Monday, 12 June 2017

#ThinkSpeak: divided loyalties

Do we have enough information to tackle progressive MS and make a real difference? #MSBlog #ThinkSpeak

Today the Mouse Doctor and I will be attending an extraordinary meeting of MS Society's Clinical Trial Network (CTN) to discuss research priorities and how we proceed to tackle progressive MS as part of the MS Society's STOP-MS campaign. The difficulty we find ourselves in is that it clashes with our Institute's strategic away day; an annual day when we go off campus to discuss strategy and set priorities for the next year. The fact that we have both agreed to attend the CTN meeting either tells you where our priorities lie, or how important this CTN meeting is. 


A lot is happening in the progressive MS space with several new developments and insights that all need to be taken into account when setting sail on a journey that once you leave harbour and have set your course it is difficult to return and start the journey again. 

The following is a list or recent developments that have affected the progressive MS space and mean we need to rethink things:

  1. Ocrelizumab the first effective DMT for progressive MS has been licensed by the FDA for PPMS (let's hope the EMA does the same later this year) and we also have a positive spinonimod SPMS trial. As a result of these two trials we now have to accept that progressive MS is modifiable, but I am aware that many killjoys in the field don't think the outcomes in these trials are clinically meaningful.
  2. There are several ongoing progressive MS trials looking at interesting compounds, treatment strategies and trial designs. I think we should wait for these to read out to learn from them. 
  3. There are at least 4 industry sponsored and investigator-led progressive trials, that I am aware of, starting. The activity in this space is unprecedented and I am concerned there may not be enough people with progressive MS for all these trials. Please note that almost all of  these trials are using an EDSS cutoff of 6.5, which excludes the majority of pwMS who have progressive MS from participating. 
  4. The MS Outcomes Assessment Consortium (MSOAC) that was launched in December, 2012, has finally reported. MSOAC was established to collect, standardize and analyze data about MS with the goal of qualifying a new measure of disability as a primary or secondary endpoint for future trials of MS therapies. The important thing about MSOAC is that the regulators, in particular the FDA, now accept a composite end-point for progressive trials. The importance of this cannot be overemphasised. 
  5. The International Progressive MS Alliance (PMSA) have now funded their collaborative networks and these will take 3-4 years to deliver important insights into new mechanisms underlying progressive MS. 
  6. Publication of the length-dependent axonopathy, therapeutic lag and asynchronous progressive MS hypotheses. The paper is not just about the musings of Barts-MS, or us blowing our horn. The insights outlined in this paper explain why the current trial paradigm in progressive MS has resulted in negative trials. If we designed the trials properly we would have gotten positive results in progressive MS decades ago. When we developed these hypotheses we engaged the wider MS community including industry. It is notable that we have representation from Biogen, Merck, Novartis, Roche and Teva on the paper. Including Pharma was no accident, we want them to invest in progressive MS and design successful trial, including trials in more advanced MS (wheelchair users).  
  7. Development and validation of a sensitive serum/plasma assay for neurofilament levels. This may be the game-changer we need for doing phase 2 proof-of-concept trials in progressive MS. The idea would be to do an area-under-the-curve analysis of neurofilament levels to assess the efficacy of a treatment at reducing neuroaxonal loss in MS. 
  8. Validation of the 9-HPT as clinically meaningful outcome measure of upper limb and hand function. The results of the 9-HPT correlate very well with the ABILHAND a patient-related outcome measure (PROM) that has face validity, i.e. it is clinically meaningful. 

Some of the issues that I think need discussing are:

  1. When does progressive MS begin? 
  2. Is MS one, two or three diseases?
  3. Should we be combing SP and PP MS populations when we do progressive MS studies?
  4. Should we be doing combination, rather than monotherapy, studies? 
  5. If we go with an anti-inflammatory platform, which is the best anti-inflammatory? 
  6. Do we need neuroprotection in addition to remyelination, or can we target remyelination on its own? 
  7. How do we design neurorestorative trials? What can we learn from Biogen's opicinumab (anti-LINGO-1) trials and other exploratory remyelination trials (e.g. clemastine)? 
  8. When doing neurorestorative trials do we need to include a targeted neurorehabilitation programme to promote recovery? 
  9. Should we be investing in a useful patient-reported outcome platform as part of the MS register to do registry trials? 
  10. Should we be including people with MS with more advanced disease, i.e wheelchair users? 
  11. Should we be doing randomised DMT withdrawal studies to see if people with progressive MS are still benefiting from DMTs?
  12. What about co-morbidities, in particular hypertension, diabetes and metabolic syndrome? Ruth-Ann Marrie has shown that treating co-morbidities may be as effective as a DMT in delaying disease worsening in pwMS. 
  13. What about lifestyle issues, for example smoking, diet, sleep and exercise? This is the elephant in the room and is the reason why we are actively promoting lifestyle issues as part of our Brain Health campaign. 
  14. What about the contribution of recurrent infections to progressive MS? Should we include preventing recurrent infections as part of this initiative? 
  15. What about premature ageing? How do we dissect out ongoing MS pathology from ageing mechanisms in progressive trials?
  16. Trial design, do we go with the standard randomised placebo-controlled trials and include time-to-event analyses? Do we use adaptive design? Standard vs. Bayesian statistics? 
  17. How do we derisk trials, i.e. give them the best chance of being positive? How can Pharma help us with derisking trials? 
  18. How do we create policy to allow the repurposing of off-patent drugs? If we don't do this is it worthwhile doing trials on drugs with no defined commercial development path? 
  19. What can we learn from other fields, or are we sailing on uncharted waters? 
  20. Which experts from MS and other fields can we consult for help?
  21. How to deal with conflicts of interests? Almost everyone in the UK has a conflict and a personal or institutional agenda? 
  22. Are the outcome measures that work for RRMS fit for purpose when it comes to progressive MS trials? Do we need to develop new more targeted outcome measures for more advanced MS? 
  23. Can we select drugs, or potential drugs, for progressive MS from the published literature or patent literature? 
  24. Can we crowd-source drug discovery for progressive MS?
  25. Managing expectations. How do we manage the community's expectations? We don't want to overhype things. What is a realistic expected outcome when tackling progressive MS? Is it slowing-down worsening disability? Stabilising, or flat-lining, current levels of disability? Or should we looking at restoring lost function?
As you can see we have an interesting day ahead of us. 

CoI: multiple

18 comments:

  1. I just watched the MSOAC short video 'MS impacts us all'. "The likelihood you know someone with MS...Almost certain".

    This is an interesting point as before I was informed I might have MS I don't think I knew what MS was. I'm not even sure I had heard of it before at that point. I have also spoken with other pwMS and they have said they had not of heard of MS before their diagnosis.

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  2. Lasting stabilisation of progressive MS is the holy grail. In my opinion it's not achievable with the compounds currently going through clinical trials (or soon to start). More radical compounds, like androgens, estrogens, endothelin modulators, nerve growth factor implants or intrathecal injections, etc.

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  3. That's a packed agenda; do you infuse your coffee?

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  4. You mention 8 recent developments and 25 issues of interest regarding progressive MS and thus create the immpression of massive ongoing activity around it.

    Yet, a careful examination reveals that you only talk about drugs, or ways to enhance (drug) trial designs. Even the information quest is under the umbrella of drug trials: you tend to support your arguments on interpetation of these trials, not on basic research. Wherever there is hard evidence present, you eagerly set it aside as circumstantial.

    If you took a step back you could see how disproportionally drug-orientanted is the road you offer. It is destined to fail in the long run. Remember the worn-away hype of Infs, Gilenya, Tysabri, BG-12 and alemtuzumab. You still talk about newer drugs, stretch the expectations to point break and then again some more. First T, then B, then memory-B, then T again, then both, then what? It is fruitful road for research, not for patients.

    How many drugs on the market before you change course and get back to answering the basics of Ms?

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    Replies
    1. There is this: https://www.geneuro.com/data/documents/GeNeuro-presentation-January-2017.pdf

      Looks promising to me.

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    2. MS can't be (retro)viral. Viral action can't explain the specific lesion topology as described in:

      1. The topograpy of demyelination and neurodegeneration in the multiple sclerosis brain
      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4766379/
      2. Cortical lesions in multiple sclerosis
      https://www.ncbi.nlm.nih.gov/pubmed/10050891

      Nor can it explain the violent axonal damage in spinal cord lesion in virtual absence of immune cells:

      3. Heterogeneity of spinal cord pathology in multiple sclerosis and variants: A study of postmortem specimen from 13 Asian patients
      https://www.semanticscholar.org/paper/Heterogeneity-of-spinal-cord-pathology-in-multiple-LI-LU/0c82c04d4dd104cadc5cf5ac6e98f6b742dac3ef

      Nor can it explain this:

      4. Multiple sclerosis following a spinal cord injury: a rare and unfortunate case
      https://www.ncbi.nlm.nih.gov/pubmed/28053730

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    3. People get MS chronologically after all sorts of things, it doesn't mean that those things cause MS. For example, most people get MS after graduating high school, but graduating high school doesn't cause MS.

      What makes you believe that a virus can't cause the lesion pattern seen in MS?

      I'd be wary of studying Asian MS patients given a lot of them have a form of NMO rather than MS.


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    4. "There is this: https://www.geneuro.com/data/documents/GeNeuro-presentation-January-2017.pdf"

      Nice..also this.

      http://files.shareholder.com/downloads/AMDA-2ZWAH8/4632525451x0x942119/46484DF3-27E3-4951-9538-8F13D7B7341A/AtaraBio_Corporate_Presentation_June_2017.pdf

      "Viral action can't explain the specific lesion topology.."

      p.21 of pdf shows lesion disappearance after treatment with
      CTL(cytotoxic lymphocytes) with EBV proteins that eliminate
      EBV Bcells and plasma cells in the CNS.

      Patient shown no further progression in 4 years. If progression is to all be from previous
      inflammation he should have continued
      to progress...instead progression was stopped in weeks
      and hands came back. Moral of the case is effective therapies work quickly and don't need 2 years of IV/inject/pill.

      http://patienttalk.org/killer-t-cells-a-new-way-to-fight-multiple-sclerosis-read-our-interview-with-gary-allen-one-of-the-test-subjects-for-prof-michael-pender-ms-research/





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    5. Very interesting links adam bomb.

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    6. "What makes you believe that a virus can't cause the lesion pattern seen in MS? "

      This:
      Brain imaging abnormalities in CNS virus infections
      www.neurology.org/content/70/1/84.full.pdf

      There is no resemblance to MS lesions. No Dawson's fingers, no periventricular distribution, no central veins, no ovoid shape. Just diffuse damage. Are you convinced?

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    7. Just to give you some background which might be useful, Vasilis Vasilopoulos has been a keen devotee of the CCSVI theory in the past and may still be so, even though it has now been comprehensively debunked by a number of recent studies.

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    8. The idea Vasilis is that a virus causes an aberrant immune response against CNS targets by infecting immune system cells, and this is what produces the focal inflammatory lesions seen in MS.

      In my opinion simple failure to remyelinate is not sufficient to explain the neurodegeneration seen in MS. I think something more fundamental to the survival of axons is being effected.

      MD2, thanks for the heads up.

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    9. I give you evidence that this idea contradicts the pathophysiology of MS as seen in autopsy and MRI studies. If only you took some unprejudiced time on the 5 articles above.

      Axons are constantly damaged, you are right, but the damaging agent is not on cell scale, nor is the damaging process same in brain and spinal cord. But this is too much for now.

      I think the main problem is not getting convinced by the articles i provide, but accepting to disaggree with your doctors.

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    10. I suspect I know what's coming down the line ;-)

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    11. No, you don't.
      FAMTAIS and ACTION trials are coming...

      Delete
  5. Apologies Mouse Doctor and I can't report back from this meeting as everything discussed was confidential. But it is all good news, which will emerge over the next few months and years. We were all singing from the same hymn sheet.

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