Progressive MS is a misnomer

Barts-MS rose-tinted-odometer – zero stars

I am in Milan at the International Progressive MS Alliance Industry Forum Meeting. The aims of the meeting are to:

  1. Discuss challenges understanding and measuring progression and its impact on drug labels
  2. Discuss regulatory issues, opportunities and implications for drug labels and regulatory approvals
  3. Discuss links and opportunities for industry and the Alliance to contribute feedback to the International Advisory Committee on Clinical Trials in Multiple Sclerosis activities on phenotype classification and clinical trials
  4. Share lessons from recent clinical trials/development programs and how they impact the challenges of developing drugs for progression in MS

I have been asked to speak on the implications of disease classification for drug development, regulatory approval and drug labelling. This topic is fine, but it is far removed from people with the disease, which is why I am going to base my talk on case scenarios to illustrate how absurd the current status quo is for pwMS and the wider MS community.

As a pre-read to these case scenarios, I suggest you read a previous post of mine about progressive MS.

Case scenario 1

48-yr old woman
MS x 22 year
Last relapse 8 years ago – lower limb weakness and exacerbation of bladder problems

Annual MRI scans:
Last scan 3  years ago
Marked brain and spinal cord atrophy

Poor gait, now needs to use walking sticks outdoors and can manage only 10-20m; uses scooter outdoors
Bladder and bowel problems  with recurrent UTIs
Significant cognitive impairment

EDSS = 6.5

DMTs: Interferon-beta-1a stopped 3 years

Does this patient have active SPMS?
Does she have active SPMS?

Case scenario 2a

36-yr old male
MS x 12 years
Previously treated with Rebif-44 x 6 years; failed due to ongoing relapses
Switched to fingolimod 3 years ago
Last relapse 4 years ago / MRI stable

EDSS = 3.0 (stable)

Difficulty running and walking long distance; Fitbit data over the last 3 years showing objective reduction in daily activity

Does this patient have SPMS?
Is the patient eligible for a DMT switch?
Is the patient eligible siponimod?

Case scenario 2b

36-yr old male
MS x 12 years
Previously treated with Rebif-44 x 6 years; failed due to ongoing relapses
Switched to fingolimod 3 years ago
Last relapse 4 years ago / MRI stable

EDSS = 3.0 (stable)

Difficulty running and walking long distance; Fitbit data over the last 3 years showing objective reduction in daily activity

Labeled as having inactive SPMS
Under NHSE guidelines fingolimod is stopped and 10 weeks later he presents with new onset paraplegia
MRI shows longitudinally extensive myelitis and >30 new Gd-enhancing lesions over the neuraxis

Does this patient have SPMS?
Is the patient eligible siponimod?
What happens if his treatment response is suboptimal on spinoimod?

Case scenario 2c

36-yr old male
MS x 12 years
Previously treated with Rebif-44 x 6 years; failed due to ongoing relapses
Switched to fingolimod 3 years ago
Last relapse 4 years ago / MRI stable except progressive brain volume loss (0.78% per year over the last 3 years; Icometrix)

EDSS = 3.0 (stable)

Does this patient have SPMS?
Is the patient eligible for a DMT switch?
Is the patient eligible siponimod?

Case scenario 2d

36-yr old male
MS x 12 years
Previously treated with Rebif-44 x 6 years; failed due to ongoing relapses
Switched to fingolimod 3 years ago
Last relapse 4 years ago

EDSS = 3.0 (stable), but has noticed increasing forgetfulness at work and difficulty using a new software system
T25W & 9HPT stable
SDMT worsening:
2017 = 48 
2018 = 45 
2018 = 41
2019 = 39

Does this patient have SPMS?
Is the patient eligible for a DMT switch?
Is the patient eligible siponimod?

If you work through the logic of each of these case scenarios that are based on real-life examples you will quickly see that the current status quo is not compatible with the biology of the disease and makes very little sense; in other words, classifying MS as three diseases is absurd.

CoI: multiple

29 thoughts on “Progressive MS is a misnomer”

    1. Yes, progressive MS or more correctly the pathology driving progressive MS is there from the beginning and is the ‘real MS’.

      1. Is it simply that some PwMS suffer that pathology in a more severe than others?

        If the disease is the same for all of us, how can it progress so differently in pace and harm?


  1. Rebound post-fingolimod is now so well described, why take a chance by stopping fingolimod? Surely you can classify MS as active without having to withdraw the current DMT, in this example, fingolimod?

    1. Yes, I agree. It seems foolish to classify someone as having inactive SPMS on a DMT. But stopping DMTs to see what happens is not an option either. This creates a real catch-22 siutation that regulators and payers don’t understand.

  2. I’m sorry Prof G, but this is all getting so boring (perhaps boredom is my main MS symptom). Another week passes and you board another flight (you need to take some personal blame for global warming) to attend another international talking shop (the age of austerity seems to have had no impact on the travel and subsistence budgets for MS doctors and academics).

    While a discussion on whether MS is 1,2,13 diseases may be intellectually stimulating for those that way inclined it is irrelevant to this of us with the disease. The case studies are based on real cases – so we are looking at people in their prime who are getting more disabled and no real future (in terms of health, dreams etc.). We, who read this blog, are these people – so the scenarios don’t come as any surprise to us.

    Instead of renaming, running through case studies…… surely it’s time to j pick the biology of the disease and then identify treatments which stop tissue damage, brain atrophy… These talking shops deliver nothing of benefit for patients. They just lead to some consensus and a commitment to have a follow-up talking shop some point in the future.

    I’d be interested in how this all goes but I don’t hold out any hope that it will result in any tangible benefit for me or others with the disease. At least Mrs G will get a Gucci scarf and you can enjoy some seafood risotto with a bottle of chianti.

    1. Whats the difference between a (drummer) neurologists and a (drum machine) neurologist cyborg machine…you only have to punch the information into the machine once:-).

      “It is irrelevant to those of us with the disease”….when you get denied treatment options then it is important, it you had been labelled SPMS rather than RRMS then no alemtuzumab, if you are lablled PPMS rather than RRMS no nothing until recently. Now the issue is being labelled SPMS to get siponimod…fail that and there is nowhere to go. The US lisenced siponimod and cladribine from CIS to SPMSS the EU regulators just gave an active disease indication for siponimod.

      Why don’t you lot make/find a drug…this seems to be a recurrent theme on the blog

      1. Whatever you say, it’s 2020 and we are going round the same buoys again and again. The flip the pyramid approach has not moved on – we have anti-inflammatories but no neuroprotection, remyelination or neurorestoration therapies. If you were one of the patients in the scenarios above you’d be pretty naffed off as well. I’m not hear to say how great MS researchers are and how much progress has been made. We need a. Extinction Rebellion approach. What has been achieved to date has not been good enough and young people are having their lives devastated by this disease. Too long is spent at conferences putting up endless slide shows of pointless graphics. A person diagnosed today with PPMS with no ‘active lesions’ is thrown on the scrap heap to rot while MSologists and researchers turn up at ACTRIMS, ECTRIMS, PACTRIMS, LACTRIMS… to pat themselves on the backs and discuss how clever they are. There’s a new play about Jacqueline du Pre – died of MS at 43. Have we really moved on that far in the last 40 years. A 48 yearild woman should not be reliant on an electric scooter given how much money pharma (and MSologists) ha e made from this disease. Shocking is an understatement.

      2. “The flip the pyramid approach has not moved on”…..Is that our fault..Don’t shoot the messenger

        “I’m not hear to say how great MS researchers are”…..Have you ever said a good word?…us we are punching bags but…not even a good word about your consulting neurologist? Never ever?. I’ll have to trawl through the blog to check.

      3. My neuro is brilliant.

        “Don’t shoot the messenger”. Who is responsible? Researchers? MSologists? pharma? Government? The MS industry doesn’t seem to care a jot about the MSers described above. If MS is progressive from the start the mechanisms driving progression should be effectively treated. Instead we’ve had almost 30 years of letting MSers inje t themselves with Copaxone and Interferon to then be told that you’re moving up the EDSS scale at a good rate – better buy some walking sticks and order that electric wheelchair!

      4. There you go….Praise indeed…wonder who.

        Yeah don’t shoot the messenger….Who is responsible? People with power and money I guess.

    2. It may be boring, but it has real relevance for people living with MS. I hope these case scenarios show you how absurd the status quo is.

  3. Prof G is spot on. This is so important. I have several peers who have had Fingolimod withdrawn due to being classified as “SPMS”. They have deteriorated dramatically and irreversibly within months of withdrawal of the DMD eg going from ambulant with one cane and socially engaged to being confined to a wheelchair and socially isolated. I regard this as criminal negligence. My observation is that people who stay on DMDs do better, regardless of whether they have SPMS and whether their SPMS is “active” or not (all SPMS is active its just a question of whether its smouldering or ablaze ).
    I was diagnosed with ‘Benign MS” now I am “late cane” requiring two canes to walk and using a scooter for long distances. I want to stay as stable as possible, slow the progression of my symptoms, preserve cognition. hand/arm, bladder and bowel function.
    PwMS will tell you that distinguishing RRMS, SPMS and PPMS is removed from our reality.

  4. They will never classify MS as one drug because pharma make big bucks from orphan drug status. Same pharma that fund barts and other research units. Using star wars analogy. For patients and their family’s well being. Time to decide between the dark and light side of the force. By naming and shaming pharma that are stifling research and pushing their own agenda.

  5. When I was first diagnosed as a teenager in 1965 it was just one disease …I rejoined the disease a few years ago after over 40 years of no activity ..and there seemed to be lots of different disease categories …so we seem to have gone round the Wrekin and back on this one . Not sure to what purpose but it has obviouslytaken an inordinate amount of time ,energy and research to do so.
    Appreciate that different meds could be made better available if no differentiation …but still seem to be lots of caveats around that scenario .

  6. I would certainly be interested in this debate. Is it recorded or streamed by any chance?
    Are the notes published otherwise?

      1. Kindly post your thoughts after the meeting then if possible.
        There is surprisingly very little out there on Siponimod at this stage….

  7. Some words of appreciation! Drug development and scientific understanding takes time, commitment, perseverance, teamwork….Barts blog team demonstrate all this and much more. Thank you !
    Mousedoctor’s posts on Alemtuzumab and globody demonstrate the teamwork necessary for lab to patient work (translational medicine) . The team includes students and junior staff. This role modelling will take MS research forward, as well as Prof G’s challenges to the MS world. The team’s skills and commitment are rare. The Blog is unique. I salute you all (contributors and commentators alike)

    1. Ditto. Please keep up the good work and writing about this stuff, it does matter to many of us patients. The fact you all keep this blog going consistently with so many updates alongside your undoubtedly busy and stressful jobs, and then personal lives is also impressive. Something I’m sure you are not obliged to offer with such comprehension, passion and user engagement. So thanks!

  8. The speed of progress is annoyingly slow but I am grateful that Barts keep us in the loop with the blog as much as they do, I am sure they don’t have to.

  9. Ditto to Anon, Hannah and Julie.
    The anger and frustration I experience tends to concern the fact that far too few HCPs have come on board with flipping the pyramid and comprehending MS as one disease.
    Watched Aaron Boster on one of the latest MS Views and News vids being so clear that medication should be continued: ‘if you still have an immune system, and functions in your body that you like, like seeing or eating or waving or picking your nose, whatever, I wanna preserve the reserve, I wanna preserve that function’ This is why everyone with MS should have access to DMTs and on a life-long basis!
    Good luck with trying once again to put over the one disease message.

  10. Pwms have one more cause to choose PIRT before they got this horrible foolish label: inactive SPMS!
    So let’ts go and choose Alemtuzumab or cladribine to stop the furter ongoing ‘inactive SPMS’ inflammation!

  11. I’m so glad to see that someone has taken up the “one disease” cause so vigorously. It was clear to me early on in my MS lifecourse that the disease categories were at worst meaningless and at best grey around the edges. I tried out that latter phrase on a few MDs and none of them disagreed with it. A bit more thought and observation led to the conclusion that the main purpose of MS categories was to define market segments for manufacturers and provide some prospect of cost limitation for payers. Only after drug development and approval did the “phenotypes” gain clinical relevance.

    It’s unfair to suggest that researchers have simply been spinning their wheels. I wish, however, that more attention had been paid to symptom management, specifically physical therapy. At age 69 I don’t expect significant relief from pharmaceutical advances. But I would prefer not to have to read repeatedly that spasticity is “poorly understood.” My therapists and I need better guidelines for treating this common MS symptom, based on an understanding of the mechanisms of dysfunction and rigorous experimental comparison. In return for significant advances in this area I would happily greenlight conference trips to Italy, with all the fresh pasta, truffles and Barolo a researcher might consume.

    Thanks again for the frank and very enlightening exchanges here.

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