Sunday, 11 October 2015

ClinicSpeak: Highlights and Hot Topics Lecture at ECTRIMS

ECTRIMS Highlights #ECTRIMS2015 #ClinicSpeak #BrainHealth #MSBlog #MSResearch

"Arrived back from ECTRIMS last night, tired and exhilarated. Tired because it was a busy week with little sleep. Exhilarated because of whole lot of new ideas and numerous leads to follow-up on. I would also like to thank the Barts-MS team; we had a very active ECTRIMS. Our social media presence speaks volumes for their efforts." 

"This was a very good ECTRIMS in relation to data presented. My highlights in order of priority:
  1. Positive trial of minocycline in CIS trial; where to from here? As always how do we get minocycline licensed for MS? In my 'Hot topics' talk (see below) I highlight the need for legislation to allow repurposing of off-patent drugs. For minocycline this is clearly a high priority. 
  2. Alemtuzumab 5-year brain atrophy rate; simply too good to believe. If correct these results suggest that alemtuzumab-treated MSers in long-term remission have brain atrophy rates in the normal range. There is simply no other drug that does this except for possibly HSCT in early MS (unpublished Canadian data). I am very keen to do a deep phenotyping study on this cohort of alemtuzumab-treated MSers to see how healthy their brains are and to see if there is any evidence of ongoing disease activity. It is important for MSers and neurologists to know this; it may the 'killer app' that alemtuzumab needs to get wide adoption and position it away from all other DMTs, except possible HSCT. The latter is another reason for us to do the ZEUS trial
  3. Ocrelizumab in relapsing MS results; very good efficacy with a very favourable safety profile. Ocrelizumab will allow us to flip the pyramid and use highly effective treatments very early in the disease in the majority of MSers. However, my initial enthusiasm for ocrelizumab has been dampened by Steve Hauser's comments that a large number of their patients with relapsing MS who have been treated for 10+ years on rituximab have now developed SPMS. If this is correct then anti-CD20 B-cell depletion will not be a panacea. Clearly we need to do similar deep phenotyping studies in ocrelizumab-treated MSers and we need to see what happens to brain atrophy rates over the long-term. 
  4. Ocrelizumab in PPMS results; although these were positive we will need to wait to see if the results are being driven by a subgroup of PPMSers with inflammatory activity. I would be surprised if the regulatory authorities license ocrelizumab with a wide indication for PPMS; I suspect they will push for a more restrictive license based on subgroup analyses. This study also suggests we need to focus our attention of the B-cell as being the main driver of MS disease activity. 
  5. Cognition is an early predictor of disability progression in MS. This now supports the incorporation of cognitive testing into routine clinical practice and the counselling of MSers about cognition. A focus on cognition, which is almost certainly a driver of early disability in MS, may also help the speedup the adoption of the early effective treatment paradigm in MS. Who wants to lose brain and cognition? If MSers knew this they would push for more effective treatments earlier in the course of their disease. 
  6. Brain Health; for me personally launching our 'Brain Health: time matters in multiple sclerosis' policy document was a a major achievement. We hope this document acts as the catalyst to a change in the way we view the management and treatment of MS across the world. Please download and read  the document and if you agree with the policies pledge your support. The more people who support this document the more influence it will have and ultimately it will help us achieve our vision 'to create a better future for people with multiple sclerosis and their families'. 
As promised the following is my 'hot topics' talk from Friday."

CoI: multiple

35 comments:

  1. Seems I was over enthusiatic over antiCD-20 I was hoping it would block progressive disease ... Btw is the presnation video or at least the slides available anywhere .. I would love to know further details ..

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    1. This comment has been removed by the author.

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    2. yes the population's baseline can really skew results , ideally this needs to be tested on treatment naive patients with early disease.. hope we get more details soon

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  2. Prof G,

    Thanks for this - I always value your takeaway key messages.

    I'm still glad I opted for Alemtuzumab 8 years ago. I don't think any of the currently licensed drugs / those in Phase 3 can match its effectiveness. Conversion to clinically defined SPMS is a plus point for any RRMS drug - treat hard and early with a drug like Alemtuzumab is the best chance to push out conversion to SPMS.

    When I was diagnosed in 2005 I saw that researchers in Calgary were examining minocycline. I wrote to them to ask if I could participate in a trial. I can't believe ten years on it hasn't got much further.

    There was little new for SPMSers. Also little real news on neuroprotection or neurorestoration. The anti-lingo trial is another which is dragging its heels.

    Any thoughts on the results we should be looking out for in the next 3-6 months? We must be nearing the end of anti-inflammatory research / trials.

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  3. Do T cells drive atrophy? B cells focal lesions?

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    1. the lymphoid cells i bet drives atrophy due to relapsing MS

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  4. I continue to be flabbergasted by how often the alemtuzumab news gets sidelined on MS websites. These guys need better PR and stat.

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  5. I had Alemtuzumab sometime ago - under the excellent Prof Coles. I have an annual clinic check (bloods / EDSS) and usually an annual MRI. Currently I'm told there is no evidence of disease activity. What further tests can you do Prof G to check if my disease is really dormant? Would it include the biomarker testing mentioned on is site earlier?

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    1. the MRI data on long term follow up of Alemuzumab was very good.

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  6. Prof G,

    Was there no news on stem cells and repair? 4-5 years ago there was a lot of media coverage about Prof Scolding and stem cell repair trials, but its gone very quiet.

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    1. there were the anti lingo studies but these were reported at the AAN

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  7. In point 3 you state
    "However, my initial enthusiasm for ocrelizumab has been dampened by Steve Hauser's comments that a large number of their patients with relapsing MS who have been treated for 10+ years on rituximab have now developed SPMS. If this is correct then anti-CD20 B-cell depletion will not be a panacea. "
    and then you state in point 4
    "This study also suggests we need to focus our attention of the B-cell as being the main driver of MS disease activity...."
    This seems contradictory. Are B-cells returning to a deleterious phenotype over time as Dr. Hauser seems to suggest?

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    1. Re: "This seems contradictory."

      I agree. We may need treatments that take out both B cells and plasma cells. However, we need to try and work out what it is about B cells that are driving disease activity. Is it because of their antigen presenting function, their regulatory function or is because they harbour EBV.

      If we need to target both B cells and plasma cells then other therapies may prove to more effective than anti-CD20 treatments.

      Yes, working out how the highly effective treatments work will help us find more effective treatments.

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  8. Prof G,

    Is there any reason the think that Alemtuzumab delays or prevents the onset of SPMS any better than the antiCD20s?

    Thanks

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    1. Re: "Is there any reason the think that Alemtuzumab delays or prevents the onset of SPMS any better than the antiCD20s?"

      No, the follow-up of the ocrelizumab-treated cohorts is too short. Let's hope Steve Hauser, Tim Vollmer, the Swedes and other MSologists with large cohorts of MSers treated with rituximab publish their long-term follow-up data.

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    2. Would I be correct in thinking that patients who were prescribed Rituximab off label would have more active disease and would have failed other therapies beforehand? Could this play into them moving to SPMS?

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    3. at ectrimsin three poster alone there were about 1300 people on rituximab including PPMS

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  9. Hi Prof G

    Just want to give you and the team a massive thank you for this blog. I am in the middle of a relapse and freaking out about my cognitive function. I am going in with all guns blazing now to the Neuro on Wednesday armed (in a strictly metaphorical sense).

    Have a rest though we need you and burn out even can burn the Prof.

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  10. "However, my initial enthusiasm for ocrelizumab has been dampened by Steve Hauser's comments that a large number of their patients with relapsing MS who have been treated for 10+ years on rituximab have now developed SPMS."

    Did he provide any more information about this? If not, could you perhaps contact him to ask for more information? If this is true, and if these were patients treated early in the disease, then this would suggest a nearly complete dissociation between inflammation and transition to SPMS. That's tremendously important both from a clinical perspective and a scientific one.

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  11. Maybe I misunderstood or dreamt this, but I thought that yesterday there would be a report on the Med Day trial with biotin? Any news? (Thanks for the other feedback). Jill

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  12. Prof G

    1. do you know if any patient from the alemtuzumab group converted to SPMS during the 5 years?

    2. what was the age group of the patients? CIS level or shortly after diagnosis or people with long disease duration? That could explain the relatively healthy brains.......

    3. what about side-effects in that 5 year group?

    It's looks promising but 5 years is still too short a time to say if they won't convert in another 5-10 years or develop some serious side-effects.

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    1. 1. Years 0-5 80% of patients were free from 6month SAD (sustained accumulation in disability) and 69% had stable/improved EDSS scores.

      2. In there 30s. Mean years since symptom onset is 2 years. The EDSS is 2 which is the critical factor. Makes the real use of the therapy as induction.

      3. Thyroid AE peaks at year three. The others are same as before, infusion reactions and infections.

      The study extension is currently called TOPAZ and is hoped to extend for another year or so. They may continue a small number for future studies but it will revert to after this to post-marketing reporting by physicians as with other licensed therapies.

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  13. Thanks for the great work Team G and Mouse Doctor.

    I can't wait until the footage is out on youtube.

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    1. https://youtu.be/Bbc6aKbyyOQ

      To be clear I did not say NDG was going to drink 3 Sangria at 42min in contrast to what she thought but it did get a smile

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  14. Of course we cannot do a comparison in a separate studies etc etc but how does the clabridine atrophy data compare to that of alemtuzumab? This blog is an amazing resource btw!

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    1. Nicola de Stefano presented preliminary data on brain atrophy at AAN 2013. I'll ask him whether publication is under way. I believe the MR techniques used at the time were of limited use for measuring atrophy.

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  15. What about the biotin trial? Any news there?

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  16. Which presentation/poster was about cognitive impairment predicting disability? Would like to look that up. Thanks for your help!

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  17. Much thanks for this very important blog. Unfortunately, once again I feel that the news on the SPMS front was a let down. Hype followed by disappppintment. Familiar pattern.

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  18. Re "Steve Hauser's comments that a large number of their patients with relapsing MS who have been treated for 10+ years on rituximab have now developed SPMS"

    The long-term effects of B-cell suppression are unknown. Add to that SPMS some years down the line.
    Patients on off-label rituximab should at least start thinking of a way forward / way out.

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    1. Wonder what the Swedish experience is, they have alot of people taking rituimab in a few posters I counted over 1000 people.

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  19. With all this recent attention to B-Cells, why isn't anyone talking about the only oral DMT that inhibits B-cells in MS pts?
    2013 Journ Neuroimmunolgy

    The effects of teriflunomide on lymphocyte subpopulations in human peripheral blood mononuclear cells in vitro

    Li Li a, Jingchun Liu a, Thomas Delohery a, Donghui Zhang b, Christopher Arendt a, Catherine Jones a,⁎

    3.3. Effect of teriflunomide on B-cell activation and proliferation by CpG in PBMCs

    CpG treatment for 5 days stimulated proliferation in the CD19+ B-cells, and this proliferation was significantly inhibited by teriflunomide at concentrations of both 25 and 100 μM (p b 0.001) (Fig. 3A). As observed for T lymphocytes, the addition of exogenous uridine significantly reversed inhibition of proliferation at both concentrations of teriflunomide, again suggesting the involvement of DHODH in the inhibitory activity of teriflunomide. CpG treatment also signifi- cantly activated CD19+ B-cells, as determined by an increase in the percentage of cells co-expressing CD80 (p b 0.001), however, teriflunomide did not impact this shift in activation at either dose tested. Representative histograms for B-cell proliferation are shown in Fig. 3B

    In conclusion, teriflunomide can significantly inhibit T- and B-cell proliferation, potentially reducing the expansion of autoreactive lymphocytes involved in the pathogenesis of MS. An additional therapeutic benefit may also be provided by teriflunomide through reducing the production of specific pro-inflammatory cytokines and chemokines. These data may help to explain the beneficial effects of teriflunomide across a range of key clinical and MRI endpoints in patients with RMS, and suggest actions on multiple inflammatory cell types via both DHODH- and non-DHODH-dependent pathways.

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    1. The effects of teriflunamide in the pivotal trials were not that great but at ECTRIMS this year there were some interesting posters

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