Siponimod controls progressive MS by enhancing regulatory cells….It’s behind you!

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As we are in pantomine season when the baddy (ghost) is behind you about to pounch, and when you ask I wonder where the baddy is? The audience shouts out “he’s behind you” and you don’t turn your head, you slowly turn your body as the baddy turns to stay behind your back, so when you turn round, there is nothing there. So you say “Oh no he isn’t” and the audience says “Oh yes he is”. You say “Oh no he isn’t” and they shout louder “Oh yes he is”….It’s comical (OK… you have to be there).

So in sceince every thing that inhibits an inflammatory disease is now due to the action of regulatory cells and this is the “insight” we get here and as the T regulatory cell that doesn’t quite work out, its the regulatory B cells a also. You don’t look anywhere else than that to get an explanation. So if you say it isn’t that the science community shout back loud and clear “Oh yes it is!”. Cells are called regulatory because the cells make IL-10, a T cell inhibitor, but a well known B cell growth factor. But that’s ignored and they are regulatory cells and the science mafia say “bang that into your head”.

However, to be devil’s advocate I say the reason the drug works may not simply because they augments regulatory T cells, my colleagues shout “Oh yes it is”. But the my answer is “It’s behind you as you are not looking in the right place”

For the Non-British readers Out there have a watch at apantomime..the kids love it..

However, this is too easy an explanation to say it is all down to regulatory cells. It is the same-old, same-old and every thing works the same way. Therefore, you have to ask why does that one work well and why doesn’t that one work? You are telling me they both work by augmenting T regulatory cells.

So the real reason is…”It’s behind you” you are not looking in the right place. Now I am happy to accept that balance is important, but most evidence suggests that inhibition of T and B cells is not what you really need to combat progressive MS. So I don’t buy the simplistic answer that augmenting regulation of T & B cells is the answer. But, if this really is how siponimod really works, then it says to me we need more than this if we are going to get to the bottom of progressive MS.

What do you think?

Siponimod enriches regulatory T and B lymphocytes in secondary progressive multiple sclerosis. Wu Q, Mills EA, Wang Q, Dowling CA, Fisher C, Kirch B, Lundy SK, Fox DA, Mao-Draayer Y. JCI Insight. 2020 Jan 14. pii: 134251. doi: 10.1172/jci.insight.134251. [Epub ahead of print].

BACKGROUND: Siponimod (BAF312) is a selective sphingosine 1-phosphate receptor 1 and 5 (S1PR1, S1PR5) modulator recently approved for active secondary progressive multiple sclerosis (SPMS). The immunomodulatory effects of siponimod in SPMS have not been previously described.

METHODS:We conducted a multi-centered randomized, double-blind, placebo-controlled AMS04 mechanistic study with 36 SPMS participants enrolled in the EXPAND trial. Gene expression profiles were analyzed using RNA derived from whole blood with Affymetrix Human Gene ST 2.1 microarray technology. We performed flow cytometry based assays to analyze the immune cell composition and microarray gene expression analysis on peripheral blood from siponimod-treated participants with SPMS relative to baseline and placebo during the first year randomization phase.

RESULTS:Microarray analysis showed that immune-associated genes involved in T and B cell activation and receptor signaling were largely decreased by siponimod, which is consistent with the reduction of CD4+ T cells, CD8+ T cells, and B cells. Analysis done by flow cytometry showed that within the remaining lymphocyte subsets, there was a reduction in the frequencies of CD4 and CD8 naïve T cells and central memory cells, while T effector memory cells, anti-inflammatory Th2, and T regulatory (Treg) cells were enriched. Transitional Bregs (CD24hiCD38hi) and B1 cell subsets (CD43+CD27+) were enriched, shifting the balance in favor of regulatory B cells over memory B cells. The pro-regulatory shift driven by siponimod treatment included a higher proliferative potential of Tregs compared with non-Tregs, and upregulated expression of PD-1 on Tregs. Additionally, a positive correlation was found between regulatory T cells and regulatory B cells in siponimod treated participants.

CONCLUSION: The shift toward an anti-inflammatory and suppressive homeostatic immune system may contribute to the clinical efficacy of siponimod in SPMS.

COI multiple

Speaking to MD2 today about what type of science do we do?

MD2 suggested we follow the “Danish School of Science”

This is typified by Hans Christian Anderson…No not fairy tale stuff…but we would rather say the “Emporer has no clothes :-)”

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MouseDoctor

16 comments

  • Thanks for the video. Prof G’s Buttons is very good.

    MD – your spelling is atrocious (please don’t use the dyslexia excuse, you were just lazy at school).

    Can’t the Mouse Docs publish a few papers why Prof G is living it up in Washington? You two must have done some work in 2019 that worthy of being published.

    • Yep my spellin is pretty bad..that’s why Youtube bombard me with grammarly adverts 🙁 and another reason why MD2 reads my papers as that mouse can spell)….I was just lazy at school, but why did I get first in class on numerous occassions, shall I bring in my school reports? I have em somewhere. Ask Mark Renshaw…he will testify to that. I went to University the first in my family, I got an ology, but yep can’t spell for toffee, hey there has to be some chinks in the armour:-)

      Can’t the MouseDocs Publish a few papers. you must have done some work in 2019.

      Baker D, Pryce G, James LK, Schmierer K, Giovannoni G.Failed B cell survival factor trials support the importance of memory B cells in multiple sclerosis. Eur J Neurol. 2020 Feb;27(2):221-228

      Yes indeedy we have done some work and the most recent publication went online this week…haven’t you read it yet? It has implications for some people. A real game changer I think…But in what way? Two long posts have been written and are waiting in the wings. They may appear in a short while

      In addition the first two of the trillogy plus one, I don’t know what you call 4 episodes I’m too thick, have been accepted and will be online any day now as we have the page proofs and the open access is just being sorted. The third has been reviewed two times already and is back with the editor and so should be any day now for that one, the forth is in the science ether undergoing review and the fifth part of that story is in our heads, the tools have been made and we are just waiting for some Student power (yep slave labour…we get degree and medical students and we put them to work doing research projects) to move the insiration into the reality. The blog post is already written and has been since Novemeber when we presented the story for the first time. However, if I blab too soon we may get scooped. Once the third paper arrives its too late.

      Then there is the the potential immune-cure idea that is sat in Google Docs but being lazy it has only taken me 7 years to write that one and then we have the back catalogue to write and submit and we must get the spasticity trial submitted I wrote it last year..it’s on my to do list for 2020 along with a number of other. However at the moment I have my teaching head on and also need to get my grant writing head on.

  • I don’t understand the overblown hype about siponimod.

    How is it even superior to even Gilenya, let alone any other immunosuppressant? How can anyone say it controls progressive MS by any means at all when it had a selection bias trial (ie. including “active” SPMS which is no different than late stage RRMS)?

    Even with all these “active” SPMS patients included, it showed a pitiful 23% reduction in progress above placebo. Take these “active SPMS” patients out of their trial and siponimod has zero response above placebo on progressive MS as both the FDA and EMA found and this is exactly why siponimod has not been approved for all SPMS.

    My point is who cares how it works if it does not work on the real or “non-active” progressive MS?

    • Yes it was your homework did you find it?

      As for “Error” and “Death”….I am abit stupid and it is too cryptic for me to understand

      Who cares how it works…tell that to the people who are taking siponimod, I suspect they care. If I said who cares about how HSCT works , what’s the response?

      • I have no idea what you are going on about.

        1. Why is siponimod superior to any of the immunosuppressant DMDs (ie. cladribine, Ocrevus, Gilenya, alemtuzumab, DMF) of “active” SPMS or later stage RRMS?

        2. If siponimod has no effect above placebo on “non-active” SPMS, how can one make a claim that it controls progressive MS? Why would one look at it’s MOA when it has no effect on “non-active” progressive MS?

          • In my opinion, all MS is active; in other words, we need add-on therapies to target those processes that siponimod does not target.

          • I value your opinion, Dr. G., but any DMD immunosuppressant that targets the adaptive peripheral immune system dampening will work as well as, or better than, siponimod in “active SPMS” or “late stage RRMS”.

            This includes cladribine, fingolimod, natalizumab, ocrezulimab, alemtuzumab, DMF or HSCT. How does siponimod then justify it’s exorbitant 88,000 dollar/year price tag in the USA for their drug?

            According to your pyramid, they all are working on neuro-inflammation. Siponimod has no effect above placebo according to EMA and FDA to work on “non-active” SPMS using their own data. They will say the trial was not powered to look at the differences in active vs non-active SPMS. Why were “active” SPMS or late stage RRMS patients even allowed in the trial if they were searching for a drug for an unmet need?

            Siponimod, therefore, has little to no effect, just like every other immunosuppressant, on progressive disease through dampening or inhibiting negative changes in innate immunity.

            My guess is there will be whole bunch of very angry patients taking siponimod who have worsened.

          • Not wishing to be churlish, but in other words, Siponimod does not control progression. The title of this post is fallacious. Hardly in keeping with a grant application to the MS Society for research into progressive MS.

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