What ever GA does it must do it badly..otherwise it would be more effective. Now it’s a B cell modulator



Glatiramer acetate immune modulates B-cell antigen presentation in treatment of MS Darius Häusler, Zivar Hajiyeva, Jan W. Traub, Scott S. Zamvil, Patrice H. Lalive, Wolfgang Brück, Martin S. WeberFirst published March 17, 2020, DOI: https://doi.org/10.1212/NXI.0000000000000698

You can not have it both ways. In the European Medicines Agency blurb it has said that glatiramer acetate (GA.Copaxone) is believed to target the mechanism thought to be responsible for the pathogenesis of MS.

Therefore as the mechansims thought to be responsible for MS, has changed over time, so has the mechanism of action of GA.

However one detail has escaped the many, many, many GA studies and this is……………the fact that GA does not appear to be a highly active disease modifying drug. Therefore it says that by what ever the mechanism it works, if must not be that effective. Because if it has dramatic impact on an essential mechanism then the efficacy has to be higher. You can’t have it both ways.

I have suggested that an effect on memory B cells is important to show efficacy. There is the hypothesis. So what is seen?

Essentially no impact, so the hypothesis is either wrong or GA is not that great or GA works via a different mechanism. You know what I think. Now there are a few papers where there is an effect on memory cells and this is a percentage and not absolute numbers

Now do people think?…or just put out a mechanism….In this study it is reported that MHC class II is upregulated and we knwo this is involved in presenting protein fragments to CD4 T cellsor and interleukin 10 increases so its immunoregulation. So next we can do the experiment in mice and it upregulated MHC class II in the mouse, so now let’s see what happens in EAE.

It increases antigen presentation…which is rather odd when we are told that the potent B cell inhibitors work because they decrease antigen presentation.

However, as we know GA is magic because it can increase antigen presentation not to activate T cells but to …….you guessed it…to induce the standard mechanistic chestnut……yep to make T regulatory cells….the scurge mechanism of mouse EAE. There you have it Glaterimer acetate makes T regulatory cells…QED.

Now remember you cannot have it both ways. Lets look what it did to EAE and as you can see the results are actually rather rubbish, so does this mean that T regulatory cells are also rubbish at controlling immune responses, as you can’t have it both ways.

So a significant difference on one day only when you has 4 failures in your GA group. This says to me, that GA doesn’t really work in the beasts when given this way.
Now I have had MD2 do this experiment and it simply does not work this way in our hands either. To get it to work you have to do something else.. Maybe as we are in lock down it maybe time to dig this stuff out of the archive.

So a doubling of T regulatory cells essential does nothing to EAE, if you can kid yourself that this is relevant to MS but you have to recognise that the animals essentially all get sick…so the mouse data if translated into human studies would say that daily subcutaneous GA will not work in MS.

You dont’ get half a relapse after all. Now we know there is a significant effect with glateriamer acetate in relapsing MS but is it a highly effective agent..remember you can’t have it both ways.

P.S. I have to say I am not that convinced that you can use these models to tell us much about the role of B cells in MS, as Mouse EAE responds to anti-CD20 about as well as it does to subcutaneous glatiramer acetate.

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  • MD Why do people waste their time and effort doing this stuff, even I can see that the data looks rubbish.

      • I makes me wonder how well do you sceintists interpret data. Why do you report this stuff MD? If you think it is rubbish why bother?

        • Good question. If we work with animals, the UK government want us to talk about animal research and as the blog says it is about good and bad research news. One role of the blog is to discuss our own work in public. As you are aware we have shown an interest in B cells and therefore you get a disproportionate amount of posts on B cells because it puts our work in the context of what is out there. We have gone on the record to say that B cell depletion does not do much in mouse EAE. Therefore, you have this study saying GA works via B cells. This would question our work….However it actually supports our work because you can see that the effect in EAE is minimal, so even if GA works via B cells it says this is irrelevant.If you do not question stuff it becomes law.

          P.S. It provides an altmetric that people don’t want….Last week I got blasted by one author for giviing it a rubbish review….they did not answer the critisim. Altmetrics are rubbish and so often the tweets are just a bit of back patting.

        • Because explaining why the writer thinks it is poor is educational, both to the writer and the reader. The reader can then use the discussion to inform their understanding and to see the rational that is used. Discussion of ideas is how science works, it is about doubt not certainty. Nothing should ever be rubbished out of hand, it should be shown to be rubbish using evidence.

  • > I have to say I am not that convinced that you can use these models to tell us much about the role of B cells in MS
    … or possibly not much of anything? How often do we read about some weird intervention that ‘cures’ MS in EAE mice?

    My favorite is probably the sildenafil cures MS study – don’t get me wrong, sildenafil definitely helps with MS. Addressing the exact symptom we mostly use it for in the general population (so not pulmonary hypertensions :-))

  • Who keeps funding these GA pieces of research? I used to find this funny, but now it seems odd or dangerous?

    • I think it is generally Teva funding this type of stuff, if they find a lab who can get it to work it keeps it in the neurologists eyes….If you look at the disclosures and funding statements it is not clear, but why would you do this.

  • Pardon me if I cannot wrap my scarred brain and spinal cord around this. I started Copaxone in 2007 when diagnosed at age 49 after 3 exacerbations in 12 years and several workups. I was on CombiRx study randomized to copaxone and placebo avonex. My Dr., Dr. Panitch was an early Interferon pioneer and a great doctor. I thought Copaxone was a decoy for the anti myelin ducks 🦆 (Simple talk). I thought it was Israeli Teva’s was of mimicking Bee Sting Therapy which I saw Charles Mraz administer and got to meet his wife. The Proteins… I keep reading the downside of Copaxone and I appreciate your experiences. Wonder sometimes if Menopause was the effective component. I have RRMS. No exacerbations since 2007. Disabled. Too old to change now.

    • The Panitch who injected gamma interferon into people and made them worse, Panitch…I guess pinoeers get it wrong sometimes:-)….only Joking if you are not willing to fail there will be no progress….and now look where we are with beta interferon.

      If copaxone works for you great….the downsides are largely injection site reactions and relapses if the treatment does not work effectively….However GA is held up as a beacon of light on how EAE saved the MS World…I’m thinking of writing an article the New Emporers New Clothes


      • Dr. Panitch had a great bedside manner. He promised he would take care of me. That had a huge effect on me. I had placebo effect flu symptoms from placebo avonex on CombiRx study. My big concern now is gadolinium. On the study I received 9 doses in 7 years. I don’t expect you to agree but I predict gadolinium will be found to be damaging. It’s sourced in China, not quality assured, is retained in bone, brain and skin. Used indiscriminately and too frequently. Thanks for your honesty.

        • gadolinium…damaging..the evidence is there look at the FDA/EMA discussions on it and limitations

          • I have looked. I also have discussed with my a Doctors. I get the skeptical look. I recently had an ankle MRI and requested no Gad. I then had to explain to 6 different Radiology people why I didn’t want it. I saw the oncologist monitoring and he was fine with that. Accumulated Gad is not assessed. Dose,type,frequency not assessed. Purity not ensured. Even naming it Nephrogenic Sytemic Fibrosis is a misnomer. It is Iatrogenic, Anthropogenic. Not just in renal failure patients. Not treatable.

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