Wednesday, 4 January 2017

#ResearchSpeak: Anti-CD20 therapy fails to prevent worsening MS


Time to rethink worsening, formerly known as progressive, MS! #ResearchSpeak #MSBlog

One of the central hypotheses that underpins 'progressive MS' is that the oligoclonal bands in the cerebrospinal fluid (CSF) of pwMS is responsible for driving grey matter and spinal cord pathology. If we can't clear the OCBs we will never prevent delayed onset of worsening, formerly known as progressive, MS. The problem with OCBs is that they are produced by long-lived plasma cells that are very difficult to eliminate. We know that none of the current high-efficacy treatments has an impact on OCBs; at least in the short term (< 10 years). This is why we are exploring different options to look for treatments that penetrate into the CNS that potentially target plasma cells. 

The case study below from San Francisco supports other case reports and anecdotal data that high-efficacy therapies are not enough to prevent worsening, formerly known as progressive, MS. Steve Hauser treated a patient with active MS with Rituximab (anti-CD20) therapy and despite switching off new brain lesions this patient developed worsening disease. Although rituximab treatment reduced CSF levels of B cells there was evidence of ongoing CNS inflammation; OCBs were present in CSF even after nearly 7 years of anti-CD20 therapy and their were persistent T cells in the CSF. Clonally related B-cell populations were detected on both sides of the blood–brain barrier. Could these Rituximab-resistant B-cells have been plasma cells? Please remember, plasma cells don't express CD20 on their surface. Surprisingly in this patient serial MRI examinations revealed a stable number of lesions in the brain (NEDA), but new spinal cord lesions. The latter is worrying as it may mean that simply doing annual brain MRI is insufficient to monitor the progression of MS. Unfortunately, there is no mention of CSF neurofilament levels in this patient. If I was a betting man, I would bet that the neurofilament levels would be raised. I suspect that CSF neurofilament levels will be good enough, if not better, than MRI as a marker of worsening MS. 

The good news is that we have just been successful in getting a grant to test a new drug as an add-on treatment in MS to see if we can suppress plasma cell activity within the brain and spinal cord. It is clear that there is a massive unmet need for additional treatments in MS to target delayed worsening of the disease. 

 
von B├╝dingen et al. Onset of secondary progressive MS after long-term rituximab therapy – a case report. Anals Clin Translational Neurology. First published: 20 December 2016 DOI: 10.1002/acn3.377

A patient with relapsing multiple sclerosis (RMS) was treated with a standard immunomodulatory therapy, but due to ongoing disease activity was switched to rituximab. Relapses ceased, but secondary progressive MS (SPMS) eventually appeared, associated with new focal spinal cord white matter lesions. Cerebrospinal fluid (CSF) showed persistent oligoclonal bands (OCB) and clonally related B cells in CSF and peripheral blood. The treatment escalation approach failed to prevent evolution to SPMS, raising the question of whether initiation of B-cell depleting therapy at the time of RMS diagnosis should be tested to more effectively address the immune pathology leading to SPMS.

CoI: multiple

44 comments:

  1. This is a depressing post. I was pinning my hopes on ocrelizumab being a cure for MS.

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    1. I don't recall ever making the claim or suggesting ocrelizumab is a potential cure in MS. We simply don't have the long-term data. I am guilty of suggesting that PIRTS (pulsed immune reconstitution therapies) may offer a potential cure. Please not the term potential; I always use this term as it will take 15-20 years to answer this question. The 'potential cure' hypothesis is based on the autoimmune theory of MS that has yet to be proved and/or accepted by all.

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    2. Dear Prof G thanks a lot for sharing your views. Have you considered the possibility of mitochondrial dysfunction in MS pathogenesis ?
      http://www.nature.com/articles/srep33249

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    3. You might be interested in this paper we published recently(free to view). We are continuing research in this area.
      http://www.jbc.org/content/291/9/4356.long

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  2. What we have seen over the last 12-18 months on this blog is a drip feeding of bad news. Anti-B cell therapies were the way forward, but now don't appear to be as great as hoped (probably only effective for younger progressive patients with active MS lesions + now may not stop SPMS). We pinned our hope on agents to irradicate EBV - but no luck. Every time a theory is proposed it is tested and then shown to be wrong. In 2017 we should be doing better, otherwise we are in a continuous loop of (i) propose a theory, (ii) test the theory, (iii) theory proved wrong... Go back to (i). With improved imaging, computer power increasing exponentially etc. we need a new approach to deliver success. All patients want is not to get worse - that should be the sole focus of MS research. I can cope with my EDSS 3, but live in fear of 3 becoming 4, and in tens years' time being EDSS 7. If all the MS research teams collaborated on this one aim for one year, I'm sure we would see real success. Happy New Year Team G and good luck.

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    1. I think this Samuel Beckett quote sums up MS research for me.
      "Ever tried. Ever failed. No matter. Try Again. Fail again. Fail better."
      We'll keep trying.

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    2. Our mission is to 'interpret good, bad and other MS-related research new'. I have actually purchased a pair of rose-tinted glasses, but I left them at home today; they are sun glasses and there is not enough sunshine in London today.

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    3. We been saying that to get optimum benefit on should treat aggressively and early. In this case there was no or limited treatment for 16 years and as we have also said damage occurs from the get go.

      As to the influence on progressive disease..this limited control was published years ago.

      As far a I know no study has been performed where EBV is irradicated

      So you should not write things off.

      Propose theory, test theory is the current scientific process.

      "All MS teams collaborating for one year....we would see success".
      Sounds like a sound bite from Charity push...but we know we that one year would never be enough time to show anything tangible.

      Do we want everyone doing the same thing...I'm not sure as we would all be working on Tregs so if we go down a blind ally everyone goes down it

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  3. The bad news, Prof G, is that anti-plasma cell therapy if effective at all will be in pipeline for years and years and will not help those who bought into the hype around 'hard & early' and subjected themselves to ravaging side effects of that 'effective' drugs.

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    1. Best not to try at all then, eh?
      Obviously not a Beckett fan.

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    2. Surely not, but it might push ASCT further down the garden path, and leading edge neurologists will probably start doing a chemo cocktail of something like Bortezomib + Alemtuzumab.

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  4. MD2,
    http://www.gocomics.com/pearlsbeforeswine/2017/01/03

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  5. While this case is interesting (especially the continued development of spinal lesions on rituximab), I do not think that it supports the very general claims being made in this post. This patient had a high disease burden at rituximab treatment onset -- I suspect many neurologists would have classified him as already being SPMS.

    I asked one of the authors of the study whether they had observed RRMS->SPMS transition in any rituximab-treated patients at UCSF, who had been started on rituximab at low disability. They told me no. This is the critical question. This case report comes nowhere close to establishing that OCBs will drive progression in such patients.

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    1. > He began off-label treatment with rituximab in 2006. At the time he was 53 years old, he had full muscle strength, slowed toe tapping on the right, pyramidal signs worse on the right, and an EDSS of 3.5. He could bike several miles without difficulty but was no longer able to jog.

      Is that high disability?

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    2. This level of disability is associated with transition to SPMS in large cohort studies. The patient had low spinal cord volume at baseline, probable low brain volume (given the reported atrophy rates), 12 previous relapses, and high age (relative to normal age at SPMS transition). These are all poor prognostic factors.

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  6. Professor Gavin,

    I quote your last paragraph in your Post

    "The good news is that we have just been successful in getting a grant to test a new drug as an add-on treatment in MS to see if we can suppress plasma cell activity within the brain and spinal cord."

    QUESTION:
    Could you tell us WHAT new drug you refer to as an add-on treatment in MS ?

    If you received a grant for for this add-on, it would be fair to tell the community at this blog following you what kind of new drug you have will be testing ...?

    Kindly
    David

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  7. This post is reiterating the post from feb 2016 that discussed the failed intrathecal rituximab trial and spms at the NIH. The lack of plasma cell targeting and subsequent reduction in complement fixing abs as well as the failure to address activated microglial in progressive ms is still on the table. Ocrelizumab is only a treatment for ppms who show enhancing lesions. Are we any closer to eliminating plasma cells in the cns and to deactivating microglia?

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  8. Coincidence or not, I was reading yesterday about the terminal differentiation in plasma cells initiates the replicative cycle of the EBV in vivo.

    Well if it goes ahead of anything I don't know but I prefer to start a more effective DMT in the attempt to do something.

    I also take an Aspirin or generic ASA, it works and controls a little "these persistent and self-reactive plasma cells.
    I also use Coenzyme Q10 and Creatine to try to help my Mitochondria, we have to do something for them.

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  9. But excellent to know that they will be recruiting for a study of a drug aimed at cleaning the plasma cells

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  10. I hate to keep beating the same drum, but once again this post brings into question whether or not Ocrelizumab will prove to be any more/less effective than Rituxamab.

    Off label use of Rituxamab has already established its high efficacy in reducing relapse rates in RRMS patients, and the above study shows that it may not prevent conversion to SPMS in such patients despite this efficacy. The nearly 10-year-old Rituxan PPMS trials displayed that drugs moderate efficacy in treating a subset of "worsening" MS patients (specifically, younger, less disabled, and with enhancing lesions), but reiterated its inability to impact the greater population of PPMS patients.

    Now, we are on the cusp of the Ocrelizumab era, a drug that appears to have a more concerning safety profile than Rituxamab, but not necessarily better rates of efficacy. Yet the medical press is heralding this new drug as a miracle drug, raising the hopes of the general PPMS population, patients who are desperately clinging to any notion that offers even a glimmer of encouragement.

    I've heard from several neurologists that Genentech/Roche is spending incredible sums on "consulting fees" and other such backdoor methods of putting dollars in the pockets of the neurologist who will be prescribing the drug. So we are very likely about to see the widespread use of a new agent in a population hungry for treatment options, but that agent may very well prove completely ineffective for the large majority of this population, and, in fact, may present this population with an entirely new set of problems, i.e., adverse events such as opportunistic infections and cancers. Will proper risk/benefit analysis be done on a patient by patient basis, or will most neurologists succumb to the hunger of patients for any treatment option, along with the siren song of pharmaceutical company largess?

    Seems we may be embarking down a treacherous path…

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    1. The reason for developing ocrelizumab rather than rituximab are mainly financial. The paptent for rituximab was expiring so why develop a drug you are not going to make money.

      Both drugs are CD20 depleting and can do roughtly the same thing.

      Being chimeric rituximab is going to cause more binding and neutralizing antibody responses. The Babs run at about 15-25% of pwMS within the short term and these may contribute to infusion reactions and maybe the occasional anaphylactic response. Furthermore rituximab induces neutralizing antibodies and NAbs occur in about 5-15% of people and so rituximab will stop working. Nabs in ocrelizumab is less than 1%. Contrast this with alemtuzumab which is about 90% which is staggering for a humanised antibodies, not surprising this failed to make the trial report:-(

      Rituximab kills B cells via complement fixation, whereas ocrelizumab kills by antibody-dependent cellular cytotoxicity, this means to kill the target needs natural killer cells/neutrophils present, this could impact on efficacy in some tissues e.g neutrophils don't enter CNS much they are less common in lymphoid tissue.

      There presence of NAbs may be an important marketing strategy, maybe the other is the data showing that ocrelizumab is an induction therapy like alemtuzumab...surprise this data hasn't been published and it langishes in the ECTRIMS/AAN vault of dumping information never to see the light of day. (As the companies want to give anti-CD20 every 6 months they are not going to want people to realse this fact that anti-CD20 is an induction therapy based on rituximab and ocelizimab data). You just have to remember where to look to find the info...I am an elephant.

      It is not a miracle drug for PPMS but it is a treatment for aspects of PPMS. The data is there for all to see that it is not a miracle drug, but as you say people are simply hearing what they want to hear that it is much better than it is.

      Is rituximab going to have better rates of efficacy if you are monitored to check that they both deplete the right subset of B cells then they will do the same job....its simple biology.

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    2. I cannot really comment on consulting fess, but this is paying for a service of consultation, such as doing educational talks for which their time is being compensated, it is not paying to have drug prescribed. Which it can't be until it is licenced. Furthermore, it is a select number of neurologists who will be reaping these consultancy fees, because this is part of the marketing strategy.

      Companies pay market research companies/analysts to do surveys (I get asked about once a month to do these but when they find out I am not a neurologist I get booted out with nothing...so now I just send them to the junior doctors to get some pocket money. They offer the neurologist a sum of cash (hope this is declared for tax purposes:-) or a book token to answer the survey.

      I was asked how many patients a year I see. I said 5,000 as I have just been to the "MS life congress" in Manchester that weekend so I could answer without lying.....Ker-ching.

      Anyway they then say "who do you think is is a leader in the field" in Europe, USA etc. The companies then ask these people to consult for them and present to the wider neurological public as a trusted voice.

      This is why we see the same old faces, including ProfGs-although in his case I believe that he has been on the drug development committess with pharma, on the platforms of ECTRIMS/AAN.

      Sometimes the neurologists just turn up are given a slide deck to present and off they go...ker-ching.

      They do however look a real t**t when they get asked questiones about the biology of the products (no information in the slide decks-oops) and because they had nothing to do with the development of the compound and are mouth pieces. They are like rabbits in headlights when they don't know the answer. This is a good way for a biologist to have some fun at ECTRIMS..bait the mercinary neuro:-)

      I know I should not tell you all this, but it shocks me too.
      Us scientists live in a differnt world to clinicians. We have to make our poster, presentations, write papers etc. Happy to say I wipe my own bum:-)

      Are we likely to see widespread use of a new agent...yes of course. Ocelizumab may be the sell-by date maker for some drugs.

      If you have a treatment option no matter how poor would you take it?

      Of course you would look at how many people take CRAB drugs, (In the case above it is clear that the person still has active disease despite use of the CRAB). It has been said that the interferons are only 30% effective saying that it is 70% inefffective, did this stop people wanting the drug? No otherwise Copaxone would not be the number on best seller at $4 billion a year.

      It will be one more arm in the fight against MS and when the data finally surfaces (because it will) that anti-CD20 are induction treatments or one is over dosing at least then the infection risks can be de-risked and you get the benefit of alemtuzumab, without the risks of secondary autoimmunity.

      Each path has its benefits and dangers, once you understand what these agents are doing and how they work you can refine what is done and de-risk then even more.....watch this space:-)

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    3. Thanks so much for the very thorough and informative answer.

      Can you point me in the direction of the data suggesting that Rituxamab/Ocrelizumab is an induction therapy? I am going to be interviewing a researcher from Genentech later this week, and would like to have this info handy. Might make for some interesting queries during the interview. Puzzled as to how this could be an induction therapy if the depleted B cells are repopulated within 6-8 months after treatment. Are the reconstituted cells "different" in some manner? Obviously, they wouldn't be reservoirs for EBV, since the EBV load would have been wiped out along with the cells after the initial treatment.

      As for taking the drug because there are no other options, of course this will be very enticing to the vast majority of PPMS patients. But, since the data suggests that the vast majority won't see benefit (the 85% who don't have active inflammatory disease), and the drug does have some possibly significant adverse event potentials – a four times higher cancer rate than the placebo group in the PPMS trial – shouldn't this info factor into the should I/shouldn't I equation? Also, how significant is it that the Crohn's and lupus trials were halted early on because of concerns over trial subject well-being. I believe there were patient deaths involved in those trials.

      As for the "consulting fees", my neurologist contacts have informed me that they are seeing a huge amount of money being spread around here in the states to the doctors who will be prescribing Ocrelizumab. Let's face it, drug companies wouldn't engage in these practices if the return on investment wasn't there. Though the drug has yet to be approved, they are certainly priming the pump for turning this into a blockbuster once approval is granted.

      Again, thanks for all the info. The insights into the neutralizing antibody issue is enlightening. Has this become an actual clinical problem in patients being treated with Rituxamab for MS? Are patients on Rituxan generally even tested for neutralizing antibodies? I myself was put on the drug (one set of infusions) and I know many other patients who are on Rituxamab for MS, but don't think I've ever heard of anybody experiencing neutralizing antibodies, or being tested for them.

      BTW, the Rituxamab therapy I tried did nothing to halt the worsening of my disease.

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    4. Ocrelizumab phase 2 extension trial data: http://www.adelphigroup.com/acl/11-10-12/poster1.pdf

      Last ocrelizumab administration was at 72 weeks, see week 144 MRI data in figure 3.

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    5. Sorry rituximab was not active.

      Induction therapy potential is shown in phase II extension study with efficacy evident 18 months after the last dose..ECTRIMS 2012 AAN 2013

      CD19 B cells are mixture of a number of differnt types of B cells (e.g. immature, mature, memory clas-switched meory some wiped out others untouched or repopulated quickly. In people treated with rituximab most of the cells repopulating at 6 months are the mature/naive B cells and not disease causing.

      Will explain more soon.

      You are correct Crohns and Lupus development of ocrelizumab was terminated due to infections and drug-related deaths. MS is considered to be a worse disease worth the risks.

      Consulting bungs..disturbing. Luckily in NHS in UK disease is not a business for the neuros.

      Re: Neutralizing antibody will they be a problem? if they occurr I suspect it will, but I dont know MS literature without reading, if B cells are depleting it is still working, but I think it is the companies who have the neutralizing antibodies facilities. In arthritis I read a total of 273/2578 (11%) patients with RA tested positive for binding antibodies in another it was 23/99 (20%), so suspect the number with neutralizing antibodies will be less common. ProfG said 5% to me last week.

      If you are not depleting (anaphylactix) this is something to consider.

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    6. P.S. Taking to someone today about neutralizing antibody responses and that comapanies call them something else so you miss them in searches, one company used term "inhibitory" antibodies

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    7. "Induction therapy potential is shown in phase II extension study with efficacy evident 18 months after the last dose..ECTRIMS 2012 AAN 2013"

      Here is the abstract you're referring to: http://www.neurology.org/content/80/7_Supplement/S31.004.short?sid=fd052e7d-916b-4246-8024-2ce3f5bf6d3e

      It refers to the same data as the poster I linked to above.

      You've misinterpreted the results. The study lasted for 144 weeks (1.5 years) total. The *extension* phase of the trial only started in week 96. The last dose was received in week 72. So the patients were only observed for 144-72=72 weeks after their final dose.

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    8. Thanks for providing link to the poster.

      I think 72 weeks divided by 4 = 18 = 18 months drug free and in most people disease free to after only a few cycles of antibody.

      FYI. I have been hassled and emailed about 5 times with an oppertunity to make £35 for a 5 minute survey, I opened it put in that I said I see 0 patients and was kicked out with no cash Today:-(

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    9. Sorry, you're right of course. Please feel free to delete my previous comment.

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  11. Is there any plan to check OCBs on alemtuzumab in the subset of patients that go on longterm remmision? To me seems interesting to know if they lose OCBs say 10 years aftet induction, maybe doing it on HSCT patients...this could answer ingeresting questions about MS.

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    1. It's been looked at in a small number of pwMS. OCBs persist afetr alemtuzumab treatment.
      "Paired CSF samples were taken before (range 0–37 days) and after (range 3–28 months) the first (12 patients) or second (three patients) cycle of alemtuzumab treatment. In all 15 cases, analysis of the CSF demonstrated the persistence of OCB following treatment with alemtuzumab."
      http://jnnp.bmj.com/content/83/3/298.long

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    2. How about long-term use of Natalizumab?

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    3. I'm not aware that this has been done. Maybe Prof G knows.

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    4. I am interested in OCBs and tysabri as well if you have an answer to the question raised above.

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    5. Here you go.
      https://www.ncbi.nlm.nih.gov/pubmed/22041091
      http://multiple-sclerosis-research.blogspot.com/2015/01/b-cells-treatment-effects-on-b-cells.html

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    6. Encouraging - thank you

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    7. https://www.researchgate.net/publication/269692996_Intrathecal_IgG_Synthesis_A_Resistant_and_Valuable_Target_for_Future_Multiple_Sclerosis_Treatments
      Plasma B cells are not targeted by Alemtuzumab.

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  12. I think Steve Hauser's group has just stuck the first nail into the anti-CD20 coffin! Let's hope you guy's come up with something better.

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  13. I think we should all take a deep breath and relax. The anti-CD20 data in early relapsing MS is stunningly good, particularly in relation to its short term risk profile. Even the PPMS data is very good. Anti-CD20 therapy is a very good platform to build the other components of the therapies we need in MS, i.e. neuroprotective, remyelination and restorative therapies.

    The problem with this patient is that he was started on rituximab too late in the course of his disease. The question you need to ask is what would have happened if he was treated early in the course before he had acquired too much damage? I am sure things would be very different.

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    1. So any of these anti-CD20 treatments is not going to be a single silver bullet, but needs to be complemented with other treatments. Is there any likely things in the pipeline for such combinations?

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    2. Re: "I think we should all take a deep breath and relax." Isn't that what the captain said after the Titanic hit the iceberg?;-)

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