New progressive trial: putting out the flames

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Can we stop the slow burn of progressive MS? The DE-FLAMES study. #MSBlog #MSResearch


“We need your help. If you have been reading this blog and following the numerous posts on progressive MS, and brain atrophy in MS, you will know that the progressive phase of MS is present from the beginning of the disease. How do we know this? Studies of MSers presenting with their first clinical attack already have significant brain atrophy on MRI and about 30-40% have subtle cognitive impairment. When you look even earlier in people diagnosed with asymptomatic MS, or RIS (radiologically isolated syndrome), you find brain atrophy is present in about 25% of these subjects. In other words the progressive phase of the disease can be present before the disease manifests. The only reason MSers don’t have progressive physical disability from the outset is that  their brains and spinal cords adapt to damage by using up their reserve capacity. It is  only once this reserve capacity is exhausted that progressive MS manifests itself as secondary progressive MS. We think MSers with PPMS have the same problem, the only difference is they were unlucky not to have relapses. Relapses at least allow us to get in with DMTs early to slow, or prevent, further damage. Therefore it makes little sense to wait until progressive disease starts to target progressive MS. We need to start neuroprotective drugs as soon as possible in the course of the disease.”


“Our group at MS@UCLP are active in trying to test several putative neuroprotective agents in MS. In addition to two commercial trials testing natalizumab and siponimod in SPMS we have three investigator-led, or non-commercial, studies that are running. Firstly, the phenytoin trial in optic neuritis. This is testing the ability of phenytoin to prevent or reduced the loss of nerve fibres in the retina in acute optic neuritis. The PROXIMUS Study that is  testing adding-on oxcarbazepine to existing DMTs in MSers with early SPMS and the SMART Study that is comparing three agents (ibudilast, amiloride and riluzole) to placebo in SPMSers not on a DMT. We now want to do a fourth trial looking at a putative neuroprotective agent, that has a dual mode of action, as an add-on to 1st-line DMTs in early RRMS. We want to target RRMS as this is were MSers have the most to gain. Our primary outcome will be a reduction in brain atrophy. The question I would like to ask you is would you be willing to take and additional drug on top of your current DMT to see if we can slow the progressive phase of the disease? We know that 1st-line licensed DMTs are not effective at slowing done brain atrophy.”


“The following diagram illustrates what we are trying to do with our neuroprotective programme in relapse-onset MS. I think the picture is self-explanatory. I strongly believe in a combination therapy strategy, i.e. an anti-inflammatory drug in combination with a neuroprotective therapy and early treatment. The earlier you prevent neuronal and axonal loss the more you have to save and the greater impact you will  have on an individual with MS.”





“I would like to point out that all these four neuroprotective investigator-led studies we have, or will be, embarking on come from research done as part of our PROMISE 2010 programme grant. A lot of commentators have said  that nothing came of PROMISE 2010 and I say this is not true. The problem is that it takes 10-15 years to do science and a lot of interesting new ideas and trial designs have emerged from the investment in that programme. I would therefore like to take this opportunity to thank the National MS Society of the US (NMSS) and MS Society of Great Britain and Northern Ireland for there generous and ongoing support; it is much appreciated and hopefully it will lead to a licensed treatment for progressive MS.”

About the author

Prof G

Professor of Neurology, Barts & The London. MS & Preventive Neurology thinker, blogger, runner, vegetable gardener, husband, father, cook and wine & food lover.

27 comments

  • I would 100% participate in this study. Would I be eligible?

    RRMS – first abnormal MRI – 2012; formal diagnosis 2013. Went straight to Alemtuzumab for treatment – not because of any great aggressiveness to my MRI but, in large part, because of the early, aggressive approach advocated on this blog. Due 2nd Alemtuzumab treatment later this year. EDSS is, probably, 0. I have on-going symptoms but all farly subjective (i.e. nothing a neuro could detect on an exam).

    If I would be eligible – how can I secure my spot on the trial as early as possible?! Can I pre-reserve my seat, so to speak?!!

    • Why only 1st line DMTS? I assume, only being diagnosed a few months ago, I could as 'early' so it can only be the jump to Alemtuzumab that 'disqualifies' me. Why the distinction between 1st or 2nd line DMTs? Provided the proportion of 2nd line vs 1st line DMT was the same in both placebo and active groups, it wouldn't impact the validity of your results. It might also make for some interesting sub-group analysis e.g. the 2nd line DMT + neuroprotector combo might be shown to be more powerful than 1st line DMT + neuroprotector versus just the respective DMTs alone… Given your views on the poor efficacy of 1st line it seems odd to do a trial restricted only to those who are on them and stay on them?

    • Anon 12:04: Just out of interest, did you get alemtuzumab in the UK or elsewhere? Did you have to pay for it yourself?

      thanks.

  • Looks like a real head of steam is building – good work Prof G and co.

    I too have had Alemtuzumab – 2 doses. Last 5 years ago. Would I benefit from beign on a neuro-protective agent when one comes availale i.e. not a combo as the inflammation has been addressed (I hope) and I'm not on any medication.

    Looking further ahead, will we ever see treatments which migth repair some exisitng damage?

    • How have you been in the five years since your second dose if you don't mind me asking? Did you see some improvement in your symptoms following Alemtuzumab or just stability or neither?

    • Anon,

      No relapses (lots before), no activity on MRI, edss stable. Excellent treatment. I do have some deficits from earlier relapse while on rebif. Icing on cake would be recovery of some deficits. But that's another treatment i.e remyelination perhaps. If you get chance of Alem go for it.

    • To stop or slow down brain atrophy. Brain atrophy is emerging as the great integrator of end organ damage and correlates with disability progression and cognitive impairment

    • Prof G,

      Why does the statement above strike me as a statement of the obvious? I have no medical training but could have reached a conclusion that losing brain / spinal cord is bad and must lead to disabilities ( as would losing bits of the eye lead to visual impairment). I eould have thought that even Charcot could have reached this conclusion 140 years ago.

  • First relapse 1979, SPMS 2009 – what is there out there for me and my poor old brain? Still injecting Rebif and in my 11th year. Since adding Vit D3 at 1,000 units and a multivit my concentration and memory has improved a little but I am no longer me and still hope that there is something that will keep my sight and cognitive function going.

    • Hope you don't mind me asking, but how are you prescribed a DMT if you have SPMS, (if you are in the UK), and do you notice it helping (or can't you tell?)?

      Thanks and best wishes

    • You enter the SP clinical phase of the disease on a DMT and stay on it. You don't start people who SP on DMTs unless they are having relapses.

    • Ok, thanks for that. So I shouldn't be disappointed not to be on a DMT as I haven't had a relapse for many years?

  • What about those of us with no treatment yet? CISer two years after dx and fulfilling McDonald 2010 criteria. Would we be illegible? What kind of neuroprotective agent are you targeting?

    • Best to wait until we get green light. In reality we could select a few good candidates. We have loads of ideas.

  • Would love to be involved. I was diagnosed in 2010 having had optic neuritis and so far only subtle symptoms including optic neuritis both eyes, numbness, tingling, some subjective weakness and fatigue, vertigo. I am on copaxone but also take sulphasalazine for ulcerative colitis which my neurologist says excludes me from any clinical trials. Keen to stop my brain shrinking.

  • I was one of the commentators who criticised Promise 2010. I stand by my criticism. What did 2010 stand for? In reality not much for MSers. The neuroprotective trials if successful won't become available until c.2025. Imagine the brain loss those with MS will experience. Also Promise 2010 was about restoring lost function and I don't see any advances here. But the work you are doing will benefit the next generation of MSers.

    • Each group had their own remit and there we a few groups particularly focusing on repair.
      So of that work has come to fruition. However I think we have not got the message across about the drug development process. There is no quick route. I am sorry to say but we are not giving the correct message if we say we can get the quick fix in a year.

    • Mouse, i don't blame you. But there is a conspiracy of optimism. The ms societies to fundraise and they won't get much if they say a treatment from the research will take 20 years to research the market. I read 2010 (back in mid- noughties) as something that might benefit me in 2010. There have been numerous fundraising campaigns over the years promising big things by a certain date and they haven't delivered. This is the difference between MSers and researchers. The former want something now- we are desperate. The latter want a good stream of grants / funding to keep them going until retirement. By 2020 they'll be plenty of MS researchers / neuros who will be able to say they have worked in the field for 30+ years. There won't be any MSers who can say that they are back to full health, have ditched the wheelchaire etc.. It's just rhe way it is.

    • Without fund raising there will be no progress.
      I remeber about a few years ago oincoventry where I was sent that there would be a cure by 2015. At the time i thought maybe premature. Maybe it is here but the regulators dont want it. You are either glass half full rather than empty

  • Hi

    This looks interesting. I had my first definate relapse Jan 2013, but had some double vision the year before (2012), and some inflammation on a routine MRI for another condition (epilepsy) in 2011. In between the Jan 2013, and the Dec 2013 when I saw the MS neuro, I had 4 relapses in total. I have recovered completely (from my perspective) – EDSS of 1.5. My neuro is currently hoping to get me on to Tysabri, but this will very much depend on my JC virus status. If not, I will have to start on a 1st line treatment with close monitoring, thus wondered if this may be worth investigating as a backup option. Two Q's – would my epilepsy rule me out (it seems to rule me out of lots of trials!!), and would I need to come to yourselves for the treatment or would you work with other PCTs / neuros to deliver it at our local hospitals? Thanks

  • You have broken promises and wasted money. Prof G seems to be spouting different things every day. It's either claribine, alemtuzumab, HIV drugs, EBV drugs, vitamin D. I want to know what you spent 2.8 MILLION dollars on? It certainly did not result in any top tier academic output. I'd like a refund of my donations Prof G.

  • Unfortunately, we have had a troll, or bot, that has filled in the survey multiple times. Thankfully, Google Forms makes is easy to detect this kind of aberrant behaviour. We have therefore had to delete over 270 survey responses that came in this afternoon.

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