Friday, 4 November 2011

Research Trial. MBP peptide does not inhibit progression

Freedman MS, Bar-Or A, Oger J, Traboulsee A, Patry D, Young C, Olsson T, Li D, Hartung HP, Krantz M, Ferenczi L, Verco T; On behalf of the MAESTRO-01 Investigators. A phase III study evaluating the efficacy and safety of MBP8298 in secondary progressive MS.Neurology 2011;77:1551-1560.

MBP8298 (also known as dirucotide) is a synthetic peptide that is similar to myelin basic protien (MBP). This peptide can react with a molecules that are associated with recognition of infections by the immune system, which are important in rejection of organ transplants. Two types of these molecules namely DR2 and DR4 have been linked to the development of MS. Notably the DR2 type in Northern Europeans and DR4 in Southern Europeans. When MBP8298-like molecules are administered intravenously to animals with MS-like disease induced by MBP then they have the potential to inhibit the development of disease. This only inhibits MBP specific cells and so should have a good efficacy without side-effects

Could this be used to treat autoimmunity in MS?

OBJECTIVE: To evaluate the efficacy and safety of MBP8298 in subjects with secondary progressive multiple sclerosis (SPMS) who express human leucocyte antigen (HLA) haplotype DR2 or DR4 (DR2(+) or DR4(+)).

METHODS: This multicenter randomized 2-year, double-blind, placebo-controlled study included 612 subjects with a diagnosis of SPMS and an Expanded Disability Status Scale (EDSS) score of 3.5-6.5, stratified according to baseline EDSS score (3.5-5.0, or 5.5-6.5) and HLA haplotype (DR2(+) or DR4(+), or DR2(-)/DR4(-)). Upon entry of 100 DR2(-)/DR4(-) subjects, further study enrollment was limited to DR2(+) or DR4(+) subjects. Subjects were randomly assigned to either 500 mg MBP8298 or placebo, given by intravenous injection once every 6 months for 2 years. The primary outcome measure was time to progression by ≥1.0 EDSS point (or 0.5 point if baseline EDSS was 5.5 or higher), confirmed 6 months later. Secondary outcomes included mean change in EDSS, mean change in Multiple Sclerosis Functional Composite, MRI changes, annualized relapse rate, and quality of life.

RESULTS: There were no significant differences between treatment groups in either the primary or secondary endpoints. MBP8298 was well tolerated in all treated subjects with no safety issues identified.

CONCLUSION: In the population studied, treatment with MBP8298 did not provide a clinical benefit compared to placebo. Classification of evidence: This study provides Class 1 evidence that MBP8298 is not effective in patients with SPMS who are HLA DR2(+) or DR4(+).

This trial was doomed to fail on so many levels and is a waste of a drug and peoples expectations.

(a) Prof G may argue that there is no good evidence that MS is a problem of autoimmunity. The only way to prove this is to stop autoimmunity and hope that disease goes away.

(b) Although T cells drive the disease in animal models, again the evidence for the importance of T cells during MS has not been compellingly shown.

(c) There is no good evidence that myelin basic protein is a target for autoimmunity in MS. In my opinion MBP has recieved undue attention as a target in MS because it is easy to make, unlike other myelin protiens and is water soluble unlike other myelin protiens. Therefore it is easy to work with, but is a poor candidate target. It is not central nervous system restricted unlike MS and autoimmunity to this protien can induce a peripheral nerve disease. There are much better candiates, but it does not need to be the same target in everyone with MS.

(c) Without a transient immunosuppresssion, intravenous antigen is not that that effective at preventing established disease from developing further.

(d) IMPORTANTLY. Progressive MS does not respond to immunosuppression!!!, so even if it were the best drug since sliced bread then it would still be doomed to failure. In my opinion some Neuros/Companies are still convinced that all problems of MS are due to autoimmunity, but this is like having your head in the sand!!!. The data no longer stack up to support that view.......so yet another failure. Company making the drug down the tube!

On the plus side it shows that putting myelin peptides into MSers is safe, so when they select a more realistic target it has more chance of success.

7 comments:

  1. You say the trial was doomed to fail - I look at some of the MS researchers invovled and there are some big names. Is it the case that MS researchers will take on any research (even research which is doomed to fail) as long as someone pays! I was following this durg as one paper (produced by MS researchers) claimed that it delayed progression by up to 5 years. Again, how can we trust research papers when a claim like this is later proved to be wrong i.e. the drug completely failed.

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  2. When undertaking early studies you look for positive spin to help fund the next phase of the process. Whilst the positive spin is lots of benefit if we look at the intial studies the drug FAILED to reach its targets in those early studies.

    In the initial phase II study in 32 people the drug failed to show a significant benefit Warren KG, Catz I, Ferenczi LZ, Krantz MJ. Eur J Neurol. 2006;13:887-95. This is the mesage from the paper that should have been trusted because that was the aim of the study

    However, when they analysed the data as sub-groups it was suggested that people with HLA class II DR2 and DR4 (transplantation antigens) may benefit, based on information from less than 20 people.

    Therefore based on this data of a few people a phase III study was performed in over 600 people with MS that were DR2/DR4 expressing. In this trial just as in the phase II study the drug FAILED to reach its end points and there the sub-group effect was not confirmed.

    In my opinion this drug was doomed to failure because of my personal experience with this approach and my interpretation of available data. It is personal opinion.

    However there are many Neuros, including some very, very big names that still think that all the problems of MS are because of the immune system. Perhaps hence, their willingness to do trials. It is seldom about money, but a desire to be involved in a treatment that may work. Furthermore one often does better by being in a trial, even if it doesn’t work, than not being offered anything-Hence the placebo effect.

    However, there are some people that don’t put enough thought into understanding the treatments they are testing.

    I no longer think the problem of MS is just a problem of autoimmunity. This is the case even in simple autoimmune animals where you know the causative entity, this approach (as used in the trial) is not enough to stop progression. (Pryce G, O'Neill JK, Croxford JL, Amor S, Hankey DJ, East E, Giovannoni G, Baker D. Autoimmune tolerance eliminates relapses but fails to halt progression in a model of multiple sclerosis. J Neuroimmunol. 2005;165:41-52).

    So I am not sure why we should expect this to occur in a disease, where we have no definitive proof that it is just autoimmunity and the likelihood of myelin basic protein being the causative agent and the only causative agent is very slim (others don't share this opinion).

    Now couple this with the demonstration that this drug failed to inhibit relapsing disease also (http://en.wikipedia.org/wiki/Dirucotide), which was its best opportunity to work and the oberservations that progressive MS does not respond to lymphocyte depletion using Alemtuzumab and cladribine or replacement (bone-marrow transplantation) and this provides a reason why I do not think this study could work. There are other reasons as well.

    However, if MS does have an autoimmune component, which I still think it has, the approach of delivering CNS proteins via the intravenous route is the best opportunity to have a drug that works but without the side-effects of current drugs.

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  3. Dr Mouse,

    Thanks for your comment. However, I'm confused. When I was diagnosed 4 years ago the neuro explained that I had an auto-immune disease where the T cells attacked the myelin in my CNS. Now you appear to be saying that the problem of MS is not just a problem of autoimmunity and question whether it is T cells which are to blame. Does this mean that the last 50 years of MS research (based primarily on the premise that MS is auto-immune with T cells causing the problem) has been a waste of time? If it's not auto-immune with T cells causing the problem - then what is it? If there is another theory / idea, then will we see another 50 years of research into this theory. At the end of each year the NMSS website psots an article about progress in research which states that even more progress has been made in the alst 12 months, there are huge numbers of new treatments in the pipeline etc etc. Am I wrong to take encouragement from this?

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  4. The article you quote (Pryce et al.) seems to state very clearly that tackling the immune system was not sufficient in the late stages of the disease. This does not appear to be in contradiction with the mainstream idea that RRMS is a purely autoimmune disease but that the lesions it causes trigger a non - immune mediated degeneration process. This correlates extremely well with the now thousands of cases of AHSCT in MS, where success rates have been consistently and impressively high in early, recently diagnosed RRMS cases, effectively stopping sign of disease, and the less encouraging results in Late RRMS or SPMS cases where often enoug disease progression was only partially halted.

    So is it really your belief that at its onset already MS (RRMS at least) is not a merely auto-immune disease? Which are the elements supporting such hypothesis?

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  5. Dear 1:48 Anon
    I will put up post tomorrow as I can't add any links in this comment that hopefully may address your comments. But I don't think there has been 50 wasted years and I am encouraged with the pipleline.

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  6. Dear 2.27 Anon
    Your analysis is spot on. I (unlike G) like to think of MS as an autoimmune disease that develops non-autoimmune consequences. This non-autoimmune consequences can develop as disease becomes manifest.

    If we start in the beasties with potent immunosuppression, although there are some nerve tracts that suffer from the consequences of attack these animals are cured and significant disease never comes back.

    However once clinical progression develops the treatment that stops relapsing attacks does not slow progression.

    Therefore I hope that if you treat aggressively shortly after diagnosis then there is a chance that disease is halted. For example some people have done remarkably well after Alemtuzumab when given early after disease.

    However what triggers the autoimmunity?

    Could it be that oligodendrocytes damage is not due to autoimmunity and this leads to progression and the subsequent autoimmunity merely shapes the course of MS?. If you look in MS tissue there is oligodendrocyte damage without apparent involvement of T cells.

    Unfortunately it will take years to get a clear picture as we see how well people do in the long terms after treatment with the new wave of immunosuppressive drugs.

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  7. Is it the case that MS researchers will take on any research (even research which is doomed to fail) as long as someone pays!

    Dear 8:51 Anon
    Whilst there may be some neuro "Ho's", many of the big names are big names because they help facilitate trials, which are necessary to move things for forwards. Look at Prof G.... fingers in loads of pots.

    Whilst I can't speak to the motivations of other Neuros Prof G doesn't do studies that are purely for marketing or things that he thinks have no chance of working.

    However, you have to be careful about not being too dogmatic as there are many drugs that we don't know how they really work.

    Many immunologists currently think that a cell called a T regulatory cell stops autoimmunity from developing. These cells express a marker called CD25. Therefore you would think it mad to take a drug that inhibits the function of CD5-expressing cells?.

    However dacluzimab does just that and was one of the highlights for treating relapsing MS as presented by Prof G at ECTRIMS 2011.

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