Monday, 30 December 2013

Progression Starts Early



Backgound: Multiple Sclerosis has two clinical phases reflecting distinct but inter-related pathological processes: focal inflammation drives the relapse-remitting stage and neurodegeneration represents the principal substrate of secondary progression. In contrast to the increasing number of effective anti-inflammatory disease modifying treatments for relapse-remitting disease, the absence of therapies for progressive disease represents a major unmet clinical need. This raises the unanswered question of whether elimination of clinical relapses will prevent subsequent progression and if so how early in the disease course should treatment be initiated. Experimental autoimmune encephalomyelitis in the Biozzi ABH mouse recapitulates the clinical and pathological features of multiple sclerosis including relapse-remitting episodes with inflammatory mediated demyelination and progressive disability with neurodegeneration. To address the relationship between inflammation and neurodegeneration we used an auto-immune tolerance strategy to eliminate clinical relapses in EAE in a manner analogous to the clinical effect of disease modifying treatments.
RESULTS:By arresting clinical relapses in EAE at two distinct stages, early and late disease, we demonstrate that halting immune driven demyelination even after the first major clinical event is insufficient to prevent long-term neurodegeneration and associated gliosis. Nonetheless, early intervention is partially neuroprotective, whereas later interventions are not. Furthermore early tolerisation is also associated with increased remyelination.
CONCLUSIONS:These findings are consistent with both a partial uncoupling of inflammation and neurodegeneration and that the regenerative response of remyelination is negatively correlated with inflammation. These findings strongly support the need for early combinatorial treatment of immunomodulatory therapies and neuroprotective treatments to prevent long-term neurodegeneration in multiple sclerosis

We have been talking about the best treatment for stopping relapsing disease in animals over the past couple of weeks. This is a transient depletion followed by delivery of the disease causing molecules via an immune tolerogenic route. In this study relapsing neurodegenerative disease was set in motion and then at different time points further relapses were stopped. We then looked to see what had happened in the CNS a few months later. It was clear that despite elimination of relapsing disease some nerve tracts showed progressive neurodegeneration, rather disturbing this occurred even after after a single attack. With each attack different nerve tracts started to degenerate. Therefore even in this simple model of MS it can be seen that relapses cause nerve damage and therefore stopping them, as quickly as possible, is important. Likewise in this case the autoimmune response can trigger a neurodegenerative condition and this progressive neurodegeneration can occur even from disease onset. From a clinical prospective stopping the disease in its tracks early was not associated with marked clinical progression but this could be seen once a number of relapses had occurred. This study further suggests that we should aim to treat early and effectively and to us it suggests that targeting T cells, at least in the periphery will not be the answer to treating progressive MS. This is not something that T cell immunologists/EAEologists are willing to accept or read. Can the odd autoreactive T cell be found in the peripheral blood and/or CNS, yes sure they can be. The immune tolerance needs autoreactive T cells to be present fr it to work. So this allows the doubters to cling to their increasingly flimsy view of T cells causing progressive MS. Yet Neuros continue to try and stop progressive MS by targeting T cell responses. So far targeting these cells in the periphery has uniformly failed to stop progressive MS. 

At what point do you stop and say that some bits of autoimmune dogma are probably not correct

This work from TeamG.

27 comments:

  1. Very interesting post, MD. Would this mean that your pyramid of targets for MS therapies (inflammation, neuroprotection, remyelination, restoration) could be changing at its base? (say with a wider step for neuroprotection). Would Laquinimod become a more intelligent treatment choice now after your publication of this study? (having both an anti-inflammatory but mainly a neuroprotective effect). Thanks again.

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    1. If you have a totally effective DMT then you may not need neuroprotection if the DMT is started early enough if not you may need DMT plus neuroprotectnt. This could be the same drug but i am not convinced this is laquinimod on its own as it is not a good enough DMT. Maybe laquinimod plus DMT but then we t know what is the side effects of two DMT together if this is the case.

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    2. MD, What do you base your opinion on, or in other words, in what (relevant) way is Laquinimod not a "good enough" DMT (according to you) with regards to what really matters? (i.e neuroprotection, brain atrophy, EDSS progression, QoL, benign safety ).

      I understand and agree that there are other and "better" DMT's with regards to ARR scores. Since Prof G and most other KOL's now seem to agree that brain atrophy is linked to long term disabilty (not relapses) I cannot follow your thought on this subject.

      MD can you please argue your case with regards to the relevant parameters stated above and state why Laquinimod is not a good ( or maybe.. the best? ) DMT with regards to the needs of the average MS'er with not very frequent relapses. ( good = total risk/benefit considering the anticipated slow-down of brain atrophy, disability, cognition and QoL )

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    3. Rekative efficacy of current DMT are based on. ARR.
      I agree atrophy would be good outcome but this is not without probkems. As pseudiatrophy can occur with a good anti inflammatory. The point i am making is that we know rekapses are not good for you so if you can deak with that deak with that also.

      I think the fda position was it wanted more trialdata. I have seen loads of neuroprotectie agents that would be no good as a dmt.is this what they have.
      He european regulators are. Shifting the goal post to have a disability outcome. Would some of the old drugs fail.

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  2. Prof M,

    I find it sad that we are nearly in 2014, yet the MS research world is still stuck in the world of our team's EAE theory v your team's EAE theory. I've got a theory - that EAE and other mouse models of MS have no relevance to an understanding of MS (a human disease where EBV, retroviruses and vitamin D play a role). A commentator once said of economists "an economist is someone who sees something working in practice and wonders if it will work in theory". This also rings true for the researchers in labs trying to create and the cure an MS-like disease in mice.

    Prof G has banged on about early highly effective treatments for MS for the last 18 months or so. This is a theory being tested as Lemtrada, now licensed in over 40 countries, starts being used across large numbers of patients. This is real research - testing a theory (using a drug) in humans with actual MS. However, the research paper above seems to suggest that even early effective treatment is unlikely to stop the progressive phase of the disease.


    I look forward to a 2014, where real breakthroughs are revealed, not the never ending debates about T cell involvement or which EAE model is best. I find it sad that, given the horrendous nature of this disease, the research world is still just hypothesising about the cause and mechanisms of this disease.

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    1. You know what is coming in 2014 as we know what is in phase iii at the moment and likewise you know the pace that these turn into available treatments. I have no influence on the speed of this process.

      As to experiment ongoing with lemtrada. Thid is great if people get acess to it. Only with data can we know. As to the EAE work you can choose to read or not but itis a glimpse of the future like it or not.

      I disagree that the paper above indicates it is too late however the human experiment tells us that nerve loss occurs from the get go. When does progression start well it is clear for people with PPMS this is early after diagnosis. I wonder how many of those people can remember an attack before diagnosis.

      I am afraid the science world will continue to theorise until neuros find the answer but without te basic science they will shot further in the dark

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  3. Does this mean that early, aggressive could be too late though? If even after 1 attack, neurodegeneration occurs/continues - how many MSers are able to get treated before a single attack? By definition - none. Or is it just the attacked tract that suffers and we have enough 'spare' that if treated early enough we can function fine despite the degeneration of the 'attacked' tract? A worry from this research is that if a chain reaction is kicked off by just the first few 'attacks' that can't be stopped then even the most early, most aggressive treatment won't make much difference in the long run? I don't think that is correct personally but would be interested in your perspective.

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    1. I am hopeful for early and aggressive and this the positive from this work. Hopefully it serves to focus the mind of the timid neuros out there.

      I think it tells us that tractd go and that thete is compensation i dont thnk that one attacj and progression occurs in this strain. This may not bethe case in other strains where one attack s it. You must remember that about ten to fifteen percent of msers go ppms so therr some people where this may be the same. Genetics may be part of this such as maleness and age.

      If we stop after one attack there is no evidence they get overty worse from a clinical pespective soi take the positive from this.

      How late is too late for progression the human studies may be able to answer this.

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  4. I guess the conclusions makes the findings in " Therapeutic laquinimod treatment decreases inflammation, initiates axon remyelination, and improves motor deficit in
    a mouse model of multiple sclerosis " ( http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3868172/ ) even more interesting?

    The results indicate that ; " Even when initiated at peak disease, LQ
    treatment has beneficial effects within the chronic EAE mouse model. In addition
    to its immunomodulatory effects, the positive effects of LQ treatment on
    oligodendrocyte numbers and myelin density are indicative of significant, functional
    neuroprotective and neurorestorative effects. "

    Why don't you argue that Laquinimod should be first line treatment, considering Laquinimods neuroprotective capabilities.... even if administred at peak-disease?

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    1. In animals there appears to be immunosuppression with this drug. In humans this appears to be far less marked. So hard to recommend as a first line.

      So when you read the paper that you mention,it is open access,. I ask you to answer this. What is occurring that would not occur if the cells and damage never occured because of immunosuppression?


      As a first line you need a stronger DMT maybe an add on, with previso

      I would happily test this agent to see how good the neurprotection really is. Seeing is believing
      .

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    2. MouseDoctor
      How do you define DMT? Is your definition something else than Disease Modifying Treatment?

      To Modify the path of the Disease must for almost all MSers mean to halt or delay disability progression and to halt or delay worsening of cognition.

      I guess you don't really believe that one relapse more or less in maybe 6-10 years is the definition of a good or bad DMT? Especially if the "good" DMT have no effect at all, insignificant effect or not possible to judge effect on disabilty and cognition.

      If brain atrophy has the strong correlation to long term disability I guess you Profs should define a good DMT as a DMT that has significant effect on slowing down brain atrophy and not as a DMT that has showed good effect on one less important symptom of the MS disease ( = the relapse )

      Await your commments.

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  5. Mouse will rightly note that progressive trials are underway. My question is when will these treatment, assuming they are successful, be available? Probably 5-10 years!

    Where's Prof G? I see that the FDA rejected Lemtrada. Perhaps G is keeping low in case Genzyme are seeking a refund of consultancy fees. Yet again poor trial design is the issue. Didn't we hear thus with Lamotrigine and Cupid?

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    1. I depends on which drug is successful.. The first possbiity id finglimod in 2014 for result then should be a short while to get licence. But for othes there may need to be one or two phade iii trials. Unless there is the BPA and a change in the process it wil be years.

      Prof G is having a well deserved family break not hiding from the FDA.

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    2. The trial design was approved by the FDA before the trial started. Problem is the FDA reviewers seem to not accept this.
      The trial was not blinded.Problem genzyme sanofi does not manufacture beta interferon so it added a layer of problem doing trials against beta interferfon to make placebo.

      Problem was the phase iii was not as good as the phase ii using a similar trial design.

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    3. "The trial design was approved by the FDA before the trial started. Problem is the FDA reviewers seem to not accept this."

      That's interesting, and not the first place I've read it. If I was Genzyme and I'd just sunk millions into a trial design that was preapproved only to have the FDA change its mind, I'd be thinking about a lawsuit. Do drug companies ever sue the FDA?

      (I know you're a Mouse Doctor and not a lawyer. I'm just thinking aloud.)

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    4. Sue rhe fda. But as they are the regulators withthe final say will pharma win
      Two european induction therapies sunk by the USA. Wil sanofi withdraw kicence from europe i suspect not as there are more msers in europe

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    5. I read a comment from one of the investment banks post the Lemtrada AdCom. The comment said that the FDA at a very early stage objected against the study design and asked Genzyme to alter it. The bank couldn't see any other likely outcome than a complete respons letter considering the FDA review pre AdCom. If the investment bank comment was not based on some misunderstanding it appears as if Genzyme didn't take the FDA input seriously enough.

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  6. Ditto, that's my question too

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    1. Which one :-(). Answer is ditto to above.:-)

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  7. Clearly if the axon is demyelinated or dysmyelinated, the axon undergoes mitochondrial changes to maintain conduction. Unfortunately the result of this is a vast increase in the energy required by the axons which will eventually kill the axon as well as the neron itself.

    So of course immunosuppression will not prevent neurodegeneration at this stage, nor will tolerance induction. The key is to prevent further axonal injury because at this point, progressive ms is a mitochondrial issue.

    Fortunately, people are working on this approach now:

    http://www.santhera.com/?docid=212&vid=&lang=en&newsdate=201306&newsid=1707174&newslang=en

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    1. So are we and hosts of other people.. But is mitochondria a cause or a consequnce most people think it a conesquence

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    2. It is interesting that in the NIH trial I posted above, the drug they are testing in PPMS has the same active ingredient as coenzyme Q10. This seems to have an effect on oxidative stress in RRMS:

      http://www.ncbi.nlm.nih.gov/m/pubmed/23659338/

      Anecdotally, I recently started taking this along with my DMD and I have almost no fatigue whereas before I had to ration the amount of activity I did per day without feeling like a had run a marathon by days end.

      It would be a shame if a treatment for neurodegeneration could be had at your corner drug store over the counter.

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    3. Sounds good but remember anecdote is not evidence and until this obtained we do not endorse

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    4. "So are we and hosts of other people.. But is mitochondria a cause or a consequnce most people think it a conesquence".

      Yes, I agree that mitochondrial dysfunction is a consequnce of MS, not the cause. In particular, demyelination, dysmyelination and also remyelination produces mitochondrial changes that issues in progressive disease. This article sums it up well and believe they are on the right track in understanding ms:

      http://www.ncbi.nlm.nih.gov/m/pubmed/21705418/

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  8. How do i define dmt. In current ckinte dmt are agents affecting gafokinium kesions and relapse this would be different from a neuroprotective dmt.
    I woukd borh typs of dmt. We spend most of our time on the latter type.

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    1. Sorry phone post english is very baf

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    2. I realise the above is the Les Dawson of Texting look to the key nextdoor on a QWERTY keyboard for translation

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