Come-on people…if one company can do it after a decade, pull your finger out and get the answer for your new drugs, so I can understand what’s going on…..I can’t wait for a another decade:-(

C

OK this is a bit tounge in cheek, as I have known the answer foone -imod for some time, but many studies not sponsored by the manufacturer have talked about percentage effects and you have to deal with absolute numbers to grasp what is going on. This a current paper below is a company sponsored study and the results are easy to see, which is not always the case. These are reported here more than a decade after the drug was approved. Studies often focus on T cells and not enough on B cells…This is a plea to show me where I need to read so that we can understand the new -imods….They are different.

As you know I have been abit of a “clad lad” and was trying to understand how cladribine works. I had got interested in this because we were trying to develop it after a certain company “spat the dummy” and refused to do another trial that the regulators wanted, So they walked away from hundreds of millions of investment, as they were coming second in a race of two. However the company were kind enough to give us the trial data and we could see that people were being sold a pup with the it’s an “all T cells World view”. They were depleted bearly past normal levels but some B cells were being smashed.

Anyway around 2010 …the -imods won the race to become the first class of oral agents for relapsing MS There are now four of them.

How do they work?

We have been lokking at this, but you say

It is simple, they works because the drug mimics the “catnip” for white blood cells, which follow a gradient of a fat molecule (catnip called sphingosine-1-phosphate) that draws white blood cells into the blood from the lymph glands. I essentially does what natalizumab does but in a different way. Natalizumab stops the white blood cells from leaving the blood and so they are stopped from getting into the brain . The -imods take this idea one step back and if the white blood cells, can’t get out of the lymph glands, they can’t get in to the blood and they can’t get in the brain and so it stops MS…..Simples

It was a simple solution it blocked T cells entering the CNS and so you don’t get MS and at one point a case was made that it does not target a subset of cells that may be involved in controlling infection. It’s a simple concept and we have all bought into it. I teach it also

Sure you take the -imod and the white blood cells disappear from the blood, your MS goes away. Stop the -imod and white blood cells come back and if you don’t do something about it disease can come back with a vengence (rebound).

So we all bought the idea, but a short while ago, I was asked to look at this and it was obvious that it was not quite that simple, which is just as well because it would mean the T cell idea of how the drug works is probably a pile of you know what.

Why?

Because the T cells that get, and accumulate into, the CNS during MS are those that a supposed to escape the entrapment (The T memory cells expressing CD45RO butt not another receptor CCR7) to protect people from infection. Therefore it should not work…but it does work……so there was a smelly fish somewhere, as something was not quite rigtht. I did not care because whilst looking at cladribine and alemtuzumab, I decided that drugs should inhibit memory B cells if they are going to work well.

I had to scrabble around the literature to see if I could get support for this idea, but it was not easy because everyone worked on T cells and nobody cared about B cells, unless they were thinking about antibody. The CD20-depleting antibodies changed that view for some, but not some die hard T cell biologists that have concocted a story about CD20 T cells. Whilst this may be true, it made me delve into the -imods and it clearly wasn’t as simple as I thought and it is clear that some cells are being destroyed and not just trapped. Maybe this is part of the reason why in some people, cells do not come back quickly when you stop the drug.

The first -imod has been around for a decade and there have been a few studies looking at B cells and sure enough memory B cells are inhibited. Now, we have got three new -imods and the question I ask, is. ….”Is there evidence that these new -imods block memory B cell numbers”…If correct I give a sigh of relief but if not I have to change my ideas to explain what is going on.

Can I explain benefit from a T cell point of view? Yes I could if I want to

This is because although it may be evident that CD45RO memory cells escape more that the other T cell subsets, it was evident to me that there were markedly fewer of these memory cells in the blood. This is clearly seen in this paper. Less cells migrating………..less MS. It seems there is a T cell subset that is less affected and these are the “effector (CD45RA+,CCR7-) T cells and notably the CD8 T cells. This is good news because these are cells that are going to get rid of the COVID-19 virus along with the macrophages. These probably won’t be affected by migration because they are already in place in the lungs to deal with the infection. So we can explain why fingolimod does not make COVID-19 worse. But what about the COVID-19 vaccine response? I think we can.

The T cells in the blood on fingolimod are not the same as the T cells in people not on an -imod and then there is the poor vaccine response. Well we can look at this paper and see it inhibits memory B cells hence no MS, but also naive B cells, hence no new antibody response to COVID-19 vaccination.

It is simples…it is biology.

Now that is fingolimod, what about siponimod, ozanimod and ponesimod? The anwers is I don’t know fully because I don’t think these studies have been done, or reported in a way it is easy to decipher so let’s not wait a decade for this to happen with these new imods….hence my provocative title to the drug manufacturers, which is a plea to do the studies with their drugs in a way it is easy to see. I accept I may have missed them.

What do I mean? This is an example of studies which were not done my the manufacturer. I won’t say where it comes from as it is not important and I don’t want to upset anybody.

In this example (above) the red line and dots are siponimod and the black line/dots are dummy drug, I think you will agree that the red and black lines, which is the averages of the red and black dots, are about the same. There are about 20% memory B cells at the beginning and end of treatment. So you could conclude there is no effect on memory B cells

Now look on the graph on the right and you can see the number of total B cells drops, lets say 90% (140 cells to 10 cells per millionth of a litre). So memory B cells are being depleted. In this example 20% of about 140 cells is 28 cells cells but 20% of 10 cells is 2 so the memory B cells depletion is 2/28 = 93% reduction. The reason why it stays at 20% is that other cells i.e. the 80% of the population, which are naive B cells, are likewise depleted. Reduce memory cells = less MS, reduced naive B cells = less COVID-19-related vaccine responses

Once we have nice data, we can try and explain how they work in MS, what are the side-effect potentials and how do you exploit their properties in the COVID and post -COVID era. Fingolimod hits four of the five sphingosine-one-phosphate receptors (S1PR4), the others essentially a maximum of two. Do the two receptors not hit by the new -imods make a difference for action in MS, response to COVID-19 and COVID-19 vaccine responses?…..I’ve been making some predictions…..coming your way soon.

The prediction is that they will target memory B cells, if they don’t our ideas need to changed or maybe some are less effective than others….But what about the effects on other subsets.

So come on Pharma put me out of my misery and give me the data for the new -imods. Stop me speculating…You know speculation to a scientists is like garlic to a vampire:-)

Bright or Mad Idea for effects on Sphingosine Receptors but what do I mean?

So is the paper Fluent in explaining ideas? The study demonstrated that “within six months, fingolimod lowers lymphocyte subsets in a fingolimod-naive population to levels seen in participants treated with fingolimod for between 2 and 12 years. The greatest reductions in lymphocyte numbers in fingolimod-naive participants occurred in naive and central memory CD4+ and CD8+ T cells, and in naive and memory B cells.

They say the work “provides insights into the utility of immunological profiling to evaluate therapy response and potential infection risk”.

Are the insights easy to understand?…Have a read and let us know your thoughts.

Mao-Draayer Y, Cohen JA, Bar-Or A, Han MH, Singer B, Williams IM, Meng X, Elam C, Weiss JL, Cox GM, Ziehn M, Cree BA; FLUENT study investigators. Immune cell subset profiling in multiple sclerosis after fingolimod initiation and continued treatment: The FLUENT study. Mult Scler J Exp Transl Clin. 2022 Aug 1;8(3):20552173221115023. 

Background: Fingolimod is a sphingosine 1-phosphate receptor modulator approved for relapsing MS. Long-term effects on the immunological profile are not fully understood.

Objective: Investigate fingolimod’s temporal effects on immune cell subsets, and safety outcomes.

Methods: In FLUENT, a 12-month, prospective, non-randomized, open-label, phase IV study, adult participants received fingolimod 0.5 mg/day. Changes in immune cell subsets, anti-John Cunningham virus (JCV) antibody index, and serum neurofilament levels were assessed.

Results: 165 fingolimod-naive and 217 participants treated for 2-12 years in routine clinical practice were enrolled. Levels of all monitored peripheral lymphocyte subsets were reduced from month 3 in fingolimod-naive participants. Greatest reductions occurred in naive and central memory CD4+ and CD8+ T cells, and in naive and memory B cells. Most lymphocyte subset levels remained stable in the continuous fingolimod group. Components of the innate immune system remained within reference ranges. No increase in JCV seropositivity was observed. No single cellular subset correlated with anti-JCV antibody index at any time point. Neurofilament levels remained within healthy adult reference limits throughout. No opportunistic infections were reported; no new or unexpected safety signals were observed.

Conclusion: FLUENT provides insights into the utility of immunological profiling to evaluate therapy response and potential infection risk.

CoI Multiple

Disclaimer: These are my ideas and only my ideas.

About the author

MouseDoctor

16 comments

  • MD,

    I only skimmed the article as it looked a combo of rant + gobbledegook. Why are we wasting time looking at drugs approved over a decade ago and which do not address progressive MS / smouldering MS? Does a headache undertake research into how aspirin works?

    Did anyone attend the recent MS Frontiers conference? Surely something new was discussed there! We seem to be going round the same old buoys – looking at immunosuppressive drugs which (I) aren’t tackling the real MS and (2) don’t address EBV as a driver of the disease.

    Time to ditch EAE? Time to ditch the obsession with suppressing the immune system? In 2022 we should be able to stop this disease in its tracks, protect nerves and stimulate remyelination. We are no better off than 20 years ago. New ideas needed. The work confirming EBV is the cause of MS should lead to a complete shift in how this disease is treated eg antivirals, or drugs to strengthen the immune system so that the ongoing EBV infection is controlled. Need some MS research maverick to shift the focus of research. The interferons, Copaxone and imods should have been ditched years ago. Research into them now is a waste of resources.

    • Rant no…prod yes…..but if we are talking about ranting me thinks kettle and black here. As for the prod….having the information helps explain the biology of their products.

      The research above was paid for by the manufacturer who makes the drugs and they can spend their money as they like, it may be about knowledge creation, it may help marketing and use of their products. Thinking about what they are doing does not consume much resource but time and abit of electricity for the computer.

      Doing research may be part of training and needs to be short and comes with minimal funding and it may be interesting to the people doing the work.

      There was no mention of EAE here and if EAE was ditched would I be bothered?
      If we ditch the obsession of suppressing the immune system one suspects your idea of targeting smouldering MS is ditched also.

      So you have said it again….What do you mean by the “real MS”?

      Do we drop everything and go after EBV? Wouldn’t it be better to get virologists to chase that angle and how do you go about it?….We hear about EBV and MS and I buy it, but we also hear of EBV and other autoimmune diseases and if this is true then it suggests it is nothing special for MS. I have given an explaination for this.

      The study linking MS to EBV in US military should have been done for other conditions, because if there was a link too, what is the real MS? I wrote to the author about it but they said not enough resource and why would you want to disprove the idea of a simple causal pathway?

      There are plenty of people who get infected in childhood and don’t get MS , so it is not going to be simple. The solution could be to infect everybody with EBV in childhood, not vaccinate or treat adults, because when you are infected influences the outcome

      Science does not confirm it disproves

      It shouldn’t be gobblegook as the concepts have been rehearsed here, but if it is I need to explain better beause there is more to come, and by skimming you aren’t learning. This may lead you to say stuff that is just plain wrong………………..”We are no better off than 20 years ago”. …….So this suggests no (effective) treatment for you and many other people who are doing better than having nothing.

      FYI. I think Ponesimod was approved in 2021, ozanimod in 2020 and siponimod in 2017 a decade ago was 2012 and that was alemtuzumab.

      MS froniters….yes ProfK was there…ProfG was involved with a virutal EBV meeting organised at the same time and I was quarantining because ProfG got COVID and I was in contact with him and so I couldn’t go where I should have been:-(

      Rant over

      • Mouse,

        I rant at you because other neuros / researchers don’t make themselves available. The core point I’m trying to make is that we should have treatments available to stop people climbing up the EDSS, stop people having to use wheelchairs, stop people from losing their jobs, stop people from having grim late stage MS. The blog stated c13 years ago and the last research day was probably c.8 years ago. I’ve seen so many failures in the last 18 years = remyelination, neuroprotection etc. we need more than anti relapse drugs. BTK inhibitors, SIZOMUS, octopus, MS Stat 2 – always “5 years away”. My ticker won’t be able to handle any more failures – I’ll need the name of your heart surgeon.

      • Well said

        My sister has celiac disease my mother 82 years has Psoriasis diagnosed at 76 hi have ms

        Where does ebv fit in this scenario

        • EBV makes memory B cells and once you have a memory B cell it is put outside of normal immune control that stops autoimmunity. I would argue most of the memory B cells will be anti-infection but a limited few could recognise something in the target tissue, once you have memory cells that is all you need, e.g. myelin transgenics that deliver spontaneous disease because their memory cells have been tickled and they migrate migrate into somewhere where there is no target, on the rare chance it gets into the target off you go.

  • Sid,
    I fully understand you my friend ❤️ it is a tough disease to have with no cure in the foreseeable future. Man, knowing that life is getting shorter faster than it should and degrading physically while on this path is a tough pill to swallow. Even with the best DMTs, the decline is ever present and a sharp decline is possible at every step you take. If my “self” is my mobility and intellect, than I am loosing a bit of myself every single day. And the seed that is now in my mind, knowing that this is the reality and not being able to fix it no matter what I do… Sometimes, I feel like it is like someone’s slow sadistic torture being inflicted on me
    This is a tough and complex disease with multiple mechanisms that are somehow coupled with one another. The doctors and the scientific community as a whole don’t fully understand the extent of these mechanisms and definitely don’t understand how they are intertwined. You know what I think? There is no cure for the “real MS” as there are at least 3 process taking place simultaneously…. We are doing a pretty good job attenuating one process while maybe slowing others in the process. We are probably around 6 -10 years away from making things even better with some tandem DMTs, but even after that, we will still have it and have to carry some of the damage it has inflicted on us.That’s it, we must recognize that physiologically, we are never going to be the best version of our potential self.
    I am sorry Sid, it is super disappointing, but unfortunately, presently, we simply have to endure!
    In the meantime, take the best DMTs you can get. try and get anti CD20 or anti CD52 as a start and make sure you do whatever it takes to get the drug that works best for you. Get a really good doctor that knows their stuff. With doctors, like lawyers, there are different levels to this game.Don’t smoke, don’t drink alcohol often, eat really healthy stuff, exercise, and live a low stress peaceful life. The rest? Not really in anyone’s control. Oh… And read! Read this blog and other resources to learn more about MS. many mornings, I wake up and click on the blog’s link and for some reason, have the feeling that Dr. Mouse will tell me, “guess what? We found the cure!”. It is a stupid thought, I know, but so is believing that I will win the lottery one day. I still play the lottery every once in awhile. In the meantime, I at least get the chance to learn more about a subject I care about very much… And in many ways learn more about myself as MS is a part of me
    Keep your chin up Sid. Endure!

  • Hi MD,
    I understand no one has a real idea about what drives the progressive side of MS. I always find Prof G’s statements rather misleading – it feels he is going too strong to make people like Sid to remember the message.

    It would be really appreciated if it is possible to explain the progressive aspect of MS – theories of drivers, and expected damage over time (I remember NDG mentioned if treated before EDSS 3.5, progression is slow, after EDSS 3.5 people tend to progress away), and how much each DMT class potentially addressed it. And it seems age-related as well – would older age pwms just progress away regardless of disease burden and DMT?

    It feels a lot to ask and almost sounds like a review article already! So ignore me if this is too much.

    Thank you!

    • Anonymous,

      Thanks for your post. My issue about Prof G, is that lots of claims are made ‘relapses are not the real MS’, ‘smouldering MS is the main driver of disability’, ‘ebv is the cause and probably the driver of the disease’, ‘combination therapies are needed’, but nothing comes of it. Anti-virals are mentioned, but no trials get started…. Some years ago my hopes were built up with the creation of the Progressive MS Alliance. Nothing has been delivered. And the head of the Alliance is of the view that once progression kicks in, there’s nothing that can be done! Something needs to shift or MSers in 20 years time will be faced with the same grim future. I’m a nice guy really – lost a perfect life to this vile disease. I used the NHS once, but there was no good outcome for me.

      • You have to start somewhere and getting funding for studies is very arduous. Combination studies probably wont happen in earnest until MS DMT come out of patent, monotherapies are too lucrative for pharma to do the complex stuff. The trials of monotherapies are alot less complex than combinations…but they are happening bit….For a long time ProfG has been banging the drum for EBV but rejection after rejection from your peers means you don’t get anywhere and trials never happen. Then you are offered something that is not really what you want, you do it and it fails is a problem.

        However people are waking up to the EBV idea…vaccines are feasible and after two papers in Nature and Science (in my opinion one sound and the other based on quicksand) the World has woken up to EBV and now things may change as people are receptive. We were banging the drum about progression for years before the progressive alliance again we were too early and people weren’t ready to think/listen about it. So targeting EBV watch this space. However, my mantra is trial desing is key…What are you aiming to do and what is the best way to do this.

        Vitamin D and Microbiome studies are ten a penny in every differnt condition because there was an accepted band-wagon and the science has been accepted….I think EBV research will go that way..

        I agree I think it is a rather sad message that nothing can be done…it has been presented more than once…..I disagree with this view.

    • ProfGs message and the “real MS” is presented in a recent paper, plenty of arguments why some people’s dogma is not correct, but I think not alot in the way of definative solutions. Yes I accept that EBV is somewher in the mix. I will put this out for people to read.

      It makes the case that the inflammation is a response to the real MS….So should we stop targeting the inflammation?. If it is a red herring and we get rid of it then either nothing happens or things should get worse. I think on balance we can say things do not get worse because people do not end up in wheel chairs quicker. Does it unmask the real MS?. Maybe
      There has got to be something in the CNS that makes this inflammation happen.

      So if this is true, a solution could be in people treated with DMT, to stop inflammation, who have died of other causes. These is a case (or is it a myth because it was never published) of natalizumab where the person died and when they did the post-mortem it was full of remyelination. Is it stop inflammation and repair processes occur. It never went anywhere as the observation was made on standard post-mortem sample where there was no permission to go research. The are cases of PML, what happens in none PML areas is the real MS there?

      Many of the features ascribed to progressive MS you can see in progressive EAE and there we know that the trigger is the immune system causing damage, in some strains the incidious clinical progression starts after one attack and in others it surfaces after three-to four unless your are male and it may be 2-3 and so you can say yes progression does not correlate with relapses, but they are a trigger for it in the animals and at that point current immunosuppressives are not going to stop it. The relapses burn out after one or more attacks just like they do in humans. Therefore I agree with NDG deal with stop stuff early. However it may be there some the first attack and because we don’t keep mice for years we dont see the clinical progression.

      As for the drivers, there is a long list….The problem is until you do something about them and it makes an impact it is hard to say any of the features are not consquences of but the cause. There are lots of ideas on the blog over the years. We have come up with so many that have gone nowhere positive, and not because the ideas were wrong in my opinion. However, if a trial fails for the wrong reasons, the treatment is seen as a failure…the mud sticks.

      There must be a trigger in the CNS that keeps drawing white blood cells in….is it a virus?. If it is why has it not been convincingly found, you can now look at the proteins being made by individual cells and you can even biopsy the lesions, what are they doing?

      We know the oligodendrocytes are not happy, do they have something inside of them or is the sickness something that they are bathing ing produced elsewhere. These answers must come from MS and can’t properly be done in animals. DrLove who could have targeted this has retired.

      Progression and DMT is a thorny issue and is one where I have clashed with ProfG as I do not take the results of trials at face value, and as the trials are done in different people at different times it makes it very difficult to compare and predict.However the trial data is compared in peoples heads. I dont think it is easy to compareatrophy of e.g cladribine after 9 years compared to after 2 years with alemtuzumab to suggest that alemtuzumab promotes repair as opposed to stops damage and allows repair to occur. Or alemtuzumab at 2 years verses ocrelizumab at 6 years to suggest that T cells are key. The data is there in Sweden in people who are treated with rituximab first line soon after diagnosis. In some parts of Sweden virtually everyone gets this option.

      I believe in treating as effectively and early as possible to get rid of the inflammation because it is on balance damaging. In my mindset I would dismiss any of the historical data from the CRAB era, they are simply not good enough in most people. However, this makes up most of the historical data on which the idea of real MS is based. If you are basing ideas on wobbly data it is had to work out what is going on. E.g. It is very diifficult to suggest the importance of memory B cells if you look at the interferon and copaxone data, but in highly effective treatments this screams out to me.

      There clearly is a driver and this is in the CNS. Is alemtuzumab really any different from cladribine or ocrelizumab if they are used at onset in the same demographic of people. I would say no, we tried to address this but the funders didnt want us to do the study…We are now unlikely to get an answer here because the regulators have stopped this from happening, at least in the UK, as you can’t prescribe some drugs first line.

      Anyway in short I cant’ answer the questions about comparing different agents because the data is not there. Maybe this is done to make it difficult to compare otherwise it would be easy to say “mine is better than yours”

      • Nice well said again

        There must be a trigger in the CNS that keeps drawing white blood cells in….is it a virus?

        What about the joints in Ra ?

        Is there a virus there too?

        In Lupus the heart ,the kidney ,the liver is there any virus there

        And Nmo are the relapses immune responses to a virus?
        Or the aquaporin channel explains everything?

        Thanks for you thoughts

        • It could be the same virus different genetics = different conditions…I know lupus and RA and MS have B cell follicles, not sure about NMO I think many people are negative or lose oligoclonal bands

      • Dr. Mouse last two paragraphs are important and the key takeaways imo. The data is insufficient and it is the classic apples vs oranges comparison. It’s a catch 22, The old SCRAB DMTs have lots of good data, but I think that we all agree that from most recent data, the new DMTs and injectables specifically are better. Now can we compare them head to head? Not yet. Can we truly say that one is better than the other in the long run? Unfortunately not.
        Personally, I would still go with the heavy hitters and follow a more aggressive route, but picking DMTs is like investing in the stock market… The right answer depends on your comfort level.
        BTKi DMTs are on their way in 3 to 4 years. Will they be a game changer? Probably not, but if they can be effective as a tandem or long term DMT instead of the conventional ones, we have another small win.
        Look at Atara’s t cell trial, they are having a tough time to show effectiveness in the short run. Is it because their therapy is no good or is the smouldering component just so damn slow? TBD, but I sure hope it’s the later part.
        This is a classic issue with research, usually the question is very simple, but the solution is rather complex. Dr. Mouse, please keep on keeping on by educating us and keeping us informed.

        • Again there is an issue, because if it is so good at getting rid of EBV, and EBV is the problem, why are the results not out of this world?

          • I’d argue the very limited figures we saw were impressive considering they were focusing on progressive patients.

            Possibly they full data is a lot less impressive, otherwise I would think one of the big guys would be dropping major investment on it…

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