Monday, 28 September 2015

NewsSpeak: finally some good news for PPMSers

Finally a positive trial for PPMS. #NewsSpeak #MSBlog #MSResearch

"As far as news, and good news, goes this ECTRIMS is going to be the best ever. As you can see from the Roche press release below the phase 3 study of ocrelizumab (anti-CD20) in PPMS is positive. Yes, ocrelizumab slows the acquisition of disability in PPMSers."

"What more can I say? Except, I would like to thank all the PPMSers who participated in this study; without your commitment this study would never have happened."

"I have been saying for years on this blog that the B cell is where all the action is in MS. These results prove that! Why? I have an hypothesis, many of you know it, but more on that later. I need to take a moment to reflect on this result, and to savour the moment, before saying anymore."


CoI: multiple, Prof G sits on the steering committee of this trial, Dr K was the PI of this study at Barts Health. 

72 comments:

  1. Fantastic news and I hold my hands up and admit that I was wrong in my views that I expressed, if that is what the actual data say.

    ECTRIMS 2015 is going to be the Ocrelizumab roadshow

    How will the T cell Immunologists react?

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  2. Replies
    1. Nice One DrK.....the Celebratory Coffee at Lunchtime will taste sweet.

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    2. My thoughts exactly.

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  3. WOW!

    But I hope that this improvement is for everybody and not just for those 'with enhancing lesions' etc

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  4. Do these results mean that ocrelizumab (and by extension rituximab) is neuroprotective?

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    1. Maybe, I think we need to see the data, we may only have a few weeks to wait as ECTRIMS is round the corner

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  5. Wow . . . congratulations may be in order. I say 'may', because the sting from the hype and subsequent letdown involving the MedDay/Biotin trial is still fresh in my mind. So I'll stay very guardedly optimistic and wait for the data.

    But if it turns out to be very, very good - I'd like to say in advance - a heartfelt thank you.

    Sincerely;

    - A sufferer.

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    1. It is a change, just think if you are newly diagnosed with MS you could get treated before RR or PP shows itself

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    2. They are also indicating in the press release that they are seeking regulatory approval so this is good news

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    3. "... just think if you are newly diagnosed with MS you could get treated before RR or PP shows itself"

      That doesn't make sense to me at all. My PPMS showed itself on day one, then hung around. There was no warning.

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    4. when you have attack the disease could recover and relapse later and you are eligible for a dmt. Your disease could progress in time and currently you are ineligible. If you have treat capable to treat rrms and ppms you dont need to wait.

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    5. Ah - I see what you mean. Thank you.

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  6. So how long do you think it will take until it is out in the market?
    What about the price range/cost effectiveness?

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    1. 2016 for registration in the UK add some years. As for price I don't know....but aat a guess as least as expensive as natalizumab probably in cost range of alemtuzumab and so there will be rationing in UK after NICE haggle on price.

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    2. Is there a way this can be fast tracked to market? MS is a serious condition and there is an unmet medical need.

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  7. Do these results mean anything positive for SPMS as well?

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    1. It will mean a trial in SPMS I suspect however it will be interesting what demographic of person is selected for such a trial. In the current PPMS trial it was EDSS 3.5-6.

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    2. More difficult to prove efficacy as some of us didn't realise we had SPMS until our EDSS was more than 6.

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  8. Very wonderful!! Double superlative!!! A new dawn...

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  9. What a brilliant result. Can't wait to see the details. Also wonder just how much the T cell mafia will be squirming?
    Well done guys!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!

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    Replies
    1. On the back of a brilliant result for Wales too ;-)

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    2. What about the EBV mafia? Does this drug diminish EBV at all?

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    3. So this is not an induction therapy and has to be taken forever?

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    4. The license is likely to be every 6 month treatmemt but if you look at published data it can be an induction treatment. will neuros give two courses and then monitor for NEDA

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    5. It certainly is not an induction treatment in RA, at about 6-9 months most patients get their symptoms back. ( I am talking of rituximab, of course - but let's face it, ocrelizumab is just a tweaked "more humanized" rituximab version to keep $$$ coming). They got rid of the mouse parts :-)

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    6. The license is likely to be every 6 month treatmemt but if you look at published data it can be an induction treatment. will neuros give two courses and then monitor for NEDA

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    7. I'm on rituximab and 'monitor for NEDA' is what my neurologist insists on doing. That translates to 'wait till symptoms rear up again and you become non-NEDA'

      I feel it would be better to take the treatment on a regular schedule while still NEDA. Why give the disease a chance to progress?


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  10. Will is be possible to use this after 2 course of alemtuzumab? As the newly diagnosed with rrms are told to get in treatment early so can they have alemtuzumab now which is available and if needed in 5 years time when ocreluximab is on the market have that? Many thanks

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  11. Good question Anon 12:50

    - Does Ocrelizumab have any mode of action on T cells?

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  12. What about off label use of Rituximab? "Time is brain". Why have patients wait for a drug that is already in use?

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    1. You will have until ocreluzimab becomes licenced to use off label after that it will be not allowed to use unlicneced product.

      Apparently we have problems getting the hospital to pay for rituximab come ocreluzimab there will be more problems

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    2. I am currently on Rituxan for MS (diagnosed this past January)

      Also, my neuro told me Ocreluzimab is specifically for MS and should be out for use beginning of 2016?

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    3. Out for use in 2016 once approved but in UK this will take sometime longer I suspect

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  13. Slowly allowing myself to believe that this really is a scientifically sound, solid result. For PPMS. At last.

    Speechless and near tears.

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    Replies
    1. I can imagine how you feel. Finally some good news for PPMS and by extrapolation SPMS.
      It's a good day.

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  14. Tears in my eyes and goosebumps at the same time. Take that, you B cells!

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  15. Let's see the data first. They may be significant, but are they relevant? So far it is just an advertisement.

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    1. All we have seen is the press release. The data will be presented next week at ECTRIMS. We will update you with the results as soon as we have them and they are in the public domain.

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  16. It looks like they are looking at only 3 months disability progression data?

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    1. An effect that was sustained for 3 months

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    2. right, but based on Dr. G's recent post, even 6 month sustained effect on disability is not enough to weed out the relapse related noise from actual unremitting disability? Or am I missing something?

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  17. Hype! Keep your expectations in check and don't get carried away. Efficacy may be nominal at best. Medicine is business and spin sells.

    Plus, this drug will be years away from license.

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    1. Yes lets seen the results first, but we have an idea what to expect from the rituximab studies and we don't have to wait long to hear about the results

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  18. That our wonderful news !!! Our and if it is then also given in CIS and RRMS from the start, you can actually park the disease and/or avoid even the SPMS .... The theory of Team G then it really is gradually proving!!! It's a good day o//

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  19. Why would this trial have positive results when the rituxan ppms trial was negative? I understand that a subset of Rituxanppms trial subjects did see efficacy, but overall the trial was deemed a failure. Since the mechanism of action between these two drugs is extremely similar, why such a different outcome? Is it possible that politics/profit motive played a part in declaring Rituxan for ppms a "failure", since that drug was due to come off patent and unlikely to turn huge profits? Should be interesting to see what is revealed at ectrims … Certainly hoping these results stand up to scrutiny.

    Also, why would MS patients suffer less side effects from this drug than patients suffering from lupus or rheumatoid arthritis,? Trials on patients with those diseases were halted back in 2010 because of the prevalence of serious opportunistic infections. I want to be positive about this news, but there seem to be a lot of reasons to not yet be over the moon…

    Sorry about any typos or grammatical errors, trying to use the voice recognition function on my iPad, which sucks…

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    1. The trial on rituxan failed when the whole population was looked at but when they did subgroup analysis it was positive in people under 50 and in those with gadolinium enhancing disease. So in this trial they loaded it up with people more like to respond such that people were under fifty 10-15 years duration and EDSS 3.5-6 which encompasses the EDSS that change the most..

      I will post the old trial paper.

      People with MS will not suffer less side effects that people with Lupus and arthritis however the drug makers believe that people with MS accept more risks to get treatment, so you will accept the risk of death. It will happen when enough people are treated just as deaths have occurred with say Gilenya due to infections. These are serious drugs with risks however compared to say Alemtuzumab the risks are not as high

      We have to see the results to make a valued judgement, but I predict the results to amongst the more positive seen, we will see next week.

      Don't work about the typos, there writing is fine compared to mine.

      Are you being cynical to suggest that because of patent rituximab was pulled...yep thats my take, however to through the trial because of that would be cynical.


      So they have learned from their mistakes and designed a trial in their favour. We will see how many were gadolium enhancing but the more people of short disease duration they have the more likely they are to find an effect.

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    2. Thank you so much for your thorough and thoughtful reply. Perhaps I am being overly cynical in thinking that the pharmaceutical company would go through an entire series of trials to get approval for Ocrelizumab, but then again given the billions in revenue the drug stands to generate I'm not sure one can be too cynical. All cynicism aside, as long as the drug does prove effective, reasonably safe, and is made accessible to all patients in need then the end result is by far more important than any underlying motives. Of course, a cure rather than just another treatment would be MUCH preferable.

      I do agree that the fact that B cells serve as a reservoir for EBV in the human body does raise serious questions as to mechanism of action for these anti-CD20 drugs. It would be nice if there were more than your group seriously looking into this possibility.

      Would you mind if I used your explanation of the trial structure and the difference in risk tolerance between patients with Lupus, RA, and MS as part of a blog post on my well read MS blog "Wheelchair Kamikaze"? I would, of course, give you proper attribution.

      BTW, I'm now using the voice recognition software on my desktop computer, which hopefully is making for a much more coherent reply… Thanks again for your response.

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    3. Please go ahead maybe I should try the voice recognition software as my writing is so bad but they often don't like accents....non American accents.

      If you want a laugh check out two Scottish guys in a voice activated lift
      https://www.youtube.com/watch?v=sAz_UvnUeuU

      P.S. They are saying Eleven

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    4. "People with MS will not suffer less side effects that people with Lupus and arthritis "

      How can you be sure of that?
      I remember reading that people with MS are on the whole healthier - they have fewer metabolic problems - than people with Lupus

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    5. Thanks for the laugh, that skit is hilarious. Believe it or not, this crass American does know that a "lift" is an elevator.

      BTW, the voice recognition software I use, Dragon NaturallySpeaking, does have an option for British accented English, so it may in fact work for you unless you have an accident as thick as those two chaps in the elevator, um, I mean, lift…

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  20. So what does Ocrelizumab do do B-Cells that Alemtuzumab doesn't? I thought that Alemtuzumab targeted b and T cells. If this is the case then shouldn't Alemtuzumab be just as effective in progressive MS as Ocrelizumab? (Ignoring safety profiles for this point)

    Also - doesn't this give rise to the theory that as HSCT is more ablative than both of the above (HSCT would destroy more b-cells that the above drugs) so HSCT would work for progressive disease, a theory that on this blog you have disputed many times (as do some HSCT treatment centres)

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    1. Alemtuzumab acts as weedkiller for the immune system causing a very long lasting reduction in white cell numbers though interestingly the B cells bounce back and overshoot baseline levels, which may explain why B cell autoimmunity occurs so frequently as regulatory T cells take much longer to recover if they ever do properly.
      Ocrelizumab selectively targets B cells in the main leaving other polulations relatively intact and as far as I know B cells do not overshoot on repopulation. We'll know more when we see the data.

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    2. What does ocrelizumab do that Alemtuzumab doesn't....It kills B cells and some other stuff that we are writing up at the money. Alemtuzumab does not hit B cells in lymph gland tissues very well as it appears the mechanism of depletion may not be complement mediated but antibody dependent cellular cyctotoxicity (Type II hypersensitivity).

      However,, we will concede the point that if B cell depletion is effective in PPMS then HSCT should be too. However we have to see what the ocreluzimab results are. They may have loaded the trial with people with gadolinium enhancing lesions and this we would argue will respond.

      However the fact that people with progressive MS can still progress after HSCT, should warn us of the the likely real result. We have to wait and see what they results are.
      Likewise HSCT and Alemtuzumab takes out other cells and this may also be a reason why the two are not the same

      Roche would be very sensible to load a trial with responders

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    3. Or it could be that the T-cell mafia is right because there is a subset of T-cells that express CD20:

      http://www.jimmunol.org/content/193/2/580.full.pdf

      This would be a very select oblation that Rituximab/Ocrelizumab targets that things like HSCT or Alemtuzumab may or may not destroy.

      But since it seems Rituximab has to be re-infused every six months the desctruction of the t-cells would be more consistant than what is found in the induction therapies.

      This could be a road block for the EBV mafia.

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    4. The anti CD25 results have not been adequately explained by the T cell mafia.

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    5. From the article:

      "Although we did not perform functional assays,
      we show that CD3+CD20dim T cells can be either CD4+ Th cells
      or CD8+ cytotoxic T cells. Together with previous reports that CD3+
      CD20dim T cells can assume a proinflammatory Th17 phenotype (9),
      our data suggest that CD3+CD20dim T cells represent a functionally
      heterogeneous population that may also potentially be involved in the
      MS disease process."

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    6. We need to see the B/Tsubset data from treated individuals before we can make any assumptions.

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    7. MD2 - in its weed killer role, how is it that alemtuzumab has such a long lasting effect? If the drug is completely gone at a month after, why do certain populations take so long? Surely the half life of the cells in these populations is shorter than years? I think I remember reading about cd5 cells (?) still being low at 5 years out.

      The other thing I don't understand is that the levels of the populations are if I remember a mouse study correctly low in peripheral blood, but not as affected as those in lymph nodes. Do we understand this finding and what relevance it might have to side effects and what seem to be relatively low post treatment infection rates?

      I've taken the stuff - thought it was worth the risk. It just seems to have a fairly unusual range of effects when compared to most other immune modulating drugs.

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    8. This has never been adequately explained to me either. Perhaps someone can help here?
      It suggests effects on bone marrow stem cells too. Hope it's working well for you though without any attendant side-effects.

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  21. This is wonderful news, but the soon to be published figures will shed more light on the situation. Though this does generate some questions: Why have we not seen any improvement for PPMS patient with stem cell immune reboot therapies? Why does natailuzmab appear to slow SPMS conversion? In the bigger picture is it possible that EBV is the most deadly virus in human history? If EBV went into history with polio etc how would that effect health care?

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    1. Good question...and one suspects here lies the answer

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    2. " Why have we not seen any improvement for PPMS patient with stem cell immune reboot therapies? "

      Havent we? AFAIK there have been some positive results with HSCT and PPMS.

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    3. " Why have we not seen any improvement for PPMS patient with stem cell immune reboot therapies?"

      Haven't we? AFAIK there have been some positive results with HSCT and PPMS.

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  22. "Why would MS patients suffer less side effects from this drug than patients suffering from lupus or rheumatoid arthritis?"

    Possibly because of the difference in dosage. Typically, rituximab was given at 1000mg twice over two weeks in RA. Ocrelizumab was given at 300mg twice initially and 600mg once thereafter in MS trials, I believe. A considerable difference in dose.

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  23. "The primary endpoint of the ORATORIO study was time to onset of confirmed disability progression (CDP), defined as an increase in EDSS that is sustained for at least 12 weeks."

    Presumably, the drug achieved larger such times compared to placebo. Does it matter?

    Example:
    Patients A and B take part in the trial. One month later, patient A suffers a temporary disability progression (+0.5 EDSS score) that lasts 8 weeks. It does not count as CDP. One month after that, patient A suffers another disability progression (+0.5 EDSS score) that last 8 weeks. No CDP, according to the definition above. 6 months after the beginning of the trial, patient A has no CDP whatsoever. Three months later he suffers his third episode that leads to disability progression for 12 weeks. This means CDP after one year.

    During the same period, patient B suffers one disability progression (+0.5), one month after the beginning of the trial, that lasts 12 weeks. That means, CDP. Then, 8 months pass and nothing happens.

    Patient A had one year to CDP, but patient B had 4 months to CDP. Who is doing better?

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  24. Ia anything known about the comparative risks of taking Ocrelizumab vs.Tysabri? Or is that data unknown at this time? I saw that SIRS claimed one patient in one of the Phase 2 trials, but that doesn't necessarily mean it was PML.

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