Thursday, 11 October 2012

ECTRIMS MS-STAT Trial. A treatment for progressive MS

J. Chataway, A. Alsanousi, D. Chan, D. MacManus, K. Hunter, J. Foster, C. Bangham, D. Wilkie, J. Nicholas, S. Clegg, C. Nielsen, N. Scheurer, V. Calder, J. Greenwood, C. Frost, R. Nicholas. The MS-STAT trial: high dose simvastatin demonstrates neuroprotection without immune-modulation in secondary progressive multiple sclerosis (SPMS) – a phase II trial

Background: Statins are widely used and well tolerated for the treatment of hyperlipidemia and have reduced cardiovascular morbidity and mortality. In addition, they have multiple effects on the nervous system, both anti-inflammatory and neuroprotective, that include increasing endothelial nitric oxide synthase activity, reducing excitotoxicity and augmenting remyelination. 

Objectives: To assess whether high dose simvastatin can slow the rate of whole brain atrophy, and/or disability in secondary progressive multiple sclerosis SPMS. 
Methods: In a double-blind, placebo-controlled phase II trial, 140 patients, with evidence of progression for 2 years prior to enrolment, EDSS 4.0-6.5, 6 months off disease-modifying treatment, were randomised in a 1:1 ratio, to 80mg simvastatin (40mg first month) or placebo for 2 years. Primary outcome was the rate of whole brain atrophy per year, measured using brain boundary shift integral (BSI). Secondary outcomes included Expanded Disability Status Score (EDSS), new or enlarging T2 lesions, relapse count and adverse event profile. 
Results: 140 patients were randomised as planned (70 per arm), with 9 patients lost from final follow-up. Cohort demographics: 70% female, age 51 yrs (mean), duration of MS 21yrs, and SPMS 7 yrs. Baseline median (IQR) EDSS 6 (5.5 to 6.5). The simvastatin group had a statistically significant benefit over the placebo group for the EDSS at 2 years: difference -0.246; 95% CI: -0.453 to -0.064). There was no difference in relapse rate or T2 lesion activity between the arms. At the time of abstract submission, the BSI data is not available, but will be presented at the meeting 
Conclusions: This trial, in actively progressing SPMS demonstrates a positive effect on clinical disability and a putative neuroprotective role. No anti-inflammatory effect was seen. A phase III trial is warranted. ClinicalTrials.gov, number NCT00647348


                 Statins must be working on something else

Team G started working on statins with Prof. John Greenwood (one of the authors above), who came up with the idea that statins may be useful for MS, many years ago. At that time we thought that statins may control blood brain barrier dysfunction (See figure), some other guys in the USA thought it was cytokine control, fitting the dogma of the time

This appears not to be the case as the drug does not seem to be affecting the relapse rate, although there is some support for this from other studies. Importantly in the context of this study my fear of disease worsening in progressive MS has not being realized.  What did I mean? Well statins can block the action of a molecule called Rho. This is involved in the movement of a cells skeleton called actin. So statins could affect growth cones of of nerve processes and so could impair new synapses from being formed. This would block compensation mechanisms called plasticity during MS.  This has not happened which is great.

What appears to have happened is that there is benefit in progressive MSers.

According to reports the annualized rate of brain volume loss was just 0.298% compared to 0.589% among those given placebo (P=0.003). There was also significant reductions, as measured by EDSS and MS Impact score. 

Whilst this is clear that this is not a cure and the drug does not halt progression but it is slowing the rate of progression, which is a good start. Couple this with an immunomodulator and I would predict there is even more activity. 

However, this looks promising, statins are cheap drugs, are commonly used for cholestrerol-lowering effects.  Not all statins will be useful because some of them do not get into the brain and so would be unlikely to be nerve protecting. This study looked at the affect of one of them.

So now it is time to get a phase III in SPMS and a phase II in PPMS to take this forward. Now here comes the problem.

Who is going to pay for the trials? This study was supported by Charitable cash and funds from the UK National Institute of Health Research. Phase III studies add a further significant layer of cost. It is not only this but also who funds the cost of gaining regulatory approval with the FDA and EMA? 

Pharma have teams of people doing this and they still sometimes mess up and delay things. Academics have no expertise in this area. This study was not done by pharma and the statin is now generic, because it is out of patent. So moving this forward will be much slower than would occur with Pharma involvement.

Let us hope that Dr. Jeremy Chataway, the clinician who led the trial has got the midas touch for controlling progressive MS, as he will probably be involved in a number of trials for progressive MSers in the near future (However, that is another story)  

20 comments:

  1. It will be so tragic if further trials are not done.

    Will it help reduce disability progression in RRMS too?

    Is this good enough evidence for MSers to take simvastatin even without Phase 3 trials?

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  2. It is good enough...

    This is sort of the problem of making data public before it reaches its conclusion. If you can get you hands on the drugs (so all you need to do is eat a load of fried eggs to get your cholesterol up before getting your cholesterol checked :-)) then people will try them rather than wait another 5 years. This is when pharmaceuticals become nutriceuticals and we now what usually happens there.


    First I think we have to see and digest the data, it needs to be properly peer-reviewed and the whole content published.

    The problem of taking drugs outside of trials is assertaining drug-drug interactions as a safety measure

    Next I have to sit on the fence and tow the party line and say we should follow the process before making recommendations. However I am no real Doc and should not be making recommendations

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  3. Am I missing something or shouldn't this be being given much more fanfare than it is? As far as I am aware this is the first ever drug, in the history of MS, to show meaningful impact on progression (as opposed to residual relapses) in SPMS? That's huge news isn't it?! If this was Pharma, it'd be all over the news by now...

    It is only phase II but it is also quite a big phase II of 140 people, given the results statistically significance. The results are also pretty powerful - half the brain atrophy isn't a marginal success. If I had SPMS I'd be demanding my neuro prescribe these off-label on the basis (a) there is nothing else for me and (b) this is strong evidence of efficacy and (c) we know about the safety profile of statins through their 'usual' use. As for phase III trials, surely this should be funded by the various MS societies - I can't think of a better use for their funds than a trial of a cheap drug that could make a real difference in progressive MS. It also seems arguable that this could (should?) be a drug used alongside immunomodulators in RRMS to prevent progression towards SPMS....

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  4. Re "drug-drug interactions": I doubt we will learn that even if somebody does Phase 3 trials.
    We already have so many DMTs. Who will test drug-drug interactions with each of them?

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  5. How does this square with your blog of 14.9.11 that statins don't work (maybe different statins?), and in August that statins might prevent the interferon DMTs from working, therefore, not good for RRMS. Maybe they are only drugs to be used in progressive disease, or you need to look at drug-drug interactions closely

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  6. It'd be all over the news by now...

    Britsh Reserve :-)

    John Greenwood lives next door to a well known news reporter. and di a charity cycle with him.I am sure they will know when to make a splash


    "How does this square with your post14:9:11 that statins don't work"


    We report on the studies as they occur some will be right many will be wrongif you look at 30:9:11 there was a more positive study in optic neuritis

    It is always the problem of armchair science doing analysis of others effort. It is lazy and you need to do the graft and do proper trials. Likewise looking in this way there is no selection. It many be the case that at some stage MS may not respond to simvastatin. We have said that trials involving EDSS 4-6 may be best because this stage has most rapid change and so easier to spot differences occurring

    At the time Prof G said "This is not a very good study as it was retrospective from case records and is therefore potentially confounded by bias" and said "You may be interested to know that the Simvastatin trial in progressive MS being carried out"

    Trial design is evolving and this is good news as is movment in the right direction. I am happy to see that UK clinicians have been at the forefront of this push, but


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  7. "I can't think of a better use for their funds than a trial of a cheap drug"

    Read posts on the "clinical trials network" for example and you will see this is what has been going on for the past few years.

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  8. Being one of the original researchers who looked at statins as potential immunomodulators back in the day, it is hugely satisfying to see an unexpected benefit of statins namely neuroprotection. Not sure anyone would have predicted this but that's the beauty of science!
    This is exciting news and let's hope the funding comes in to push this on and get it into MSers asap.

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  9. Hello,

    Sounds like this is the sort of trial that charities and MS societies could undertake

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  10. Patrick
    The cost of doing a phase III trial is huge and would swallow up the research budgets of charities. As the article states there is also the significant cost of gaining regulatory approval. I suspect partnering with pharma will be the only way to proceed. I guess we watch this space.

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  11. What's happening now? I have secondary progressive MS, so may benefit me? What do l do?

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  12. My neurologist has asked my GP to put me on 80 mgs of Simvastatin but I have Primary Progressive MS - this seems to be only trialled on people with SPMS. Don't know then if I should take it??!!

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    1. Simvastatin seems to be functioning by slowing neurodegeneration in SPMS, the same should be hopefully seen in PPMS too. Might be worth a go.

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  13. Hmm anon 3 pm, did you have to persuade your neuro to ask your GP to prescribe? If so, how did you do the persuading? I ask because so far I have been unsuccessful at doing the same. Thanks

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  14. I asked this in another bit of the blog, but no response. Are all high dose statins as good as simvastatin for MS? I ask this as the more modern stronger statins such as atorvastatin and rosuvastatin have the same effect as 80mg of simvastatin at a much lower dose (re cholesterol). Although simvastatin and atorvastatin are relatively cheap, I think rosuvastatin is more expensive, therefore prob still under licence therefore maybe a way to get big pharma on board.
    Surely there must be loads of MSers out there who are being treated with high dose simvastatin for high cholesterol problems. Has anyone asked them how their MS is doing?

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    1. The evidence is for simvaststin and not te other ones. If ghe mechanism of action is due to blockade of Hmg co A then they should be similar. But they are not all created equal. Some do not get into brain so they would not be much use as a neuroprotectant.

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    2. Mouse, what is your opinion on taking teriflunomide 14mg and simvastatin 80mg as a combination therapy? I need simva for lowering my cholesterol anyway just not this high dosage but got MS so are there any contra indications? As you know the mechanism of action of teriflunomide could there be any complication with statins in general? Thanx.

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    3. Opinion. Where is the evidence that it is worthwhile. Yes there are contra indications with all drugs and the 80mg is very high compared with cholesterol lowering dose and side effects can occur. Depending on how you see statins work there could be complications as maybe two immunosuppressives could be additive.

      I personally cannot recommend this course of action unless part of a controlled study.

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    4. Thanks Mouse, a perfectly fine OPINION. Will wait and see then.

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  15. so I am just trying to do some research on this as my friend has just been diagnosed at age 53 with progressive MS and the neurologist has suggested with this drug or Biotin-megadose and I can't seem to decide which one is more useful. My friend went from walking to wheelchair in a month and has not regained any mobility back from her waist down. is there any hope of her ever getting even part of her mobility back where she can at least stand and take a few steps on her own? I'm at a loss and don't know where or who to turn to for help.

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