Monday, 16 December 2013

Gilenya is not so good in secondary progressive EAE



BACKGROUND: There has been poor translation for the use of immunosuppressive agents from experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS), into the treatment of MS. This may be due to the fact that most EAE studies examine prophylactic, pre-treatment regimes that prove to be therapeutically-ineffective in long-established, often progressive, MS. FTY720 (fingolimod/Gilenya) is a sphingosine-1-phosphate receptor modulator. This is a new oral agent that markedly reduces the number of relapses in people with MS, compared with currently licensed injectable agents such as the beta interferons. FTY720 has activity against lymphocytes but may also influence oligodendroglia and could therefore have the potential to influence progressive MS, by promoting remyelination.
METHODS: The effect of FTY720 was assessed in relapsing-progressive EAE in mice.
RESULTS: Early intervention during relapsing EAE could completely inhibit subsequent relapses, inhibited the accumulation of neurodegeneration, and facilitated motor recovery. However, when examined in secondary progressive EAE, that develops after the accumulation of deficit from relapsing disease, long-term treatment with FTY720 failed to slow deterioration when initiated late (4 months) into the disease course.
CONCLUSIONS: This study indicates that early intervention with immunosuppressive agents may inhibit the generation of the neurodegenerative microenvironment, which is no longer responsive to potent immunosuppression. However, if treatment is initiated too late, progressive, neurological-disease continues unabated. This suggests that immunosuppression is insufficient to control secondary progression in animals, as has been found so far to be the case in MS, and may warrant early intervention with FTY720 for optimal treatment benefit.

Gilenya (FTY720) is an S1P1 and S1P5 receptor modulator. S1P1 is involved in trapping white blood cells in the lymph nodes and stops relapsing remitting MS. It also stops relapsing-remitting EAE as we showed in this study. S1P5 is strongly expressed in the brain and has lead to the idea that Gilenya may promote repair and the hope that help in progressive MS.  In our studies if we blocked relapses we could see that there was some recovery in mobility.

Was this due to the drug or was it because we had stopped disease and the the natural repair mechanisms kicked in?  Maybe the former but we could not find evident that there was remyelination, maybe we weren't looking in the right place, maybe it was due to plasticity. Obviously if we blocked relapse it stopped the animals accumulating more nerve damage that occurs as a consequence of relapse. But could it stop progression that isn't attributed to relapsing disease?

Most people working with EAE do two to three week experiments. This is never going to tell us much, other than the effect on the inflammatory penumbra at best and maybe over interpretation at worse.

TeamG undertook the longest EAE experiment in history.

We set relapsing remitting disease in motion and allowed a few relapses to occur, more relapses than most researchers ever see. We then had to stop any more relapses occurring because if they occurred, it would obviously cause more nerve loss and disability and so Gilenya would stop relapses and would of course do better than placebo. So we stopped anymore relapses occurring using antigen-specific immunological tolerance induction.This involves a transient depletion of white blood cells followed by a tolerising injection of myelin and after that relapsing autoimmunity is essentially gone forever. Yep it really is that good.

Why people are trying to do immunological tolerance in MS without the prior the transient depletion that makes it really work escapes me.

However, we have shown that if secondary progression, seen by worsening in disability, is occurring then blockade of relapsing autoimmunity is not enough to stop progression.

So back to the longest experiment, we stopped relapses then waited for white cells to return and then split the animals to one group  to get placebo and another group to get gilenya. So months after starting the experiment, animals got a daily oral dose for a few months, again longer than most experiments in history. Progression accumulated slowly and unfortunately there was no drug effect.

Massively disappointing. But the results are the results

Therefore, we have a concern that something similar could happen in MS, although we would expect it would inhibit gadolinium-enhancing progressive MS.

Time will tell as S1P1 modulators are now in trial in both primary and secondary progressive MS, so this is what is important.

However, more recently there have been studies in non-EAE neurodegenerative conditions suggesting some positive impact on slowing neurodegeneration let's hope that this is the result we should find out soon.

CoI: This work was supported by Novartis.

43 comments:

  1. There seems two really important positives to take away from this study, unless I misunderstand (with the caveat that mouse EAE and MS are not the same thing and so extrapolation can't be taken for granted):

    1. It suggest a clear causal link between relapses and later progression and, most importantly, that early suppression of relapses stops/reduces progression - i.e. supportive of the 'early, aggressive treatment' view.

    2. The induced tolerance (depletion > tolerance creation via myelin injection) approach is shown, again, to be effective.

    The latter point baffles me. Why, given that almost anything that works in a mouse ends up being trialled, even when the in-animal trial design is poor, is more energy/resources not being poured into this approach? It sees likely to be one of the best prospects on the horizon for controlling, at least, the relapsing stage of the disease so why is this not the number 1 focus? Is it a matter of collaboration and communication between neuros and between neuros and pharma? How widely known and understood is this approach or is it just something MouseDoc is sat on without actually getting out there to promote the approach? Why isn't it being shouted from the roof tops as a great hope for MS and getting funding etc?

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    1. 1. Correct Early and Aggressive seems sensible to us..Time is Brain and each attack is not good news.

      (a) The data does suggest indeed that clinical progression occurs as a result of damage from relapses
      (b) The number of relapses however many not determine when clinical progression starts some it occurs after a few attacks some a few more. This I believe is the case in MS also.
      (c) Treat early and aggressively stops relapses and and slows clinical progression, I won't say stops progression because even after a single attack some nerve tracts will go histologically, however clinically the animals are effectively cured.
      (d) This effect is very robust and works as well or better than any other treatment ever published in EAE.
      (e) This works of two injections one with the depletion agent and two the immune tolerance
      importantly either alone is not totally effective after depletion the cells come back and disease starts again, the immune tolerance is not effective enough once the immune system is primed, unfortunately the "Powers of immunology" don't like.

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    2. So, again, this begs the question - how do we go from highly effective EAE/concept to human trials? It seems incredible (i.e. scandalous) no-one is properly investigating this dual approach?

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    3. 2. Yes it is very effective works later than any other treatment ever, you also do not need to know what is causing the autoimmunity, you give the animal a full selection and it chooses what is interesting to it. It uses two approaches that have both been tried individually in MS.

      However problem....It also says that immunology is not the answer to everything and that T cells do not necessarily mean everything and to some Neuros and scientists this is a very big problem and this science mafia control the literature, as any card carrying EAEer works on T cells.

      We cannot easily prove the unprovable that T cells are not driving the progression but immunologist reviewers cannot accept this and so this work has

      (a) Struggled to be published in high impact journals
      (b) Struggled to get funding for further development

      The rejections are rather soul-destroying.

      The original concept was made in about 1994/1995 the in vivo data on a poster was seen by someone who published the concept in a transgenic abit later, however theoriginal concept was published by my old boss in the 1960's.. We spent years jumping through hoops with reviewers and countless journals the concept was published in 2005.

      After one attack there are 500 T cells left in the CNS compared to hundreds of thousands during an attack are these cells enough thats 450 more than normal.If you do it by sections that it one in a large number of sections and if you do the treatment there are very few T cells left in the CNS but you find the odd one is that enough. If you do the depletion there may be 99% cells gone but is the 1% left enough, if you do a T cell assay and there is no proliferation but there is always a bit of background turnover is that enough. Without T cells being present the tolerance will not work because it needs them to be present to switch them off. There is always a get out of jail clause for the immunologists who are looking for reasons not believe the real possibility that T cells are not the centre of the universe....No wonder I am a cynic.

      What is the beauty of this approach
      (a) It works
      (b) It works in more than on persons hands
      (c) The principal has worked in other forms of immunology and is not species specific.

      What are the barriers to translation..resource. No one wanted to fund it.

      At the time we were concerned with safety and if we got it wrong like the altered peptide ligand it could make MS worse. We were sticking antigens on cells or beads and it they clump they could cause stroke. It turns out that now both these approaches have been used in MS..they could,still cause stroke if they get it wrong

      (a) Depletion agent. In our studies we used anti-CD4. It is no longer available or companies that have it won't give it to us. We would have to pay to get antibody out of storage and manufacture the deletion agent. Can we use others yes we can. The question is do humans and mice recover their immune response at the same rate...the answer is no

      (b) Antigen source. Peptides are not good enough because there is not the full range of potential autoantigens and makes ssumption that you know what the cause is but the auto antigen is not known or is it....Proteins are needed.

      BSE comes along and so there is no way we can use brain material.

      You need companies to make CNS proteins of standard required to get into human this needs company support are companies interested in one-off treatments

      Is this work dead. No it isn't but without effective funding it has been trickling forward.

      Has this approach been taken forward. Yes and it has, it has been used in humans (not to treatment MS) by TeamG .

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    4. It seems that in this order to induce tolerance with autoantigens, they need to be administered chronically for tolerance to be maintained.

      http://www.ncbi.nlm.nih.gov/m/pubmed/23738007/

      The only MS drug on the market that has the remote chance of doing this is Copaxone which is why I chose it. All the other drugs don't address the real problem in MS which is restoring self tolerance.

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    5. The dual approach has been ignored because no company had both arms, there are some companies delivering antigens via the subcutaneous route which is the wrong route in my mind, it needs to go intravenously. This approach was tried in secondary progressive MS with MBP and failed just as I told them it would as it would have been predicted to happen and the company is no more..So opportunity missed.

      There are trial using peptides fixed to cells and there is another giving alpha B proteins i.v. in MS, both in my mind run the risk of failure both know about the dual hypothesis concept.

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    6. The depletion step adds another layer of complexity the problem is if (or I guess when) the studies fail that is the end there is no second chance.

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    7. For tolerance to be maintained they need to administered continuously,

      In the EAE experiments here there was only one administration, there was an adjuvant/antigen depot, and in some studies with skin grafts the graft acted as a continuing depot.

      You are correct restoring self-tolerance is the name of the game

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    8. Exactly. This is why you take Copaxone every day. Since it is a mimic of myelin proteins, it make sense that it could induce tolerance.

      http://www.ncbi.nlm.nih.gov/m/pubmed/9933117/

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    9. P.S. Sadly I think our human trial will need to be terminated, as we have not had enough volunteers, and progress has meant that it will be difficult to carry this on.

      So it will be anecdote......when we really needed antidote.

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    10. Copaxone is random polymer of four amino acids found in myelin basic protein, namely glutamic acid, lysine, alanine, and tyrosine. Thing is those 4 amino acids will be found in hundreds if not thousands of other proteins so to say it is a mimic of myelin proteins is disingenuous. If it induced robust tolerance you wouldn't get any more relapses and yet you do.

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    11. Copaxone was originally developed to induce EAE, but the found it actually prevents it.

      The rest rest of the world acknowledges this fact:
      Glatiramer acetate
      Glatiramer acetate (Copaxone) works differently to Interferon beta. It is designed to mimic the proteins in myelin and is thought to prevent the production of the immune cells which attack the myelin, thereby reducing MS symptoms and related damage to myelin and nerve fibres.

      http://www.ms-uk.org/mobile/fa=page&id=322&section=1#.Uq8Lmp8o6BZ

      It seems logical that it can induce tolerance and appears to work in many people based on the longterm followup reports. But because it does not fit into the cookie cutter measure if effectiveness based on a two year trial, it is deemed as useless from people as yourself.

      This is the main problem. There are too many people working on solutions for ms that are band-aid treatments such as immunosuppression. I am glad the scientists who developed Copaxone developed this Drug because it is a step in the right direction.

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    12. I have some magic beans you may be interested in purchasing?

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    13. Wow, I really wouldn't have expected this type if attitude from someone working on MS research. So what exactly have you done to help people with MS? I can only imagine your lists of accomplishments.

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    14. "Step in the right direction"

      I think a company (Merck Serono?) is developing Cop2-the next generation based on a different mix.

      The academics claim it works better than Cop1

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    15. Regarding the effectiveness of GA, this from a meta-analysis of studies.
      http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD004678.pub2/full
      The salient conclusion is this.
      "Benefit of glatiramer acetate on clinical relapses seems to be more consistent. However, an increase of probability (28%) to remain free of relapse was found at 1 year but no more detectable in the follow-up. The mean number of relapses was reduced over time from 1 to 3 years. These results should be considered with caution due to a significant heterogeneity among included trials. When the average number of relapses is considered, results are no better after correcting for heterogeneity. This heterogeneity might reflect differences in patient selection, since risk estimates of controls (basal risks) appear uneven across studies. Using a random effects model, no significant decrease in the average relapse counts can be observed at one year and two years, while a single study suggests that the frequency of relapses experienced at three years could be slightly reduced by less than one, on average, in glatiramer acetate-treated patients. In this respect, it should be noted that the weighted mean difference may not be an appropriate measure to analyse relapse counts. Actually, this variable seems to follow a positive asymmetric distribution (standard deviations tend to increase with increasing mean values across studies) rather than approximating the normal function, as it is assumed by the weighted mean difference analysis."

      If GA was really inducing tolerance, why would you need to inject it on a daily basis?

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    16. "So what exactly have you done to help people with MS? I can only imagine your lists of accomplishments."
      We are easily searchable on PubMed. We can leave the significance of our achievements for others to judge but I do think we've made a contribution.

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    17. "So what exactly have you done to help people with MS?

      Apparently nothing, as you seem to tell us all the time :-)

      MD2 is not so fond of the biology behind Copaxone as you can tell, which has had more turns than Lombard Street, but if it works for you great which is the important point

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    18. Agree with MD that if it GA works for you then keep doing it.

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    19. "If GA was really inducing tolerance, why would you need to inject it on a daily basis?"

      If you would take a break for a minute and read the study I posted, tolerance is induced only when the autoantigen is continuously induced. MouseDoctor brought this point up and I posted this study to corroborate what he is saying. I think he get the idea about what is needed to stop RRMS without generalized immunosuppression.

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    20. "I think a company (Merck Serono?) is developing Cop2-the next generation based on a different mix."
      With the addition of eye of newt? ;-)
      I'll get off my high horse now.

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    21. Teva has shown you don't have to inject every day with the new Cop1 Plus formulation, funny they waited until the daily dose patent was running out to show this.

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    22. In our studies (and others) long-lasting tolerance is induced with a single iv infusion of myelin antigens (after transient T cell depletion. It is not necessary to do this continuously.
      Assuming you're the same poster, it was you that mentioned GA.
      Also if GA is working via T-regs, why are they so short-lived that you have to keep giving it on a daily basis?

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    23. "Teva has shown you don't have to inject every day with the new Cop1 Plus formulation, funny they waited until the daily dose patent was running out to show this."

      There is an issue with some people on daily injection that you get a reaction such as tightness of chest, racing hear, etc. I never had this but it only lasts a few minutes and occurs in a minority of patients on occasion. This is thought to be an allergic reaction to GA. So if they go to a 40mg shot given every other day, I can imagine this will occur more frequently which is why they probably went with the daily 20mg shot in the first place.

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    24. Teva ought to be giving you an honorarium! ;-)

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    25. I don't think Teva would want this information spread around, but this is my guess why they originally went with 20mg daily inections. Since there are so many people who cant tolerate daily shots it seems a shot every other day would be more palatable, but they must have a reason why this was not the original trial dosage.

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    26. Yes you are right teva never gave me an honorarium :-)

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    27. I know this is off-topic from the original title of the blog post, but this is an important question - are you guys saying that Copaxone doing anything for MS is as much a fantasy as Jack's beans? That it really isn't any better than placebo?

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    28. No we are not saying that, The data is out there that copaxone has effects above placebo and therefore is beneficial in RRMS

      However MD & MD2 do like to point out that there is probably a lot of trollop that surrounds this drug. In fact there is probably a lot of trollop that surrounds most drugs
      Copaxone has had as many mechanisms of action as there has been dogmatic ideas over the years and some data in EAE well we wont go there.

      Given the claims of mechanisms of action in some papers then the level of efficacy should be very,very high.

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    29. Point taken. I remember reading about the FDA approval hearings for Cop-1, and the data in its favor was fairly flimsy. And one of the justifications for approving it was that pwMS needed something (other than IFN-b). So, when I read comments like above, I sometimes wonder why I've been injecting myself with the stuff. This also begs a larger question - should more research be done to determine if GA really has any benefit? Most neurologists just accept it as a first-line treatment, and many people have given many dollars (I believe the cost is up to $4000/month in the U.S.) to Teva.

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    30. I think one of the problems with how drugs are evaluated as it is only based on the results of a placebo controlled trial for two years. There is no need to understand the mechanism of action, just how well it does during this two year period.

      But if you look closely at Copaxone, it seems to be a therapy that may induce therapy over time. In essence you are tolerizing yourself by injecting copolymers that are mimics of meylin protein.

      http://www.ncbi.nlm.nih.gov/m/pubmed/23203082/

      My point of view is that it may take time for this to show an effect, just like you do not lose allergies after you start allergy shots which could take as long as five years if it works.

      But the thing that convinced me to go with Copaxone is the long term follow up studies that shows that those on continuous therapy for 15 years, 53% have stable or improved EDSS scores and 2/3rds have not progressed to SPMS:

      http://www.ncbi.nlm.nih.gov/m/pubmed/20106943/

      The argument against the extension study is that it is not placebo controlled. But having a long term placebo controlled trial would be inhumane.

      So in summary, in my opinion (as well as others on it for long term) Copaxone can stop MS in some people if they stay on it and are able to tolerate the shots. It is not the best drug to quickly shut down disease activity so would not be a good choice for highly active disease, but it seems like a good and safe option for some. But what we need is a way to determine who is a good candidate for this therapy.

      And I do not work for Teva.

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  2. Thanks for the above - they certainly help to understand the problems and frustrations. It still seems a ridiculous situation - there you are, sitting on something that, whilst not without risks (which is hardly something new for MSers to deal with in a therapy), could be the closest thing we have to a cure for, at least, the relapsing stage of the disease and it is 'trickling' forwards at best. Meanwhile, fortunes, presumably millions, are being poured into making the next 'versions' of GA and IFN for patent protection purposes.

    Can't Prof G use his contacts and profile to promote this possibility greater? He goes to every major conference - shouldn't he be evangelising about this potential approach and getting widespread support for taking it forwards? The main UK MS neuros all seem to know each other - why not pull a group together to devise a plan to move this on? The MS Society seems to fund all kinds of speculative approaches to the tune of many hundreds of thousands, sometimes in the 7 figures - if Prof G and a number of other neuros and academics such as yourself approached them with a plan, I can't image you'd be rebuffed?

    I'm not meaning to be critical - far from it - but it's relatively easy to sit back and look at all the challenges, be cynical about pharma and immunologists etc but if you really believe in the potential of this approach then I think you have an obligation to be unrelenting in pushing it forwards.

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  3. We are still moving forward but you either go for proof of principle or you have to think how you can apply it safely and globally. We have done both. But the process is slow when you do not have a team to do everything that is needed

    MS charities are not protein manufacturers, pharma is and to develop pharmaceuticals as an academic is not easy, especially when you are already doing one. However if reviewers don't like proposals there is not much the MS Societies can do as they rely on their reviewers to guide them. That is academic life

    As to frustrations it is not all ours and I show the email I got this morning on this subject matter from a collaborator of ours.

    "Dear All
    So after all that, the tolerisation manuscript has now been accepted. Merry Christmas and thank god it is finally out there, this has been one painful journey for some really good work (well in my opinion anyway!)".

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    1. P.S. You'll hear about that when it is published

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  4. Are you really struggling for volunteers to try this approach? What are the inclusion criteria? Subject to receiving a bit more info - I'd volunteer. I can't believe, properly publicised, you can't find people who would be willing to give this a try - they're are people with MS trying all kinds of crazy stuff. I'd include CCSVI in that but I'll turn this into a very different thread if I was to... ;-)

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  5. Yes struggling, this trial was for people who are beta interferon Nab positive now there are alternatives to switch to

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    1. I don't understand the link? Why does the trial need people who are IFNb Nab +ve? I don't see the connection between the approach and this?

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    2. What is the cause of autoimmunity in MS....you don't know?
      What happens if you get it wrong.....MS gets worse? Remember this has happened
      Who is going to support a treatment that you only have to do a few times?

      Is there a human autoimmune condition where you know the real target in most cases the answer is no.There are may be a few such as mysthenia gravis (anti actyl choline receptorantiboides) and now maybe NMO (anti-aquaporin 4 antibodies)

      However there is one in MS.

      These are neutralising antibodies (Nabs) to beta interferon that develop after delivering beta interferon by a sensitizing route and this stops beta interferon working and MS comes back . Therefore you know the cause it is human beta interferon. So this is an experimental human autoimmune disease

      You have a ready made supply of recombinant protein suitable for human administration.

      When you have 30% efficacy and no competition there is little incentive to worry about neutralizing antibodies. When you have competition with drugs at 50% efficacy and there is 50% efficacy of beta interferon usage if you exclude the NAb positive people, then there is incentive to do something about Nabs.

      If you remove NAbs then beta intererfonwillwork again and block MS

      If you make the antibody response worse, you neutralise the beta interferon, which what the individual is doing anyway, you can live without beta interferon and there are lots of other interferons that can compensate for loss of beta interferon.

      If you can show you can control one human autoimmune response you can then go after others. In MS is you make a guess of the antigen and it does not work you can say that antigen is not important rather than wondering if the target is wrong or the technology is wrong and you mitigate the worry of not making the disease worse..

      Hope that explains the approach

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    3. So if you get it to work for one autoimmune condition you could do it for another e.g. Stop ITP, thyroiditis etc.

      The principle is common,my ex-boss showed this approach to work in skin allergies in the 1960's Which reminds me to look at the paper as this was done before the invention of monoclonal antibodies.

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    4. That makes sense but, given recruitment has been problematic (I imagine because the 'prize' in this particular trial is not a cure for MS, it is just IFNB working again - not especially attractive an upside) there must be another route forwards? I am certain that if you are able to deplete the immune system and have a promising candidate for the antigen tolerance, there are plenty of MSers who will step forwards, fully aware of the risks involved.

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    5. The percentage is smaller than with Beta-interferon, but NABs are a problem with Natalizumab too.

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    6. even alemtuzumab so I am led to believe

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  6. I would have enrolled if I had known about it, but I'm not on interferon and live in the US. This is truly the way to cure RRMS without having to delete or suppress your immune system and would most likely eliminate SPMS if treated early.

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