Monday, 26 September 2016

ResearchSpeak: ECTRIMS highlight ocrelizumab NEDA data

How important is rebaseling when assessing NEDA rates? Essential - just look at the stunning ocrelizumab NEDA data. #ECTRIMS2016 #ResearchSpeak #MSBlog

"The poster below is another one of my ECTRIMS highlights. There is little doubt that ocrelizumab is a highly effective DMT. However, how does it perform if you treat-2-target of NEDA (T2T-NEDA)? I have been saying for sometime that to implement T2T-NEDA in clinical practice you have to rebaseline your metrics after the DMT in question has had time to work. For most maintenance DMTs this is 6 months."

"The analysis below shows that if you do this with ocrelizumab, then over 80% of subjects are NEDA from 6-24 months (figure 3). To the best of my knowledge this is the best NEDA data out there after rebaselining. I have yet to see the HSCT rebaseling NEDA rates, but I suspect they will be in the same ballpark. What is also important to highlight is the remarkable observation that 57% of the IFN-beta (Rebif) treated participants were also NEDA in this epoch. Based on earlier interferon data this is much better than one would expect. It looks as if from contemporary trials that the efficacy of Rebif has improved. Why? One reason could be that the population of trial participants have included subjects with more benign MS or Rebif has gotten better. I suspect both are correct. Most subjects in the Opera studies received RNF (Rebif new formulation). We know that RNF is associated with fewer NABs (neutralizing anti-bodies), which affect its efficacy; hence there are reasons to expect that Rebif's efficacy has improved. I am sure a lot of people will jump on the Rebif NEDA data to support its continued use as an effective DMT in the 'majority' of MSers."

"It will be interesting to see how the regulators, payers and/or healthcare commissioners respond to this data. I sincerely hope the regulators give ocrelizumab a liberal label that will allow first-line use in MSers with active disease. This will then allow HCPs and their patients to decide on which DMTs they want to use. However, as always in price-sensitive markets the payers and commissioner may have a different take on things particularly if ocrelizumab is priced at a premium."



CoI: multiple

14 comments:

  1. I am sure that there is a clinical and psychological phrase for something like this - like Schroder's Cat or Fermat's theorem - but this is my tuppence: is the age of NEDA great for the majority and terrible for the minority?

    In other words, if a blockbuster drug like Ocrelizumab comes along and beats the living daylights out of all the other competition, then does this cause companies that do R&D into MS think: well, let's focus on other neurological diseases that have a greater unmet need?

    After all, the amount of money we are going to have to invest to beat an 80% NEDA is going to be - well - at least that new Ferrari I had promised myself and a new kitchen for my husband (in the very unlikely event that the head of that Pharma company is a woman).

    And so what happens to the other 20%? The progressive ones.

    Yes, yes, Ocreluzimab might help them too - or some of them. And yes, yes, we are looking at lots of old, repurposed drugs into progression...

    But think on it. The big highlights (Ocreluzimab aside) of recent progressive research have often been into things that are hardly going to make a company a gazilion dollars.

    Biotin for reducing progression? Get high dosages off the internet, no sweat.

    Alpha Lipoic Acid for limiting brain shrinkage in progressive MS? Dr's Best does them best.

    Clemastine for remylaniation? An OTC drug.

    The danger is this: that we will get Panorama highlights like 'MS cure!!!! Really!!!!!' and we will get Daily Mail write ups 'Drinking ten bottles of wine a day stops MS in mice!!!!' and people will come and say: 'Have you tried having your jugular vein taken out and replaced with a tube?' or 'I read on the Internet that eating lots of cinnamon helps people like you."

    And we will smile and wait for a progressive blockbuster drug.

    And we will wait.

    And we will wait.

    And Neurologists will tell us that this is a very exciting time for people with MS. And we will think: 'I'd feel more excited if I could feel my legs'.

    And each time drugs for RRMS reach NEDA levels, I can't help but feel that - bang - there goes the research investment into a drug that stops progression.

    Sorry to sound down. Hey - this is great news for those for whom drugs work.

    I am just saying that every silver lining has a cloud.


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  2. This is helpful, although I never like to see discussions on how wonderful DMTs are without mention of the side effects.

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  3. My first "statement"

    I never before posted a comment on Barts blog. But now I have done it, and it goes as to be followed - I go straight to the point:

    With all respect, all this hype of Ocrelizaumab, I can not look away from the fact the high incidence of patients reported malignancy in the PPMS study "Orattorio": 2.3 % incidence(!) in Ocrelizumab arm, compare to 0.8 % in the placebo arm. Especially breast cancer showed a footprint among these malignancies, with 4 cases. Furthermore, if we add the breast cases in the 2 RRMS studies, OPERA I and OPERA II, then we have 6 cases of breast cancer all together. In the placebo arms none ...(!) I doubt it is a pure coincidence

    Also Professor Mark Freeman illustrated in an interview at ACTRIMS 2016, held in february, doubts about Ocrelizumab, especially in long term treatment. He starts to talk about ocrelizumab at the 3:50 mark in this video:

    https://youtu.be/EzM1NbZ-7nU

    My point is, that you very often at Barts Blog posts (sorry for being straight forward) tend to get carried away in this blog about efficacy results vs safety risks. For time being it is Ocrelizumab that is more or less fully embraced.


    It does not take an Einstein (sorry again :-) ) to understand that B-cells have a big part to play in our immune system, at least in the long run, and given the short run of this study in PPMS, with regard to high incidence of malignicies, probably there is at price to pay for some of us also in the short run.

    And to my knowledge, Ocrelizumab´s "sister" Rituximab, had several cases of PML in other indications and rather incidence of opportunistic infection. Of course the big pharma company Roche will do everything in their power "to talk for their sick mother" and say that ocrelixumab is totally different compare to Ocrelizumab. But I will never buy it: there are extremelly strong commercial reasons and rational to alienate Ocreluzumab from its sister Rituximab.

    Anyway, when I read about Rituximab safety issues, stated ind FDA´s prescribing information, I tend to listen.

    http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/103705s5311lbl.pdf


    Also, I think you withhold the facts that Ocrelizumab was halted in phase III several years ago with regard to several deaths due to severe infections, several fatal, in RA and Lupus.

    http://www.roche.com/media/store/releases/med-cor-2010-03-08.htm

    I think you should bring in the full safety context when you discuss plus and minus.

    Key Question:
    is it worth the risk taking Ocrelizumab . Each of one has to ask this key question depending.

    I hesitate personally, but then my MS disease (RRMS) is not so aggressive. For some Ocrelizumab may be the last stick to try to stop or delay an aggressive progression.

    But my point, repeated once again, is that very often blog posts on Barts MS-blog posts gets to much carried away, and you tend to embrace the positive perspective, i.e. "full" half-full glass, as in the case with this Ocrelizumab, and withholds the safety risks. You can do better - be more balanced!!

    Probably my post will be "banned" and not be published. But I say the above in the interest of having a balanced view on, in this case, Ocrelizumab, and other agents safety risks, that ultimately will serve the interest for all of us with ms .

    And yes, I think Barts MS-blog do a great job, but rather often get to carried away. Be more balanced and involve a discussion about the risks and safety, as in the case with Ocrelizumab.

    Kindest regards to you all with MS

    Charlotte

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    1. I agree with much of what you say here, Charlotte.

      I was very surprised at such a simple, two-dimensional statement from Prof. Giovannoni when he stated in an earlier post on this blog that he would want to be on Ocrelizumab if he had PPMS. Without the background of careful consideration of the risks of this drug weighed against the potential benefit, this came across to me in the context presented as an unqualified statement.

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  4. Long term suppression of B-cells has to carry serious risk surely, mainly with regard to malignancies and conditions in which they play a vital role?

    I'm still backing induction treatments, where after a heavy blow at least the immune system is able to reconstitute back to a level where it can keep a lid on such potential risks.

    Quick question, what is the NEDA statistic for Lemtrada after rebaselining? Side by side against Ocrelizamub.

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    1. I sincerely hope Prof G will answer this question, I sense a reluctance to address the very misleading way in which the long term Lemtrada results were presented.

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    2. Re: "Prof G?"

      I will get to this and do a detailed post.

      The issue of causation is a complex one and will needs to be carefully considered and put into perspective. It is important not to throw the baby out with the bath water. We almost did that with cladribine only to find out that the cancer signal was due a zero, or an abnormally low, rate in the placebo arm. Now that we have more data and an appropriate comparison with population data there is no cancer signal in the short and intermediate term with cladribine. This is one of the reasons why Merck are going back to the regulators for a license.

      We need a measured approach with anti-CD20 therapies. Is there a real signal or not; i.e. is it a false positive or chance finding? Unfortunately, we don't have enough data at present to answer this. In addition, the biological plausibility for anti-CD20 therapies causing solid organ cancers over a 2-3 year period is not there. Breast cancer is very common (1 in 8 women get breast cancer) and breast cancer probably takes years, and possibly decades, to evolve (multiple DNA mutations and natural selection of cancer cells). I am not aware of any mechanism to explain how anti-CD20 therapy will cause, or speed-up, this process. If it is via immune mechanisms (immune suppression) then a breast cancer signal is odd. With immunosuppressive therapies you usually see a signal in the skin (squamous and basal cell carcinomas) and with lymphoproliferative disorders (lymphomas) first. The latter usually co-exists with opportunistic infections, which have not been noted in the MS population that are relatively well.

      I am sure Roche will have compared the rate of breast cancer across the trial programme with what the expected rate is in the general and MS populations and submitted the data to the regulators. The regulators will then make a call on whether or not this is a real signal or not. I am aware, however, that we don’t have enough data at present and this will have to collected as part of the post-marketing surveillance studies.

      What you also have to balance up against the undefined risk of possible secondary malignancies with anti-CD20 therapies is the risk of untreated progressive MS. For most people with PPMS the latter will trump the undefined risks of secondary malignancies. I must also point out to readers that breast cancer is one of the cancers that can be detected early via screening programmes and it is a treatable condition; long-term remission rates (5-year disease free) with breast cancer is now close to 80%.

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    3. Re: NEDA on Alemtuzumab with rebaseling; very high Yr2 = 74%, Yr3 = 72%, Yr4 = 71% and Yr5=69%.

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    4. I, as a PPMSer, bear in mind that chemotherapy can make MS progression worse.

      I would need a lot of convincing that data is not being manipulated to make things look better now.

      And as for no mechanism relating to anti-CD20 - we don't even really know how MS progression works. Not knowing the mechanism does nothing to ameliorate a phenomenon.

      I may have PPMS, and I know exactly what I may be up against, but I have no death wish.

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    5. Re: "I have no death wish."

      This why personalised medicine and patient involvement in decision making is so important. Nobody can force you to be treated against your wishes.

      The problem we may face in the NHS, however, will be the opposite; no access on the NHS despite an EMA approval. The latter will be more of a problem for PPMSers than eligible individuals saying no to treatment because they are not happy with the potential risks of treatment.

      I think we should park this discussion and wait to see what the regulators have to say. They may say no and then this discussion will not be relevant to PPMSers.

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    6. Thank you Prof G, and I look forward to your detailed post on this.

      I understand the purpose of rebaselining is to ensure the drug has time to work before measuring its success. But to rebaseline every year in the later years, like four and five, seems to only serve to present the data in a better light. Subjects who achieved NEDA in year five potentially failed every year prior! After year two, data should be about *maintaining* NEDA from that point forward!

      I'd be very interested to see data that has not been rebaselined after year two.

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    7. These figures are sustained NEDA in those study participants who only had 2 cycles of treatment (~60% of the cohort). You can't judge an induction therapy the same way you do a maintenance-escalation therapy as breakthrough activity on an induction therapy is an indication to retreat and does not necessarily mean you have failed the treatment.

      Therefore NEDA rates on alemtuzumab, cladribine and HSCT need to judged and interpreted differently to NEDA rates on maintenance treatments.

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