Friday, 8 February 2013

Research: Glatiramer acetate and the neuroprotective effects


Glutamate-mediated excitotoxicity is supposed to induce neurodegeneration in multiple sclerosis (MS). Glatiramer acetate (GA) is an immunomodulatory agent used in MS treatment with potential neuroprotective action. Aim of the present study was to investigate whether GA has effects on glutamate transmission alterations occurring in experimental autoimmune encephalomyelitis (EAE), to disclose a possible mechanism of GA-induced neuroprotection in this mouse model of MS. Single neuron electrophysiological recordings and immunofluorescence analysis of microglia activation were performed in the striatum (brains) of EAE mice, treated or not with GA, at different stages of the disease. GA treatment was able to reverse the tumor necrosis factor-α (TNF-α)-induced alterations of striatal glutamate-mediated excitatory post-synaptic currents (EPSCs) of EAE mice. Incubation of striatal slices of control animals with lymphocytes taken from EAE mice treated with GA failed to replicate such an anti-glutamatergic effect, while activated microglial cells stimulated with GA in vitro mimicked the effect of GA treatment of EAE mice. Consistently, EAE mice treated with GA had less microglial activation and less TNF-α expression than untreated EAE animals. Furthermore, direct application of GA to EAE slices replicated the in vivo protective activity of GA. Our results show that GA is neuroprotective against glutamate-toxicity independently of its peripheral immunodulatory action, and through direct modulation of microglial activation and TNF-α release in the grey matter of EAE and possibly of MS brains.


During it long history in MS, Glaterimer acetate has inhibited EAE by more mechanisms than we have had hot dinners. If delivered in certain ways the drug is immunosuppressive, so it will be secondarily neuroprotectective, others have found it to be neuroprotective in non-autoimmune models. In this study GA stops glutamine (major nerve transmitter)-induced nerve damage through effect on microglia. whilst this may be encouraging one has to wonder what is the significance, as GA has not yet been found to have a neuroprotective effect in progressive MS.

16 comments:

  1. Whatever the flavour of the month mechanism is GA always seems to have those properties. Yet it's efficacy in MS is modest (at best!).
    I do wonder about the partiality of these studies at times.

    ReplyDelete
  2. Im not so exited about copaxone..

    "he data showed no beneficial effects on disease progression in both MS forms, a slight beneficial effect in the reduction of risk of relapses in RRMS patients and no benefits in PMS patients."

    http://summaries.cochrane.org/CD004678/the-use-of-glatiramer-acetate-copaxone-r-in-people-with-multiple-sclerosis

    ReplyDelete
    Replies
    1. I'm as underwhelmed as you are! No wonder they're having to resort to skullduggery.

      Delete
  3. That's why a COMBO of Copaxone and Laquinimod might be the best combination. TEVA stated at their recent conference call they will start registration trials this year where Laquinimod will be combined with Copaxone as well as Laquinimod in combination with other drugs ( Aubagio? )

    The data in the recently published patent application look very promising.

    link:

    http://www.freepatentsonline.com/20130029916.pdf

    ReplyDelete
    Replies
    1. Is this a Teva rep talking? Who would want a daily injectable and a tablet in this day and age? The results would have to be spectacular

      Delete
    2. Does this data show that Copaxone and laquinimod are rather rubbish when given as a signle drug administration, which is not something a rep would want to do but together they do more. Yes they maybe trying to creat interest in a study.

      In terms of relapse inhibition laquinimod did worse that the intereferons in trials with about 20-25% inhibition of relapse, glaterimer acetate is about 30%, so putting the two together will you get 30% or 50% inhibition?, they hope 50%. If you did laquinimod with a potent immunosuppressive would this lead to side effects with immunosuppression? However what was interesting was the apparent effect of laquinimod on atrophy suggesting it may be useful to inhibit progression. So doing this as an add on to immunomodulation may have some legs.

      If they combine with glaterimer acetate, they (TEVA) make both products, with interferons they have to do deal with interferon producing company unless they are making their own generic.

      In terms of other drugs they filed two patents on laquinimod and copaxone WO2013016684 and beta interferon (WO2013016686), which shows if you give more laquinimod you don't neeed a combination. May be it is time that the Patent data base implemented the ARRIVE guidelines to such animal data. They would need to show deviations etc because this is where the impact is needed because these studies are being used to support drug development. Now that would make a real difference

      Delete
    3. I believe, as the recently posted poll-results on this blog, that relapses (3% !! ) are not the main-concern for most MSers. EDSS progression (59% !!) and Brain atrophy (38% !!) seem to be strongly correlated and MSers seem to believe the same. As I understand at least prof. G agrees with this..

      Since relapses fade over time. Please provide the arguments why it is clinically relevant for the average MSer to have one less relapse in maybe 10 years ( comparison of pooled data for BG-12 / Laquinimod ) if you have no effect ( maybe negative effect ... ) on Brain atrophy with BG-12? Difficult to read it otherwise since Biogen refuse to show full data on Brain atrophy for the Define and Confirm studies... Interesting as well that not a single abstract for the upcoming AAN ( related to BG-12 ) deals with safety... Can it be lymphocyte suppression, increase of creatinine and fear of patient monitoring that is the cause?

      Not even the EMA ( according to their guidelines on Multiple Scleroris ) believe it's clinically relevant if you have effect on relapses but no effect on the progrerssion of the disease.

      Please provide your best arguments why you belive the " % " of change in relapses are the most important aspect.

      Delete
    4. Please provide your best arguments why you beleive the " % " of change in relapses are the most important aspect."

      Who said this? Not me and Not Prof G, Do I think stopping relapsing attacks is a good idea..yes but we have been through this endlessly but tell this to a person left with disability they did not have before the relapse that they are unimportant.

      The question is why develop lacquinimod at all, the affect on atrophy is the most interesting

      Delete
  4. Nonsense, MD! If these drugs are that good then they'd work in improving progression, which they do not. Disability caused by a relapse is a bad thing, however, the MSer then going into remission is purely a result of their own biology, not the medicine, hence why when they eventually move into the progressive phases of the disease, these treatments do nothing.

    A drug that actually works will fix the damage caused by MS. A drug that doesn't do this is merely snake oil.

    ReplyDelete
  5. If these drugs are any good they would work in progression which they do not.

    Glaterimer acetate failed in progressive MS, but placebo group did not progress and I think laquinimod was tested in RRMS.

    I am not going to spend my time defending these drugs that is Gs domain but in terms of a combination you do not know what will happen because it has not been done.

    Immunosuppressives do not appear to inhibit the development of progression but they do impact early in disease. The question is if you start early does that stop MS in its tracks, the optimist says yes or yes maybe. We will been to see but look at the AAN abstraxts and the ORACLE results are there give immunosuppression at clinical onset? and it delays conversion to clinically definetive MS. Will they be disease free we need to wait and see.

    "A drug that works will fix the damage caused by MS, the rest is snake oil"...is a blinkered view. It will be much harder to reverse the damage, than stop the damage occurring in the first place. Of course we want drugs that reverse the damage, but (a) drugs that repair myelin are some way off and (b) drugs that regrow nerves are further away.

    ReplyDelete
    Replies
    1. MD, I guess previous poster meant that a drug that has effect on relapses , but not on brain atrophy / edss progression is "snake oil". What is your take on that? Wouldn't it be strange to find it meaningful for the average MSer to be recommended a drug that suppress the immune-system with no effect on brain atrophy / edss?

      Regarding clinical data there are plenty of evidence showing great effect on brain atrophy and edss for Laquinimod. Coming AAN has one on three year data for Laquinimod treatment.

      Since relapse frequency seems to fade over time ( for the average MSer ) don't you think the currect focus on relapse prevention ( hardly measurable in absolute numers... only a " % " with no real clinical meaning for the average MSer , at least if you take into account safety and complience problems.

      For some reason, maybe you have not taken the time to eveluate Laquinimod with respect to its effect on brain atrophy, EDSS progression, safety, you seem to have a quite skewed perception and don't seem to appreciate the positive properties Laquinimod has in comparison with other MS drugs.

      For MSers with frequent relapses I understand the meaning with immunosuppressive drugs, but for the average MSer , and as a backbone with excelent safety and effect on the disease I find Laquinimod to be a very interesting option for the future MS therapy.

      I noticed NICE has started to create guidelines for Laquinimod.

      Delete
    2. GA looks to be a dead horse, and Teva are flogging it in more ways than one. Trials into high dose laquinimod look interesting in both relapsing and progressive MS. I don't quite get the argument though with laquinimod. Does it have little effect on relapses, so you continue to relapse, but then bounce back with little extra disability because of its neuroprotective ability?

      Delete
    3. What you need to consider is that the difference in absolute number of relapses per year between e.g Laquinimod and BG-12 is not more than maybe 1 relapse in 10 years ( for the average MSer )

      40% vs 25% sounds a lot , but in reality it is not.

      Any ideas why Biogen still refuse to provide full data on brain atrophy for BG-12 ;) ?

      Delete
    4. As Prof G, he is involved with BG-12 but if it is not in public domain then he is not going to talk about it. If they are hiding data you think should be positive, then the chances are it is not positive, otherwise a marketing opportunity is being lost.

      However the trial data was only published in Sept 2012 and imaging studies are usually published after that, it can take months for papers to be published so it may be in the publishing ether.

      Biomarkers in Neurological Diagnosis and Therapeutic Monitoring
      Effect of BG-12 on Brain Atrophy and Lesions Volume: MRI Results from the DEFINE Study during First and Second Year of Treatment (IN3-2.002)http://www.neurology.org/cgi/content/meeting_abstract/78/1_MeetingAbstracts/IN3-2.002

      Delete
  6. "For some reason, maybe you have not taken the time to evaluate Laquinimod".

    I am not sure what you are talking about, yes laquinimod maybe looks interesting as an effect on atrophy was hinted at, not as a immunosuppressive TEVA decided not to file for RRMS. Unless Teva put it on the agenda then there is no laquinimod, unless it shows some value in further studies then there is no laquinimod. The point of the combo is to deal with inflammation that laquinimod is not dealing with that is the point of the combo

    ReplyDelete
  7. We seem to have been visited by the Teva collective!
    That being the case perhaps they'd like to comment on their "Citizens petition" to the FDA re BG-12!

    ReplyDelete

Please note that all comments are moderated and any personal or marketing-related submissions will not be shown.