15 sites in England and Scotland over this one year period. People are in trial for two years. The last patient recruited on New Year’s eve 2015 will be in trial for two years after that, which will take us to end of 2017. And the analysis will take a good six months after that. So we would hope to begin reporting results in 2018.
If the trials are successful, how long until treatments are available?
I think it depends on the extent of the results but I think if we see positive results it tells us a number of things. It first of all illuminates what’s going on in MS. If a particular drug is successful then it must be interacting in a part of the process that’s important in progressive MS, and turning it down or switching it off. So it will illuminate understanding, and then we would have discussions with the regulatory authorities on how to take it forward. And that’s a complex process, and licensing and labelling is very much a discussion in progress. It would need to go to a final individual disability led stage.
Is the process made more complicated by the fact that the drugs are already being used for other conditions?
This is a very interesting point and it’s starting to be debated. It does and it doesn’t. If a drug is owned by a drug company, they would own the licence to that, and they would fund the research and development programme. But then when the drug becomes available it would have a certain cost attached to it – and that may be a considerable cost. That’s the traditional model for a drug that’s owned by a pharma company. Here we have repurposed drugs that are generally out of patent and are being tried for a different indication in this phase 2 trial. So then I think there’s an evolving discussion about how to handle these drugs if they are found to be, or show good hints of being, effective in their trials. That’s an ongoing discussion with the regulatory authorities.
Take part in the MS-SMART trial
If you’re interested in taking part in the MS-SMART trial visit www.ms-smart.org
Trial participants should
- have secondary progressive MS
- be able to walk at least 20 metres (with the support of two crutches) or up to 500 metres without help
- be age 25-65 (inclusive)
You can’t take part if you are currently taking a disease modifying treatment for MS or if you’re taking an SSRI anti-depressant.
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