What do you expect from an effective DMT in progressive MS?

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In clinic yesterday I was discussing the natalizumab SPMS trial with a SPMSer. It dawned on the MSer, after some discussion, that even if the trial was positive and they were randomised to active agent they would probably not notice any discernible effects at a personal or individual level. The reason for this is that we, the clinicians, don’t expect an effective drug for progressive MS to stop disease progression but to merely slow the rate at which SPMS (or PPMS) progresses. In other words if you were progressing a rate X before the drug you now progress at rate Y, which is simply a slower rate of progression than before. If this was the case you would have no indication the drug was necessarily working. Of course we would like the drug to stop disease progression all together, i.e. stabilise your disease, or hopefully improve your neurological functioning, but this seems unlikely based on observations from other progressive trials and in animal models of SPMS. I have already discussed this issue in some detail before on this blog (see previous survey), but would like to revisit it as I am not sure how to best communicate this information to potential trial participants in a clinical situation. I don’t want to MSers volunteering for progressive trials to have unrealistic expectations.

Any ideas or suggestions would be helpful?

Other posts of interest on progressive disease


27 Apr 2012
Survey results: neuroprotection. “I am reassured that 55% of MSers expect and effective neuroprotective therapy to stabilise of improve their disability progression; this is a realistic expectation and something that may be 

01 Apr 2012
A few weeks back one of the readers posted this comment: “Sick of conferences like MS Life. It’s pure spin on the scientists’ part. Firstly, how about you introduce truly efficacious therapies for progressive MS and then you’ll 
18 Mar 2012
I also spoke to them about the need for better trial designs for progressive MS and described the study design we are promoting using frequent lumbar punctures and neurofilament levels as an outcome measure. They were 
24 Aug 2012
Despite significant progress in the development of therapies for relapsing MS, progressive MS remains comparatively disappointing. Our objective, in this paper, is to review the current challenges in developing therapies for 
17 Aug 2012
Development of protein biomarkers in cerebrospinal fluid for secondary progressive multiple sclerosis using selected reaction monitoring mass spectrometry (SRM-MS). Clin Proteomics. 2012;9(1):9. “The methods of this study 
15 Aug 2012
Objective: The goal of this study is to assess the safety, therapeutic efficacy and mechanism of action of idebenone in primary-progressive multiple sclerosis (PP-MS) patients. Study Population: Adult, untreated patients with 
19 Jul 2012
Giovannoni. Primary progressive MS. ACNR 2012;12(3):9-12. Although PPMS is relatively uncommon it remains a significant clinical problem both diagnostically and therapeutically. PPMS is almost certainly part of the MS 
07 Jul 2012
Our strategic plan 2012-2016 identifies progressive MS as one of the three key priority areas for MSIF’s international MS research going forward (along with paediatric MS and stem cells). This important research area has also 
21 Jul 2012
But perhaps we should also introduce the Clinical Trials Network (CTN), which was set up specifically for Progressive MSers. This has been reported in some places but may not be common knowledge. As you know all too 
28 Aug 2012
We compared OB+ versus OB- patients regarding progression to expanded disability status scale (EDSS) of 6.0 and to secondary progressive MS (SPMS). Cox proportional hazard models were used to compare the outcome 
16 Jun 2012
BACKGROUND: Treatment options for MSers suffering from progressive forms of MS remain inadequate. Mast cells actively participate in the pathogenesis of MS, in part because they release large amounts of various 
29 May 2012
Participants and treatments: 493 MSers with primary or secondary progressive MS were recruited to the study from 27 centres across UK between May 2006 and July 2008. It was a requirement for participants entering the trial 
30 Jun 2012
Background:It is unclear if all patients with relapsing-remitting multiple sclerosis (RRMS) ultimately develop progressive MS. Onset of progressive disease course seems to be age- rather than disease duration-dependent.
13 Jul 2012
Thus, to develop safe therapeutic approaches for patients with progressive MS, it is essential to elucidate how mitoxantrone exerts it benefits. Accordingly, we initiated a prospective single-arm open-label study with 19 
16 Feb 2012
Challenging the dogma (1): progressive MS and remyelination. In response to a comment concerning dogma in the field of MS, I am going to publish a series of posts that are designed to “challenge the dogma”. Dogma: 

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.

33 comments

  • Just say it to them as you said it here and put it in large letters on top of the page in whatever papers they have to sign.

    "YOU WILL NOT NOTICE ANY EFFECT AT A PERSONAL LEVEL.
    IN THE LONG RUN YOUR PROGRESSION MAY SLOW DOWN."

  • What about other drugs running in phase II (like MIS416), where in 50% of the patients their disability has improved after only 3 months?

    • This is very small phase 2 dose escalation study; the improvement in EDSS may simply be noise. I think we need to wait for larger phase 2 and 3 studies to see what happens.

  • Can I ask a question: with ppms is the end game always severe bed bound disability? Or can you 'plateau' at edss 7 for instance – until death?

    • No it can plateau. We see this in about 20% of MSers; they reach a level of fixed disability and then seem not to get worse. Prof. W. Ian McDonald used to refer to this as burnt-out MS. The latter is not a well-described entity in the literature, but those of us who see a lot of MS know about it. Is burnt-out MS a permanent state? I wish I could say yes, we would need to follow MSers in this state for many years to be confident that this was the case.

    • Yes, RRMS can burn itself out! If it occurs early and lasts greater than 15 years we call it benign MS.

  • Once MSers enter the non-relapsing progressive phase of the disease the ability of the motor system to recover has been exhausted, or so we believe, this is why we don't expect recovery. However, in MSers who are still having relapses there may be some reversibility; so there will be some MSers who improve. Other factors that can help improve functioning in progressive MS is optimising medication, i.e. coming off medications that can make neurological function worse, improving fitness and overall well-being with exercise, treating fatigue, losing weight, treating and managing depression , etc. So it is not necessarily relentless progression. Things can be done.

    • You have said often that relapses are not good as each relapse leaves added disability.

      But if relapses show that you are treatable and could still improve, then relapses are not all bad.

    • If somebody thinks he/she is already SPMS, and then gets a relapse, that person is going to be quite relieved. Because it shows the MS is not that advanced

    • Yes, relapses are a marker of ongoing inflammation and a marker of response to DMTs. The IFNbeta trial is SPMS showed that SPMSers with relapses responded, albeit it a moderate response.

  • If the end game is pretty bleak, then, why is HSCT (stem cell treatment) considered more of an option? The results on whether it can 'halt' progression seem to be mixed… there are some studies from Russia that seem to suggest it can. Others from the US seem to suggest it can't.

    But if you are faced with a slow and inevitable decline… why not try more aggressive treatment (if the patient considers the risks worth it?).

  • Firstly, my commiserations on Team Barts’ (and other boffins at Queen Mary University) poor showing on this week’s “University Challenge.” I was shocked that some of your medical students were struggling to answer biology questions they ought to have been familiar with. One question was very specific to neurology and has been discussed on this blog, but your students were left looking dumbfounded.

    In light of this specific post, one of the reasons why new medicines are being rejected by NICE and the EMA is because their effectiveness is way too marginal and expensive to justify funding. Alemtuzumab is struggling because of this very reason. However, if scientists could come up with drugs that either promotes even a modicum of remyelination and axonal outgrowth then you know such medicines will have an easier ride getting to us MSers. To be honest, I believe that novel agents to slow down MS progression will not get the greenlight from NICE because the results won’t be revelatory. In such a situation health bodies will always drag their feet and the only people to lose out are MSers.

    Now I’m sure you’ll retort by saying “If only it was that easy,” but until you start to focus on more revelatory drugs for progressive MS it will always be a cottage industry. The Holy Grail is finding medicines that produce remyelination, and such treatments are being actively perused. Entire MS communities around the world are focussing on such explorations. The notion of slowing MS is a noble one, but it simply won’t be suffice to justify NHS funding. All your efforts may be futile only because marginally slowing down a disease and showing no real improvements will not be good enough. You may end up being very disappointed with the outcome, Prof G.

    Don’t go for the moon because you really need to shoot for the stars. Alemtuzumab, as far as you were concerned, was going to be a game changer, but I feel it won’t live to see the light of day. I also feel your efforts to find a way to slow down MS progression will not amount to much, especially in the light of how things with health funding and licensing are going.

    • Mr Paxman, if you are the assumed individual on TV, then I too agree with you. To simply slightly slow down progression will not be enough of a reason to break out the confetti as health authorities will most likely turn their noses at the lack of assessable neurological improvements such drugs will deliver. You guys really have to deliver something more significant or else the NHS will not be swayed and all your efforts will be wasted. You need to do something more groundbreaking to get the interests of MSers.

      I was at MS Life 2012 and some of the scientists giving lectures were pretty convinced about their abilities to produce treatments to initiate remyelination by the end of the decade, or at least early next decade. Here you guys are saying you may be able to offer drugs that might, ever so slightly, slow down MS progression. And even then that may be 5 years away. That sucks! You know NICE will not fund treatments of that nature as they will find every reason under the sun to not offer it because of a lack of distinguishable improvements. They will send you back to the drawing board and wait for more tangible outcomes. We’re living in a time where there’s actual research, as I write, being carried out on the face of Mars and yet MS progression is too big a nut to crack. It just doesn’t add up.

      To be honest, I wouldn’t want to be a part of a trial that requires me to have regular lumber punctures if all you can offer is a slight improvement in progression. It won’t be worth it.

    • One of the reasons why new medicines are being rejected by NICE and the EMA is because their effectiveness is way too marginal and expensive to justify funding. Alemtuzumab is struggling because of this very reason.

      How can you say that we do not know how much Lemtrada is going to cost.

      Way too marginal…maybe you do not read the blog for stories from recipients

    • RE: "Way too marginal…maybe you do not read the blog for stories from recipients."

      What? Are these stories from progressive MSers or the other more easily treatable kind?

    • I hope you realise that for remyelination to work there needs to be surviving axons. This is less likely in MSers who have already developed progressive disease and is more likely in MSers with RRMS. In fact some of the current DMTs have MRI data (MTR) that suggests that they promote remyelination already.

      The big problem or the elephant in the room problem is that remyelination strategies don't address the cause of MS; i.e. a possible viral cause or autoimmunity. Therefore without treating the cause the newly remyelinated axons will simply be damaged again in the next autoimmune attack.

      The diseases most likely to benefit from the money spent on MS-remyelination strategies are the genetic myelin disorders or leukodystrophies.

    • Dear Jeremy

      We have to start somewhere, right now I would go for a positive effective even if it is small. What you need to realise that a 10-15% slowing in rate of disease progression over 1 to 2 years may make a massive difference over 30-40 years of disease.

      I agree that massive treatment effects are wonderful, for example the introduction of antibiotics or vaccination or even organ transplantation, but for chronic disease the improvements tend to be slow and incremental.

      I would also like to remind you that for the foreseeable future brain and/or spinal cord transplantation will remain a topic for science fiction books and philosophical discussion.

  • I'm still staggered by the lack of ambition when it comes to MS research. For the last decade i've been following MS research closely. Every few years there is a funding drive with the promise of a cure or repairing damage – Promise 2010 is a classic example. Once the money is raised the truth comes out – "actually all we are likely to be able to do is slightly slow down progession" (translation – you'll still end up disabled). Is there one research team in the world actually looking at repair – I'm talking repair of axons and neurons? I want a treatment to grt me from edss 4 to edss 2. Silly me for expecting so much given the hundreds of millions spent by ms research over the last 50 years.

    • That's no doubt the ideal outcome but wouldnt you also like a drug that could stop you getting to EDSS 6? Or at least delay that by x years? It's not perfect but the newer DMTs coming online now might help newly diagnosed MSers avoid getting to EDSS 4 in the first place. It's easier to stop damage occurring than it is to undo/reverse it – thats true of many things in life, including MS: that's not researchers' fault.

  • Is there one research team in the world actually looking at repair – I'm talking repair of axons and neurons?

    Yes loads of groups looking to regrow nerves.

  • Prof G, I suggest you don't talk about the trial for MS progression you're working on because, understandably, it just brings into focus just how little there is to offer progressive MSers. Work on it quitely.

    I think there are families that have donated large sums over many years and are now questioning its worth They feel disappointed, maybe even somewhat heartbroken.

    I would also suggest maybe not bothering to respond to the MS Society's pleas for money when they send letters saying a cure is close to happening. It's all a ploy.

  • I don't share the view of many on here. I think BG12, Alem etc are very significant steps forward and may, indirectly, stop current RRMSers from developing SPMS if the theory of reducing early inflammation prevents progression is, after all, accurate. However, I do agree we need to be more ambitious as well and look to the future. Prof G – what's the most exciting drug for MS currently in development in your view? Are there any hidden knockouts at phase 1 or 2 stage or even before formal trial that might hold potential of being truly revelatory? According to one site there are 80 phase 1 or 2 MS trials in progress and 71 'pre-clinical – do any of those appear to hold real promise?

    • RE: "most exciting"? This is a loaded question. I inclined to favour induction therapies, i.e. alemtuzumab and ocrelizumab. The phase 2 data of ocrelizumab is stunningly good and raises questions about the pathogenesis of MS.

      I think fingolimod is also very exciting; the reduction or prevention of brain atrophy with fingolimod suggests it may be doing something else. So the PPMS trial of fingolimod may be a game-changer; if it is positive the halo effect will be enormous. Then the mode of action of BG12 and its effectiveness is also very exciting and again asks questions about the pathogenesis of MS. Similarly, the disability data of Daclizumab suggests it may also be very effective. Not to forget the Charcot Project; I still think MS is due to a virus and until we disprove this we need to keep on looking for an effective anti-viral.

    • What about less well-known, more embryonic treatments? Is there anything at an early stage that neuros are getting quietly really excited about? Something most interested MSers might not really have heard about but showing pre-clinical/phase 1 promise beyond the norm?

      With Fingolimod – how do we manage the discontinuation/rebound effect? It would really worry me starting on it knowing that if I one day had to come off it I could undo all the good work it had done to date…

  • Prof G,

    Thanks for your honest assessment. By 2020 you and prof mouse will be getting near to drawing your nhs pension. Any thoughts on what progress we are likely to see by this date?

  • Prof Mouse does not have an NHS pension and retirement is nearer 2030…if I make it that far.

    In the 1970s you could not foresee the world wide wide, iphones, PCR the human genome project, monoclonal antibodies, beta interferon, HIV, laptop computers, world wide web etc., the next game changer can be just around the corner. We will know alot more about repair by then

  • I think the more short term future (10-15 years?) will not be a complete 'cure' but with MSers on a combination trio of (a) immunosuppresants/induction therapies, (b) neuroprotective drugs and (c) myelin repair drugs. Taken together, the three could/should make MS much less significant for most albeit not completely cured and, sadly, almost certainly not reversed in terms of existing damage which is probably more like 2030, if ever where the damage is complete in terms of axon 'death'…

  • I dropped out of a trial largely because of perceived inefficacy. Now I second guess myself. Would I be better off if I had stayed on the trial drug? Unfortunately, there's no rewind button.

    Would it have helped if someone had framed my expectations in a more realistic way? Maybe. Since no one did talk about that, there was a vacuum into which flowed hopes based on patient blogs written by MSers who had benefited from the drug, perhaps even improved (the equivalent of "results not typical" on weight loss ads?) and speculation about new, positive effects found in journal articles. I was still newly-diagnosed when I started on the trial and more optimistic about how much modern medicine could help me than I am now.

    There was a thread on here about how neuros talk about the future to the newly diagnosed and how they shouldn't paint such a bleak picture of a future of disability. I had the opposite problem. At my first appointment with the MS neuro, he painted what was probably too rosy a picture and dismissed my concerns about what I perceived as slow but relentless progression up until that point. He also adamantly insisted I had RRMS. It felt to me like he was implicitly promising me a remission (which never came).

    It's hard to stay in a trial. It takes time and effort. The long days of tests seem longer as the trial goes on. At the time we lived 3 1/2 hours one way from the trial center. This meant time off from work and a lot of driving. It also took up my husband's time. At first he drove me because of my lack of endurance and lack of confidence in my ability to survive big city driving. By the time I got out of the trial, I couldn't drive at all so there was no choice.

    This is hard to sustain if it doesn't seem like it's making any difference. Plus it's easy to wonder about the trade-off. Does it make sense to subject yourself to unknown but potentially serious side effects over a drug that doesn't seem to be doing anything? There's no way around the unknowns.

    As others have said, the best thing would be to have a drug where the effects are obvious. I like this quote: "When somebody finds an effective treatment for MS, you’ll know it without the need for sophisticated statistical calculations." (George Schumacher in http://www.ncbi.nlm.nih.gov/pubmed/18716413). That's the treatment I want.

    Since that dream seems out of reach, maybe there's some way to show MSers whether the drug is working, even if they can't feel it? If you had meaningful biomarkers, at the end of the trial, could you unblind the participants and share the results? If at the end of the trial I knew that my neurofilaments or whatever had gone down X much such that there was likely to have been some positive effect on my slope of progression, I think there would be some satisfaction and reassurance in that.

    Not much of an answer to your question, but it's a hard sell.

    • We do have biomarkers, but none of them are validated and accepted as surrogate outcome measures. We are working on the problem.

By Prof G

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