The three Amigos

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This week some of us with decanting to Edinburgh for the annual Association of Neurologists meeting.

From an MS perspective, we will have lots to discuss including whether or not the UK MS community has the appetite to take on one, or all of these, studies. Which one do you think is the most important?

The SALVAGE study, which is challenging NHS England’s DMT stopping criteria and saying that even if you end up in a wheelchair it is worth protecting your upper limb function.

The ADIOS study. This is questioning whether or not we need to dose ocrelizumab continuously, or can we use it as an immune reconstitution therapy (IRT), or using adaptive dosing based on peripheral memory B-cell kinetics.

The #AttackMS study to treat MS as early as possible to see if we can maximise disease outcomes for people with CIS or early MS.

Don’t be shy we need you, and the wider MS community, to get behind these studies if we are to have a chance of getting them funded.

CoI: multiple

About the author

Gavin

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

73 comments

  • I’m not in a wheelchair yet, and am slowly loosing hand function, but have no access to DMTs as a supposed SPMSer, for me you need to challenge the classification of the various types of MS on which the rules for access to DMTs are based.

    • The 3 Amigos is addressing a specific set of questions and/or hypotheses. For SPMS we have another set of trials planned, i.e. CHARIOT-MS and a series combination therapy trials, for example, CUPID-2, PROXIMUS-2 and SIZOMUS.

  • #salvage has to be a priority

    Treating early#Msattack is discussing the use of tysabri early and for a short period but is an accepted principle already

    #adios is too focused on one treatment and as we know treatments common go and go in and out of fashion

    Being in a wheelchair only reflects one element of MS disability but ridiculously is the only element upon which prescribing is based.
    Being in a wheelchair excludes you from any treatment so we need to fight for this over the other two in my opinion.

    Being in a wheelchair does not mean it is too late it just means that your lesions happened to be where your mobility is affected.

    • Regarding wheelchair users. We are still running our #ThinkHand campaign and that is what ORATORIO-HAND and CHARIOT-MS trials are addressing. SALVAGE-MS is another trial under the #ThinkHand umbrella. We are not forgetting wheelchair users, but are actively campaigning to study this phase of the disease.

        • ORATORIO-HAND starts recruiting in the next 3-4 months and CHARIOT-MS has been funded, pending contract negotiations, and likely to start recruiting early 2019. All good news; but too slow for some people.

      • PR -Proportional representation, not Public Relations.

        As a member of the public, I will declare my COI regarding Ocrelizumab. (didn’t know I ought to have done so)

        I am on Ocrelizumab unless I can somehow get onto HSCT on the next few years. In the meantime, unnecessarily overdosing on Ocrelizumab seems a pointless risk and expense.

        Attack – but of course the Pharmaco will be queuing up to fund that.

        Salvage strikes me as the one that needs your support the most. There is no poster-boy element to it and I do think that the Govt is happy to gloss over those who they feel cannot mount an effective campaign. IMHO

  • As I still haven’t understood HOW you are going to protect upper limb function in people already in wheelchairs I cannot make an informed judgement . Doing a 9 hole test is not going to resolve any problems ..what are you proposing as a solution?

    • The 9HPT is only an outcome measure. We are planning a rehab trial to improve or maintain hand function in pwMS.

      • It’s also the salute for West Ham football club of whom the founder of Iron Maiden, Steve Harris is a big fan.

          • Do you mean Brian Johnson (vocals)…after the the sad death of Bon Scott…Back in Black was one of their finest albums.

          • You’re right. Brian. I blame my brain fog and listening to far too much ACDC at too high a volume when younger.

          • Is everyone forgetting Def Leppard? Certainly not metal but come one, their drummer only has one arm!

          • How can we forget poodle rock….the big hair and curly perm? The anthem…no that’s Rush 🙂

          • Speaking of the most ridiculous drum solos in music history, ever listened to In-A-Gadda-Da-Vida by Iron Butterfly? It goes for like 8 minutes. Comes from nowhere and goes nowhere. Hilarious.

            My wife starts her first course of Lemtrada next week. Newly diagnosed and receiving first line treatment. After hearing Jay’s story, i’m so glad we live in Australia where we can access the full range of treatments. I truly believe this drug gives her the best chance of minimising disability moving forward (she has a high burden of disease but no current disability. We believe this to be largely due to our healthy diet and lifestyle).

            Good luck to everyone with their MS journey. Prof G and MD, you are truly appreciated by the MS community globally. Keep up the good work.

    • Nice one

      Sadly you forget Clive Burr (drummer ,like me :))

      Burr was diagnosed with multiple sclerosis, the treatment of which left him deeply in debt. Iron Maiden staged a series of charity concerts and were involved in the founding of the Clive Burr MS Trust Fund.[7] Burr used a wheelchair because of his condition.

      He was also the patron of Clive Aid, a charity formed in 2004. Clive Aid has continued to raise awareness and funds for various cancer and multiple sclerosis programs around the world through the staging of rock events.[8] Burr attended many of these events. His partner Mimi was also diagnosed with MS.

      Hand function would be of great help to him

      https://en.wikipedia.org/wiki/Clive_Burr
      https://ironmaiden.com/news/article/clive-burr-ms-trust-update

      In 1994 Burr was diagnosed with primary progressive multiple sclerosis, which seriously affected his drumming skills . “I kept dropping things,” he recalled. “I couldn’t grip properly. I could barely keep hold of my sticks

      https://www.telegraph.co.uk/news/obituaries/culture-obituaries/music-obituaries/9931087/Clive-Burr.html

      • We had the pleasure of meeting Clive a few times back then. Lovely bloke and a great drummer. Sadly missed.

      • “Iron Maiden staged a series of charity concerts and were involved in the founding of the Clive Burr MS Trust Fund”. I know we (MD2 and the rest of the lab) went to all three nights at the Brixton Academy, London…we even took ProfG one night.

        Almost got on “Top of the Pops” that week to see them perform “Run to the Hill”s which they re-released only for some idiot to block my email, so I got the invite a day late:-(

        Also met Clive at CliveAid, where I got the Maiden signed poster that is now in my office. He also took me and MD2 to Earls Court…

  • They are all important in different ways and it is impossible – I think – to pitch the needs of one group of MSers against another. AttackMS is important in a number of ways for Tysabri’s future and not only outcome of its use in early MS. A lot of people now going on Ocrelizumab so how it is best administered seems really important. And the criteria for stopping DMTs surely needs to be reviewed and updated regularly as new treatments and knowledge become available.

    • Agreed, which is why they are called the three amigos, or friends. Why would we want three friends to compete against each other? Let’s try and get them all funded and off the ground. The problem is bandwidth. Barts-MS is relatively small so we may need to spread the workload when it comes to taking some of these ideas forward.

      • Re ‘Let’s try and get all the research projects off the ground’ – How do PWMS help do this? Genuine question! Knowing what needs researched and getting the money for it is very much part of an academic’s life so unsure how most MSers can help. That’s not to say we don’t want to or can’t but we’d need to know how. Fund raising activities? Would be nice if there was sthg that could be done directly.

  • SALVAGE. All worthy contenders, of course, but that is the priority I think. The System seems to base so much around mobility and is inclined to write off as hopeless cases those of us who have lost it. In fact, when lower limb function is gone, preservation of whatever still works – always priceless – becomes even more precious.

    • Yes, I agree. ADIOS will be done by the Americans before we can do it and #AttackMS will hopefully be funded or sponsored by Biogen. The for MSers on DMTs in the UK SALVAGE-MS has to be our priority.

  • Next year is 2020, but the paucity of ambition in MS research is scary. The best that is offered for a person in a wheelchair is a possibility of a treatment that might slow progression ie you’ll be able to feed yourself for a few more months / years! Surely the aim should be to stop any further progression and possibly stimulate a tiny bit of improvement eg reduce disability by 1.5 points on the EDSS. You people could learn a lot from cancer research where advances have been amazing. You’ll say they get more money, but they cover 200 diseases and we now know that MS is one disease. If I had to vote for just one of the trials it would be attack.

  • Salvage is the most important to me – preserving my basic independence is crucial for my quality of life and it is not the use of my legs that dictates how independent I am. I want to be able to clean, dress and feed myself, pick up a book or laptop, type, paint, take photographs, go out in the countryside.

  • All of them!

    But in order of my priorities:

    1: Salvage. Please don’t give up on us and throw us away! I am in this position, of begging for treatment. It is terrifying, being abandoned.

    2: Attack MS. Give the patient the choice whether to be cautious or attack MS aggressively, whether or not they want to take greater risks immediately to increase the odds of having less disability later on. The patient is the only one whose priorities matter. Which applies to Salvage and Attack. Both are about overcoming the ableist, patronising, and paternalistic attitude that patients shouldn’t be in control, shouldn’t get to choose whether to give or refuse informed consent about whatever is going to happen to our bodies.

    3: Adios. Treatments will come and go. The right to choose what treatments we do or don’t have, that’s forever. And, actually, the individuals right to be listened to and their choices respected applies to all illnesses and all of life.

    • Yes, I agree. ADIOS will be done by the Americans before we can do it and #AttackMS will hopefully be funded or sponsored by Biogen. The for MSers on DMTs in the UK SALVAGE-MS has to be our priority.

      • I was trying to be objective, but yes, really all I care about is Salvage!

        Personally, that’s what matters. I need to salvage what brain and functioning I have left.

        And, personally, the ability to walk is less important to me than the use of my brain, and my hands. If I had the option of being a paraplegic but having energy, no pain, no motion sickness/vertigo/nausea, and keeping my intellect so I could still write, I would take it. As difficult as it would be, and I don’t want to minimise the difficulty of people in that position, it would be better than even as I am now, let along how I will be in the future.

        My MS is weird, in that I can do very little, but when I’m up to doing anything, I can walk. It won’t be fast or pretty, but I’ll walk as far as the NHS wants me to for treatment.

        The principle here is what matters: patient choice, and not being thrown away because we’re seen as beyond hope. I’m not dead yet.

        Does the NHS deny treatment to those with advanced MS because it believes there isn’t evidence that it will help? Or is it because it thinks there’s no point wasting money on people who are already so disabled? The latter would be horrifically ableist.

        I tried to restrain my bitterness, but I’m going to say it anyway: this isn’t just about those with a history of being on treatment. It’s also about people like me who have lived decades with severely disabling, full-blown MS, with every symptom, but were not believed by the NHS and were refused access to a neurologist or neurological tests. I have lived through the horror of no treatment and no support for most of my life. That’s why I don’t have a record of failed DMT’s and a history of MRI scans until I went private.

        So the NHS denied me a diagnosis and treatment for decades, and now I’m allegedly sliding into secondary progressive. I’m on my first DMT, and I was given no choice of which one: Plegridy. I want Lemtrada, I want HSCT, but it’s just me against the NHS and I don’t think I can win this battle on my own.

        I’ve been seen as a disposable person my whole life. I finally got myself all the correct diagnoses, by my own hard work and money, but it’s now just another war.

        I suppose, weirdly, I’m simultaneously in both AttackMS and Salvage. I’m both newly diagnosed and started my first ever treatment last year, and at the same time I’ve had advanced MS for decades. So I guess I’m doing both. I’m saying to the NHS: ‘I started my first DMT last year, and I was put on Plegridy but I want Lemtrada or HSCT. Also, I have advanced MS and I want Lemtrada or HSCT before you say it’s too late for me, which is about to happen. Also, by the way, you destroyed my entire life and I’ve proved I was right about everything, and you still won’t listen to me.’

        The reality is, the decision on what treatment to fund will be made partly by who are considered to be worth it. It will be influenced by whether or not those people can work and earn money. Whether they can have families. Whether they can care for themselves, or do they need benefits and social services. Whether they are in a position to fight the NHS and politicians. So people who are most disabled will always lose out. Our lives are seen as having little innate value, and we are a burden to society. Though, if we were given treatment, we would be more able to do those things. But they shouldn’t matter anyway.

        • Very well said. I can’t begin to imagine what it feels like to be denied access to effective medications when you need them. All I can say is it sounds like the Bart’s team are doing their very best to advocate on behalf of pwMS living in the UK.

          • Thank you. I was denied a diagnosis for decades, so although I’m being denied access to the treatments I want/need now, it’s less traumatic than that was. But it is hard. I want HSCT or Lemtrada but I think HSCT is unattainable for me and Lemtrada is slipping away 😱

  • #AttackMS. I’ve had MS 35 years. I’m non-ambulatory, and upper limbs are going. I’ve tried all the DMT’s including Ocrevus and other off-label drugs (intrathecal methotrexate for 2+ years). None made a dent. If those newly diagnosed could live a productive life, without progressive MS, it should be a priority.

    • Yes, the #AttackMS trial supports our early effective treatment paradigm to maximise brain health for the lifetime of the person with MS.

  • Not sure I can add anything, having read the comments below. Except to say, thanks, great that you are trying to get trials into SPMS/PPMS going.

  • Isn’t ADIOS what Sweden already applies with RTX? If so, yes, it goes without saying, this is how antiCD20 should be administered. If a new trial is needed for O., it’s a shame for that money, because it will show the same results with RTX (B cell kinetics also means more often than 6 month retreatment too).

    • The Swedish data is uncontrolled and hence will be difficult to make sense of. In addition, rituximab is not ocrelizumab so it will be impossible to draw comparisons. Rituximab is not being used in the UK so this trial with rituximab would not interest the NHIR. What would be the benefit to the NHS?

    • Not easy. Ocrelizumab is not reversible therefore you can’t give it prior to a complete diagnostic work-up.

      • I’m confused. I asked about this a bit earlier
        >>
        May 1, 2019 at 11:50 am
        Does Ocrelizumab cause long term irreversible immune suppression?

        If so: from the outset or after X number of infusions.

        Reply
        ANONYMOUS
        May 4, 2019 at 9:58 am
        MD here Not sure why it would be irreversible as CD20 is not on the B cell precursors and they should be able to regenerate
        <<
        Is opinion split and there is no definitive answer or am I getting the wrong end of 5he stick?

        Thanks.

  • It’s a good problem for a mathematician and an opportunity for you to collaborate with university colleagues outside your area. Do this first and that could also help to justify your project and secure funding. Mathematicians have tools to answer questions like this, which I remember from my studies many years ago. Operations Research comes to mind. ‘Operations research, or operational research (OR) in British usage, is a discipline that deals with the application of advanced analytical methods to help make better decisions’ (Ref: Wikipedia).

  • Between the three, personally:
    Attack
    Adios
    Salvage

    The reason is I think this watchful waiting approach of neurologists- to use your language- needs to be turned on its head, and fast. Do they tell cancer patients “ let’s wait until the tumor has advanced until we treat it!?” No! The more we can do to change this paradigm the better off all people will be no matter how they advance.

    Along the same vein I’d like to see a H2H of HSCT vs HE infusion treatments….

    • You wait for a biopsy before chemotherapy though… Not in the case of this attack trial however, where there is no diagnosis.

  • You allready presented that study

    Ocrelizumab Treatment Effect on Upper Limb
    Function in PPMS Patients with Disability:
    Subgroup Results of the ORATORIO Study
    to Inform the ORATORIO-HAND Study
    Design

    Ocrelizumab reduced upper limb disability progression in more disabled/older PPMS patients. Risk reductions
    versus placebo in 9HPT progression were similar in patients with baseline EDSS score 25s (49% versus 44%, p=0.82). Progression events
    mainly occurred in patients with 9HPT >25s versus

    25s (placebo: 34.3% vs 17.8%; ocrelizumab: 21.5% vs
    9.9%); a weak trend for greater efficacy in patients

    45 years versus >45 years was observed (p=0.29).
    Conclusions:
    ORATORIO-HAND is designed to further investigate the efficacy of ocrelizumab on upper limb function. Based on
    the 9HPT progression rates observed in ORATORIO, 1000 eligible patients (EDSS 3.0

    8.0, age 18–65 years,
    9HPT >25s), randomized (1:1) to ocrelizumab or placebo for

    120 weeks (until a pre-specified number of
    progression events occur) will enable the assessment of ocrelizumab efficacy on confirmed 9HPT progression
    (primary endpoint). Screening will begin Q1 2019.

    http://indexsmart.mirasmart.com/AAN2019/PDFfiles/AAN2019-001571.pdf

  • 1) Attack
    2) Adios
    3) Salvage

    I am in the U.S., and from first hand experience, I firmly believe that starting Tysabri early on is why I am doing as well as I am 15 years after my MS diagnosis (Note: I am JCV+). After 7+ years on Tysabri, a couple years off, and now back on Tysabri again, the only other medication that I would consider at this point is Rituxan or Ocrevus. But if, as you say, Biogen will be funding or sponsoring Attack and that the U.S. will be working on Adios, then Salvage should certainly be your top priority. All the best. JSV

  • I meant use ocrelizumab as another DMT in the ATACKMS trial started after natalizumab, with 3 arms for ocrelizumab as in the ADIOS trial, cost effective and will benefit all patients and give you the data that are needed to draw conclusions for both hypotheses. The only downside is that it will be only newly diagnosed but the information can later be applied to all patients. Or have I missed anything? You can call it ATACKMSANDADIOS.

  • 1. SALVAGE (no-one else is gonna do it)
    2. ATTACK (great, but know this already?)
    3. ADIOS (up to Pharma to make drug safer and more convenient, won’t change efficacy)

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