Saturday, 28 October 2017

Late Breaking ECTRIMS News. Ibudilast sprints to the lead and shows success in progressive MS

It is time to eat humble pie


Earlier in the year I expressed concern about the use of Ibudilast in MS. 

http://multiple-sclerosis-research.blogspot.com/2017/09/hot-topic-at-ectrims-late-breaking-news.html


The wait is over and I was possibly wrong, 

It was shown that Ibudilast reduced brain volume loss by 48%. in progressive MS, so supporting the past trial in MS. As we know this agent does not stop relapses and so now the age of progressive MS really changes.

Probably as ProfG says below...we don't know if this effect was clinically meaningful, but at least it's a start.


What happens next?

We are not going to be thinking that the agent is targeting active lesions so this is targeting a different mechanism.


How does this work? 

Ibudilast is a PDE4 phosphodiesterase 4 inhibitor, you can read the post above to show how this works.

Ibudilast is also a macrophage inhibitor, and is this the key? 
We have said for some time that macrophages/microglia are at the centre of the inflammatory response. So their inhibition is a good thing.

Ibudilast will also inhibit tumor necrosis factor, which is a survival factor for plasma cells. So does it stop the production of oligoclonal bands?

Trial details


It was a 28 site trial sponsored by the NIH. The criteria were up to 65 years old, primary and secondary progressive MS. Allowed treatments were beta interferon and glatiramer acetate.  

86% finished the trial and about 5% more people stopped taking Ibudilast.

The main side effects were gastrointestinal problems including pain, vomiting and diarrhoea. There was an increase in rashes and depression. In addition, fatigue was slightly worse, 

A marked effect of magnetization transfer ratio (a measure of  tissue structure integrity) was seen, but no significance was seen with Diffusion tensor imaging .

Well done to All....The MS world changes!

CoI: None


49 comments:

  1. This is more effective than Ocrelizumab by reducing brain atrophy. Taking then in co.bination will effectively stop the disease right? Also as barts say if it's same the same mechanism in terms and ppms. Then a combination therapy effectively makes a ms benign disease? For all types?

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  2. Until we see clinical, or more detailed biomarker, outcomes I am not sure if we can claim that this is clinical meaningful.

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    1. Prof G, genuine question - how do you know whether outcomes are clinically meaningful? I've seen it in the context of several trial outcomes, but I don't understand the concept - what is the point of the trial if the results aren't meaningful? And how do you decide whether they are or not?

      Apologies if you've answered before, could you point me in the direction of previous posts on this if you have.

      Thanks

      Delete
    2. A phase II is about getting hints of a surrogate so another trial will have to be done using clinical endpoints...will they use hand function or lower limb outcomes as the primary target. We will see clinical data once they analyse the results more.

      Delete
    3. Ah, yes, that makes sense.

      Thanks for the clarification, MD

      Delete
  3. Looks like someone was blabbing you say !

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  4. The usual hype. Big news / great news... followed by analysis of the data which will show that the news wasn't so big / great. This will be another damp squib. surely the only thing an anti-progressive drug needs to do is stop disability worsening. Why give percentages? I understand there were 10,000 attendees at the ECTRIMS conference. I hope a good time was had by all. Was it of any value for people with progressive disease? I doubt it.

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    1. Dear Ebineezer it is not christmas yet so please be a bit more cheerful. Why give percentages...the placebo was 0.0002 and the drug was 0.0001 but what was the units 48% is prettry easy to remember. I am not the author I did not have a camera photographing the slides...this post went online within a couple of minutes and was being typed as the talk was progressing. Was the meeting of value for people with progressive MS....I suspect because of this meeting there will be more people with advanced MS treated with something...I call that progress..I hope you do.

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    2. Progress is not happening at all and never will .

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    3. Sorry to say this is progress, I have to disagree with you the evidence is in front of your eyes....maybe should have gone to spec s****rs :-)

      Delete
  5. "It was shown that Ibudilast reduced brain volume loss by 48%. in progressive MS"

    This is the best slow of atrophy measure thus far

    So basicaly you have to rethink all your aproach to treat people in wheelchairs
    Will you push another round of immunosupressive drugs "think hand" campaign? will it be clinical meaningful against this results?

    Md great attittude

    Price 20mg 127.00 USD

    Obrigado

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  6. Thanks MD, great news! It takes a big person and a great researcher to admit when they are wrong.

    This is a game changer for all MS, particularly progressive forms. Do you now believe that it is "hot" microglia that is the APC or "ring master" that cause the peripheral immune system to mobilize and causes relapses or progression of disease?

    Do hot microglia drive the "field effect" after removal of Gilenya and Tysabri or relapses after a URTI?

    Most importantly do you think Ibudilast will be an equally important add on therapy as a neuroprotective therapy to current anti-inflammatory DMDs? How will this be affordable for any healthcare system?

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    1. "Thanks MD, great news! It takes a big person and a great researcher to admit when they are wrong. "

      200% Agreed

      Thanks for this Md

      Obrigado

      Luis

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  7. Where do I get it/get on a phase III trial? Sign me up.

    I don't care if it's not 100% efficacious, I'm progressing too fast anyway, and that wheelchair has been beckoning far too often recently. It'll buy me some time, and I'm a desperate woman.

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  8. isn't ALA reduce whole brain volume loss to the same extent?

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    1. Phase 2/3 trial

      Results were published in June 2017. Researchers found that treatment with lipoic acid reduced brain atrophy (shrinkage) by 68% compared with placebo. The treatment was reported to be safe and well tolerated. Common side effects were injuries, infections and gastrointestinal disorders.

      The study involved 54 people with secondary progressive MS, who took either 1,200mg of lipoic acid or a placebo (dummy) drug every day for two years.

      Delete
    2. Yep its was presented at the Ectrims last year ,but no one care

      Conclusions: LA demonstrated a 68% reduction in annualized PCBV and suggested a clinical
      benefit in SPMS while maintaining favorable safety, tolerability, and compliance over 2 years

      https://www.ectrims.eu/wp-content/uploads/2016/09/ECTRIMS-Highlights-Release-Day-3-lipoic-acid-shows-great-potential.pdf

      obrigado

      Delete
    3. Remember we are not talking DMT..if it stops inflammation it stops brain volume loss from occurring, but in this case relapsing inflammation may be still occuring so we are not comparing apples with apples

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    4. As we have said many times there is no interest in developing these fatty acids and so no money to be made, so it is a losing battle...that we will loose:-(

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    5. Losing battle. As one of the biggest NHS Trusts in London. Treating thousands of patients. Barts can produce a list of supplements for MS patients to take at their own cost. Those who do are registered and their MRI taken every year can show of theres a benefit. Not purely controlled and purely monitored. NHS is already paying for all the monitoring anyways that is done in clinical trials. The real reason this will never happen because it will cause fury among the pharmacy chiefs who in return will cut your research grants. It's a losing battle is matter of perception/opinion.

      Delete
    6. Well, surely that's one for the MS Register, then, that way no-one loses any grants and we all benefit from the data. A lot of sites now link to the MS Register, so the clinical results are available for registered pwMS. (Yes, it's all anonymised, don't worry).

      Annual MRI scan??? Us progressives don't get those - or any treatment - no DMTs for us, just monitor your own decline. Do you wonder that we're desperate?

      Delete
    7. "so it is a losing battle"

      Indeed ,in the end the looser will be ........

      Pwms

      Obrigado

      Delete
  9. Thank you MD for great news!

    It is meaningful that the trial includes not only SPMS patients but also ~50% of PPMS patients. The reduction of 48% is the average for both PPMS and SPMS. 67% in SPMS patients.

    A ray of hope for PPMS patients.

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    1. That wasn't a typo, right? I can't find any other reference to this 67% number.

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    2. The claim that the atrophy slowing was 67% in SPMS is incorrect. Bob Fox has just informed me that analysis hasn't been done yet.

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  10. JoH, ibudilast is available in e.g.: Japan, and since it's not approved in the US, your doctor might be able to help source it for you. But if not or if it's too expensive, you can contact any of the trial centers and they'll eventually get you to a recruiter. The company is probably going to take a few months to set everything up for a P3 trial though.

    Check out the trial centers here:
    https://clinicaltrials.gov/ct2/show/study/NCT01982942?term=Ibudilast&draw=1&rank=7&show_locs=Y#locn

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    1. I saw Dr Chattaway just after the data was announced... he said paraphrased...just think if the company had supplied the drug for the UK study...they would have two trials in the bag..

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    2. In which case, I think I'm out of luck for now, as I'm based in the UK. And I don't think Ibudilast is available here at all, it's not on the BNF.

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    3. I see it being sold on Alibaba... but I don't know how safe/legit any of that is.

      Delete
  11. This will need further checking namely the techniques used to assess brain atrophy. In this trial the annual atrophy rates were 0.1% for ibudilast and 0.2% for placebo.

    These rates are way below what would be expected in this population. A healthy person after the age of 35 is estimated to have a annual rate of atrophy of about 0.34%.

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    1. Note the THC trial failed because in part the placebo arm did not progress....There is probably a massive plaebo-effect as we have said many times before you do better in a trial even if you are not on active drug because you are much more monitored.

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    2. Yes but in that trial the annual PBVCs for both THC and placebo were in the region of -0.5 to -0.9 which is to be expected for a progressive MS population. So either these are very special patients or the measurements are performed in a different way.

      Delete
  12. Adding to the previous comment after checking the full data presented, atrophy was measured using MTR a more sensitive MRI technique for this purpose than the classic MRI technique used in the Alemtuzumab and ocrelizumab trials.

    Hard to compare apples and oranges :)

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    Replies
    1. They measure MTR and the difference was in the 70% range, DTI was not different.

      Delete
    2. You’re right, I misread. The primary endpoint was measured using BPF (brain parenchyma fraction), different from SIENA used in other trials. So we still cannot compare directly with other DMT trials.


      But I also find the results on ibudilast interesting and potentially exciting, particularly if reflected on clinical measures as well

      Delete
  13. The most interesting and exciting thing I have heard/read in relation to MS research, along with Pender's work. This, as someone with PPMS beginning at a young age, with no marked relapse symptoms but slow progression, is really catching my attention. Slowing/stopping progression without stopping relapses? Now that would blow it all out of the water, wouldn't it? About time. No one should get too cocky about their pet theories on MS.

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    1. I met Prof Pender in Paris at ECTRIMS2017, he is so enthusiastic..Got a lesson on EBV from him. He has transplanted about 10 people with his anti-EBV approach.

      This news is exciting...we will see where it leads us

      Delete
  14. I just could not understand yet what the difference is from Ibudilast to the other TNF-a inhibitors, if the inhibition of TNF-a makes MS worse?!

    Because Ibudilast has an action on Microglia (as well as Minocycline), it would be an inhibitor of glial cells, and would decrease TNF-a, and as far as I came to read about Ibudilast as soon as I learned of the studies with it for MS, in 2014, it's also a drug investigated for use in Chronic Fatigue Syndrome, because it has a hypothesis that SCF would be caused by a virus infection of the Herpes family (including and mainly EBV) in the Vagus Nerve, and the hypothesis holds that the treatment of SCF would be based on microglia inhibitors and antivirals.

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    1. I would like to know why 5% more people stopped the study than the placebo, is there activation? I don't know.

      As for TNF inhibitors and worsening I agree it is very interesting I have been thinking about this, I have a few ideas but they are not ready for prime-time yet.

      Delete
  15. MD here is an interesting article I thought you would like in case you have not read:

    https://medicalxpress.com/news/2017-10-simulations-multiple-sclerosis-disease.html

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  16. Hello MouseDoctor... so you say the study didn't show enough? more data needed... for now fluff?

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  17. Can't... they have limited funds. NIH didn't pay for the entire thing, although they paid for a lot of it.

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  18. I have a question. What are the theories behind brain atrophy in MS?

    1. Gravity (happens to all of us)
    2. Loss of cells in the brain (happens to all of us)

    3. ???

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  19. any news on when phase 3 will begin?

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