Friday, 22 September 2017

#ChariotMS & #ThinkHand: therapeutic lag explains why we don't have treatments for progressive MS

We need to do longer studies in progressive MS #ChariotMS #ThinkHand


Summary: This post explains therapeutic lag and why people with more advanced MS don't see an immediate response to DMTs.

I have been invited to give a grand round talk at Imperial College this morning. I have chosen the topic: "Is progressive MS (more advanced MS) modifiable?".  This is an extension of our #ThinkHand campaign to get the wider neurological community to accept that MS is potentially modifiable throughout its course. Despite us posting and reposting about reserve capacity, therapeutic lag, MS being a length-dependent axonopathy and the asynchronous progressive MS hypothesis we still get questions such as: "Why don't pwPPMS, or pwMS with an EDSS >6.0 respond, to HSCT and other DMTs?"


It is the same issue in relation to responders vs. non-responders to ocrelizumab in the PPMS trial. It is very difficult to know who is a responder and non-responder based on the current data from the ocrelizumab PPMS, or ORATORIO, trial. Why? Simply because clinical trials are designed, or powered, to get a significant read-out in a reasonable period of time. It doesn't mean that if someone with PPMS does not stabilise, on a high-efficacy therapy, in say a period of 2 years is a non-responder. Because of therapeutic lag, it may take much longer to see a response to treatment, particularly in pwMS who are older and have less reserve capacity in the particular pathway (usually the legs) being assessed.

I often refer to the study below which showed that interferon-beta treatment, a moderate efficacy DMT, would probably work in PPMS provided the follow-up is long enough; in this case 7 years. In this study PwPPMS who had only been treated with IFNbeta for 2-years clearly did better at 7-years than those people treated on placebo over the same period of time. There was a lag in the impact of interferon-beta on the outcome.

Why a lag? One interpretation is that the impact of anti-inflammatory medications in progressive MS may take several years to play out. In other words progression in someone with PPMS over the next 2 years was primed by inflammation from years ago. Suppressing inflammation today will have no impact over the next 2-years as the damage priming progression over the next 2 years has already occurred. All anti-inflammatory therapies will have a lag in terms of showing a treatment response in progressive MS.

Does this make sense?

To illustrate this concept I drew the picture below, which has now been published in our length-dependent axonopathy paper. Importantly in this study, the actively-treated subjects (INF-beta) only did better than placebo-treated subjects in terms of upper limb function (9HPT), cognition and brain volume loss. There was no difference in terms of the EDSS and T25FW, which assess lower limb. The reason why there was no difference in lower limb function is almost certainly due to loss of reserve, i.e. too many nerve fibres supplying the limbs had been damaged already for an anti-inflammatory to make a difference. The other issue is that in this study the treatment period was too short. Please note this study is only one of many studies showing the same effect, a greater impact of anti-inflammatory therapies on upper limb, compared to lower limb, function and is one of the reasons we are running our #ThinkHand campaign and trying to get support for our CHARIOT-MS study.

In the ocrelizumab PPMS, ORATORIO, trial the treatment effect was almost double in the arms compared to the legs. This is why I have little doubt that ocrelizumab is effective in PPMS. If the trial was extended for longer the treatment effect on lower limb function will have gotten greater simply because of lag; survival or Kaplan-Meier curves diverge further with time.



I am convinced we are correct about 'therapeutic lag' and the MS community is beginning to take this it into account when designing progressive MS trials. This means being clever about our studies and getting the regulators to accept the 9HPT as a primary outcome measure. The MS community has made it clear that they value arm and hand function more than leg function, we now need the wider community to help get this message across. There is also an economic argument for taking DMTs into wheelchair users to protect upper limb function; once people lose their arm function they lose their independence and the costs, both medical and social, for looking after these become very high. 

Just imagine what happens to your self-esteem and quality of life when you can't transfer your self from your wheelchair to the toilet and need a carer to help you go the toilet? When we asked people with MS what hand and arm function they valued most many pwMS stated being able to go the toilet without help.

As you can see we will continue to make the case for doing trials in more advanced MS. This is why we need your help getting the CHARIOT-MS trial funded.  The CHARIOT-MS study will compare subcutaneous cladribine to placebo in subjects with more advanced MS (EDSS 6.0 to 8.0), using the 9-hole peg test as the primary outcome measure.

If you are a wealthy philanthropist reading this post? DrK (@KlausSchmierer) is looking for a large donation of ~£2M to support his application to the NIHR for the CHARIOT-MS study. He needs to bring the costs of the study for NIHR down to under £2.5M to have any chance of getting this trial funded and to help people with more advanced MS.

Tur et al. Interferon Beta-1b for the Treatment of Primary Progressive Multiple Sclerosis: Five-Year Clinical Trial Follow-up. Arch Neurol. 2011 Nov;68(11):1421-7.

OBJECTIVES: To investigate, during the 5-year period without treatment after termination of a 2-year clinical trial of interferon beta-1b for the treatment of PPMS.

MAIN OUTCOME MEASURES: After 5 years without treatment, the EDSS and MSFC measures were scored for 63 and 59 MSers, respectively. Neuropsychological and magnetic resonance imaging assessments were performed for 59 and 50 MSers, respectively.

EDSS = Expanded Disability Status Scale

MSFC = MS Functional Composite ( a composite 3 tests the PASAT, 9-hole peg test and the timed 25-ft walk)

9-Hole Peg Test = test of upper limb function

Word List Generation Test = cognitive task

RESULTS: After 5 years without treatment, the interferon beta-1b group had better 9-Hole Peg Test (p=0.02) and Word List Generation Test (p<0.001) scores, and MRI measures in the normal-appearing white matter were significantly better. During the entire study period (from trial baseline to assessment at 5 years without treatment), the placebo group showed a greater decrease in brain volume (p=0.004). The in-trial increase of lesions correlated with the worsening of the EDSS score during the 5-year period without treatment (p =0.004).

CONCLUSIONS: Modest but beneficial effects of interferon beta-1b on clinical variables and brain atrophy development were observed 5 years after trial termination. Moreover, in-trial lesion activity correlated with EDSS progression after trial termination. Therefore, we provide evidence to consider immunomodulation as a sensible approach to treat primary progressive multiple sclerosis.

CoImultiple

48 comments:

  1. It is beginning to make sense to me. Does lag apply to people with an EDSS above 8.0? If yes, why don't you include these subjects in your trial?

    If I was wealthy I would have no hesitation in giving you the money you need. I think your ambitions are very honourable.

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  2. Also adds to the arguement for treating ms early and hard.

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  3. i bought into barts' therapeutic lag theory the moment i read it about 2 or 2.5 years ago. i bought into it partly because the neuros at the time were insisting my partner had ppms (which i didn't agree with, and i turned out to be right) and so it was in my partner's interest for therapeutic lag theory to be correct (i was biased) but in part i bought into it because it reflect my experience with my partner's ms. she was ultimately declared to have rrms, but even rrms there is a progressive component and everything i saw made me believe (hope) the theory is correct.

    but the title of this blog post - #ThinkHand: therapeutic lag explains why we don't have treatments for progressive MS - is a bit misleading, isn't it.

    therapeutic lag is not why you don't treatments for progressive ms, is it? beurocracy, dogma, capitalism and laziness could reasons why we don't have treatments for progressive ms, but not therapeutic lag :)

    thanks for the post. it troubles me that everything i concluded 2 years ago, against the advice of neuros we consulted, is turning out to be right. i should be thrilled (being a know it all that i am), but i'm troubled instead of thrilled- how is it that a lawyer with no scientific background who spends 6 months living and breathing ms articles concludes exactly what you've been writing about in the last 6 months and your colleagues still have trouble grasping it?

    if i stop playing doctor and if i stop reading copious amounts of articles, who is going to help my partner in the future? neurologists? i've lost all faith :(

    and rather than making me smug, it's making me so very sad and concerned

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    1. ps. apparently sour grapes make the finest wine :)

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    2. if i say i'm on our terrace watching the aus sunset and drinking fine wine, does that help the context? :) (if not, at least it will help explain the amount of typos in my original comment). my partner's at work, thanks in part to the therapeutic lag theory, which i'm very pleased about because apparently some study published by msra has concluded that people with ms who work longer stay happier and healthier lol

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    3. My context is that, responding to the original accusation of "sour grapes", MD's diligence in fact revealed something very interesting about the development of autoimmunity in general and also revealing something of a paradigm shift in the immunology of MS. So, I think in this particular case my statement has merit. It certainly doesn't referring to the above comment.
      Enjoy the wine and I'm assuming it isn't sour ;-)

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    4. lol wasn't an accusation, just a most loving reference to my fave comment re sour grapes.

      also a reference to my bitterness that on a friday night i'm at home catching up on ms news instead of enjoying hobbies i used to have because i feel if i'm not up to date in the world of ms, the neuros around me ain't gonna be. that's not to say i'm not in favour of celebrating your small 'victories' or successes - if it wasn't for them, my partner wouldn't be at work and i wouldn't be enjoying the very non sour wine with bitter-sweet feelings: i suspect my partner (and by extension, I) would be in a much worse position then we are now.

      so thanks... even if much of my thanks gets lost in translation.

      now, just waiting for more hints re neuroprotective properties of cannabis oil with thc which doesn't affect cognition and more information on how ocrelizumab is or is not associated with breast cancer and how exactly (and it what doses) it can be used as induction treatment... and i'll be over the moon ;)

      i said the other day 'sour grapes can make the finest wine' is my fave comment in a very long time :)

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    5. Nice post
      Edwin Hubble was also a lawyer

      You´re not alone i am almost 2 years like
      you

      Obrigado

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  4. "The MS community has made it clear that they value arm and hand function more than leg function".

    This is so wrong. We value all our functions. The issue discussed was whether after having lost leg function you would still want treatments to preserve hand function. Next time you do a 10k think how you would feel if your ability to walk / run was taken away. At least with your hip, there are good doctors who can get you back to near normality i.e. you recover your health / functions.

    What annoys me with these posts is that you expect us to be grateful if treatments / treatment strategies become available which slow down worsening disability.

    Your goal has researchers / doctors should be getting someone at EDSS 7 to EDSS 4 i.e. real improvements. Please have some ambition. Recovery, repair, re-gaining the ability to walk should be the goals. Allowing an MS patient to continue to cut their toe nails for 1.3 months longer than if they hadn't been treated is piss poor. I look at Wheelchair Kamikaze and the situation Andy's wife is in and it gives me a real insight into the lack of real progress made to date.

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    1. i don't disagree with you, but what are they meant to do in the meantime? the state of ms research is such a tragic mess, they have to celebrate what they think is progress even if it's 20 years late - otherwise what? give up and cry? meh.

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    2. I've had MS for 15 years and have lost track of the number of false dawns. All the MS societies have raisefd money for myelin repair, 'regaining function' etc. and nothing is ever delivered. I don't doubt the commitment and effort of the research teams, but there is something wrong with their approach. When you look at the massive strides made against some cancers and HIV, why are neuros still prescibing treaments which only reduce relapses by 30%? Why in 2017 are there no neuroprotective agents. Prof G thinks ebv causes MS. This has been speculated for some 30 years, but nothing ever comes of it. We keep sailing around the same buoys. There's no urgency in the approach, it's all about applying for research grants, producing a paper and then doing the same again. Our lives are short and with MS are even shorter. We need someone to drive this forward and patients to benefit. Too much blogging, pontificatng, attending conferences... They picked the low hanging fruit with relapses. The real issue was neuroprotection and repair, as this is a neuro-degenerative disease.

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    3. I mean think about it. It took 30 years of research to have 3 OLD cancer drugs Rituxan, Cladribine and Lemtrada. 30 years! Now they are THINKING if some existing Treg cancer drugs can help MS too. People that had chemotherapy 20 years ago are living between us and are stable ever since, and we are wondering if HSCT is a scam. People with bad cases of MS, not benign. And even now that we have them, the favorite drug among neuros is Copaxone. No hope.

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    4. As a caregiver of someone with MS, I understand your desire for urgency—I feel it too, everyday in the pit of my stomach. But I also know that the system itself slows things down. Part of that is necessary (due diligence to make sure that the drug won't hurt them more than it helps), but also partly because there is not enough funding and a lot of red tape.

      Do I wish things could go faster, and that we had $10 billion a year being put into all kinds of crazy research? Absolutely. And if I was rich I would donate to the study that is asked for in this post. But I also celebrate the little victories, because even if they won't help someone today, they might mean the difference for someone diagnosed 30 years from now.

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    5. Vectron, $10billion a year was not needed for rituximab - swedes have been using it with success for years. the point that's being made is that even things that could have been accepted earlier haven't by treating neurologists. $10 billion a year is an excuse.

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  5. Thank you Dr Giovanonni for your posts which I find easy enough to understand. I'm guessing you would still prefer to treat all of your patients with one of the more efficient drugs rather than the Interferons or Copaxone? Do you know more yet about the cancer risk with Ocrelizumab and any idea when this drug will become available in the UK? Do you have real concerns about the problems of neutralizing anti-Alemtuzimab antibodies?

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    1. ...apologies, I should have written 'Prof' Giovanonni. I so wish I had the money to fund the trial. Perhaps you could appeal to all those over- paid footballers and TV personalities?

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  6. Finally, do we have a basis for a cure of ms?

    www.medicalnewstoday.com/articles/319469.php

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    1. Way too premature, and whether it will be significant is contentious and other researchers report this approach may not work. I suspect a degree of hype to raise venture capital for their recently formed company.
      "Another recent study, published in the Journal of Neuroinflammation at about the same time as the Neuron article, questioned the feasibility of preventing this type of axonal degeneration in slowing MS-related disability, based on experiments in mice."
      https://jneuroinflammation.biomedcentral.com/articles/10.1186/s12974-017-0831-8
      Let's not get to carried away.

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    2. Can't see the relation between these two reserches. This one is a gene therapy through the liver.

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    3. What does Wallerian degeneration as to do with adeno-associated virus (AAV) immunotherapy and Tregs?

      In what way are this two studies comparable?

      Obrigado

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    4. I guess for something that stops ms, although claims of reversing ms are a little premature, unless the world has completely misunderstood brain degeneration and animal loss. Then really all other research to treat ms is pointless? Seems really promising area of research! And the logic of the efficacy makes sense even to a non medical person like me!

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  7. Has any donor come forward yet? If not, I suggest DrK gets his walking shoes on and does some good-old-fashioned cold-calling. There is no substitute for face-2-face meetings when selling ideas and getting commitment out of people. Using the blog is a lazy way of doing things and unlikely to work.

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    1. Yes, I am sure you are correct. But we need to know who to contact and their contact details. Another strategy may be to go the micro-donation route. I will discuss with DrK next week.

      One of the problems we have in the UK is charity/donation fatigue; everyone is always trying to raise money for something.

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    2. Have you tried JK Rowling?

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    3. Clive Burr? The Mouse Doctor should have contacts with his wealthy friends.

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    4. We were nearly the recipient of an Iron Maiden PhD studentship....but sadly the university (UCL)frightened them off with the way they discussed the cost. They set up a fund to help Clive and other people with MS. Clive sadly lost his battle, but he did take MD2 and me to see the Maiden at Earls Court..Up the Irons!

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    5. Clive Burr died in his sleep at 56 and Michelle Obama's father
      at 58..and yet some people here post like the disease is cured.
      This is from interview w/ the original Iron Maiden singer:

      How was the thing when there was the benefit for Clive Burr?:

      I was asking Clive and they still haven't given him the money yet, so that's f'ing bad man. That really pissed me off because that money was to give him extra money to get a new car and get it fixed up..you know when you are slightly disabled and stuff..but he doing really well, he really happy but I just wish Iron Maiden would pay him the f'ing money. It took me two years for me to get my money from Iron Maiden as well.
      http://www.metal-rules.com/interviews/dianno.htm

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    6. Been a drummer for 27 years ,really like Iron maiden and also Nicko

      Obrigado

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    7. Indeed yes and not only in the UK. I've not heard it deemed "charity fatigue" before. Even with 30,000 donations thats like $66 each and that'd be a problem. Consider the size of the MS Online Community and reach thereof.

      For US or Canada donations to fully engage would mean the research need impact at least to a significant extent pwMS in said nations. Will Cladribine ever make it to these markets? Given costing in compare and politics at hand?

      It might be a better plan to seek 1 million via varied entities and shoot for another within the global MS population or some such formula?





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    8. I think you are making a fundamental error. You need to get your proposal peer-reviewed first and then raise money. Why should the wider community trust DrK and Barts-MS that this is a good investment. As an entrepreneur I am acutely aware that is only good ideas and well planned and executed business plans that are successful in raising money. I sure medical research is no different. The fact that Pharma is not in this space suggests there are problems.

      Can I suggest you take a step back and start again? Get your proposal peer-reviewed, respond the reviewer's concerns and only then raise the money.

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    9. DrK is planning to submit a grant application to the NIHR in October and that will trigger a formal peer-review process.

      You raise an important point. When we did our EBV saliva crowdfunding campaign a year ago it went through a rigorous peer-review process with CrowdaCure.

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    10. Re: "JK Rowling"

      We have tried, but she keeps a low profile. I have asked my daughter, who is studying in Edinburgh, that if on the off chance she meets JK to explain to her about our project. However, JK has let it be known that she does not support MS research outside of Scotland.

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    11. Could there be some sort of collaboration with your team, a Scottish university and the MS Society Scotland? Do the research in Scotland.

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    12. MD I think you should go back to the Maiden and ask them for a large slug of cash. They could afford to fund this study with the proceeds of one or two concerts.

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    13. "go back to the Maiden and ask them for a large slug of cash"
      Ask the band's songwriters..they've all the money..the others in the band are only worth 15 million each.

      Bruce Dickinson Net Worth: Bruce Dickinson is an English musician, airline pilot and broadcaster who has a net worth of $115 million dollars. Bruce Dickinson is a singer, pilot, writer, musician, and actor, among other professions, and is the lead singer for the heavy metal band, "Iron Maiden"

      English musician and songwriter, Stephen Percy “Steve” Harris has an estimated net worth of $60 million. Steve Harris is the lead composer and lyricist for of the British heavy metal band Iron Maiden.

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    14. Bruce is an entrepreneur, I asked him for a signed photograph for a the nephew of one of the lecturers, on their behalve, after he had just lost his dad and a signed photo may have helped cheer him up...didn't get that or any sponsorship for the charity run I did. I see less tight ducks bums:-)

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    15. He as a farm in here
      Maybe i will meet him

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    16. Aside from Rowling's connection, and Iron Maiden, there are others who are famous, and perhaps wealthy, or who may have large social networks, who could be approached regarding funding. Below is partial list I have compiled. I reside in US, so many of these folks relate to US. Some retired, deceased, etc. Just the folks I can think of. Excuse the typos.This said, a good cause is a good cause and they may have interest in supporting:

      Ryan Asdourian, Seahawks Mascot
      Bryan Bickell - Blackhawks forward (ret.)
      Neal Cavuto - news
      Allesandra Ambrosia - MS Ambassador - dad has MS
      Amy Schumer's dad
      Jamie Lynn Sigler - Sopranos
      Roy Davis Jr. - Chicago bluesman
      Shemar Moore's mom
      Andrea Sachs - senior writer Time
      http://www.nhl.com/ice/news.htm?id=712561
      mom of drive by truckers singer
      Dad Of Chris Pratt - deceased
      Richard Pryor - deceased
      Jack Osborne
      Terri gar
      Comedian on Seinfeld
      michelle obama's dad
      Squiggy - David Landry
      Ann Romney
      Jonathan Katz
      clay walker - country musician
      peaches sister (Canada punk)
      Dr. Spyer wife of Edith Windsor - gay rights activist
      Montel Williams

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  8. Sod coming to us for money, Prof G. Go to your friends in Big Pharma. They are willing to fund crappy short films for Shift MS, but not this? It is all spin.

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  9. Can I ask what you think, Prof G, of this report that has just come out that links MIF, D-DT Molecules to Progressive Multiple Sclerosis? The study, “MIF and D-DT are potential disease severity modifiers in male MS subjects,” appeared in the journal Proceedings of the National Academy of Sciences.

    I was interested to read that MIF activation has been implicated in West Nile Virus and that, in addition, the use of Rituximab has been shown to reduces macrophage migration inhibitory factor in patients (http://www.tandfonline.com/doi/abs/10.3109/03009742.2012.654817?scroll=top&needAccess=true&journalCode=irhe20)

    Has MIF crossed your field of view before and does it challenge your MS is one disease argument if there are specific molecules that are just found in progressive MS male patients?

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    1. No

      MIF is is a macrophage factor...macrophages are a central cell in the pathogenesis of all aspects of MS. If you look back at a few posts ago there was a suggestion that ibudilast is an inhibitor of MIF. The results to be presented at ECTRIMS

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  10. I think, Dr KS, it would be great if you could post - please - a brief 'pitch' to generous donors. I might know a few. Can you write a one page summary on an MS Doc file and put up the link to that attachment, so that I can disseminate, and others can too, to philanthropists and to their minions? Thank you.

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    1. iaino 11.46
      Good suggestion. £2m is such a huge sum, but only 100 donors x (gulp)
      £20k each. I might know a few too ;-)

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    2. Anything we can do to help Klaus please dont hesitate contact us, you have our info.

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  11. I agree with all the urgency. but to take the edge off, don't forget that environmental and lifestyle factors can also have a significant effect on the progression of MS, and you can crack on twith those things immediately. Endeavouring to take in as low sat fat as possible, avoiding dairy,doing high dose vit D3 & omega 3 oils, look into the Lipoic acid reducing brain atrophy study, populate the gut with most diverse mix of probiotics possible, get exercise in any way possible - these things are moving from being ignored to being evidence based. As per www.overcomingms.org and carry on. Wish I was a wealthy philanthropist.

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