Tuesday, 23 May 2017

#ThinkSpeak & #ClinicSpeak: do PPMSers need a DMT?

If you have PPMS how would you want it treated? #ClinicSpeak #ThinkSpeak #MSBlog

I have had another email from a US colleague who is worried about the risk-benefit ration of ocrelizumab in PPMS. He/she is worried about the risk of secondary malignancy with ocrelizumab and is therefore going to 'continue prescribing off-label Rituximab instead'. I pointed out to him/her that the safety data on Rituximab-treated PPMSers in real life is too small to assume it is safe in PPMS and that he/she is prescribing a therapy that has been shown to be ineffective in PPMS. Because Rituximab is effective in RRMS does not mean we can extrapolate the RRMS rituximab data to PPMS and assume it will be effective in PPMS as well. 



It is interesting to see how the mind works and that someone is prepared to extrapolate efficacy data from RRMS to PPMS, despite the rituximab PPMS trial being negative and ignoring the fact that the ocrelizumab PPMS trial is positive. 

Could there be an efficacy difference between rituximab and ocrelizumab that explains the results? I have recently learnt that ocrelizumab is a much more potent B-cell depleter than Rituximab, i.e. ~10x as potent. Could this explain its therapeutic effect in PPMS? A 600mg dose of ocrelizumab is therefore ~6x more potent than 1,000mg dose of rituximab. The large punch provided by ocrelizumab may explain and efficacy difference particularly if we are targeting the hard to get to meningeal and intrathecal B cells? Let's hope an ocrelizumab CSF biomarker study is done to explore this possibility. Another way of looking at this is to see what impact ocrelizumab has on cortical gray matter atrophy and B cell follicles using imaging. We think some of the gray matter atrophy that occurs in MS is due to the meningeal B-cell infiltrates. 

I also pointed out to my colleague that to assume that ocrelizumab increases his/her patient's risk of secondary malignancy may be premature; the ocrelizumab malignancy signal at the moment could be a false positive signal. We really need to wait for more data to emerge through post-marketing surveillance to clarify this issue. We have the same issue with oral cladribine; the only way to assess secondary malignancy risks with DMTs is with long-term follow-up studies. 

It is interesting to see the spectrum of opinions about ocrelizumab treatment of PPMS. On the one hand some neurologists are saying it is not effective and hence they are not going to prescribe it for their patients, on the other hand some are saying they don't think it is safe and therefore they will prefer to prescribe a treatment that has not been shown to be effective in PPMS and yet others accepting the results and agreeing that their patients should receive ocrelizumab. In reality all these options are right and it simply reflects the complexities of clinical decision making that lead to variable adoption rates of new innovations. 

CoI: multiple 

29 comments:

  1. I visited my neuro 2 months ago and asked their opinion about ocrelizumab. I was told there were some cases of PML with rituximab, therefore they expect this will be the case with ocrelizumab once it is broadly used and more data become available.
    Was this a reasonable assumption or was it an inaccurate extrapolation?

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    1. It is possible, but the question for the people using rituximab what was their other treatment history, probably polypharmacy

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    2. https://www.youtube.com/watch?v=J4prsO-FDzs
      22:35
      PML was only with steroids and rituximab
      risk 1 in 30,000
      no cases of PML with rituximab or ocrevus in ms

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    3. lol that's old news adam bomb, there was a case of pml on ocrelizumab the other day (i think the first one)

      i think the poor bugger was switching from tysabri.

      if only every practitioner didn't have an opinion on how to get people off tysabri, maybe there would even be some guidelines for now :)

      oops, no biogen wouldn't like those very much.

      yeah no money, no interest to find out how to transition people off tysabri, so we'll all just work according to our opinions

      but if the patient dares have an opinion, then we are scientist who practice medicine according to science and evidence....

      lol :D

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  2. Thank you, thank you. A balanced and very honest piece of writing.

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  3. 'recently learnt that ocrelizumab is a much more potent B-cell depleter than Rituximab, i.e. ~10x as potent.'

    All the drugs do the same thing...so you knew if it worked better it was
    just do to more intensity.
    Real question is Ocrevus 100x more than betaseron and 1000x than Copaxone.

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    1. If it is 10X better depleter why is it given just as often as rituximab the 600mg dose is not ten times less than the rituximab dose

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    2. When we designed the trial we wanted to maximise CNS penetration which is why we gave two infusions of 300mg every 6 months and not one infusion as is done with rituximab and ocrelizumab in the RRMS studies (OPERA 1 and OPERA 2).

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    3. Potency of the anti-CD20 monoclonals is and issue in relation to lymphoma treatment. Patients who don't respond to rituximab may respond to ofatumumab. Whether or not this is relevant to MS needs to be explored.

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    4. "When we designed the trial we wanted to maximise CNS penetration which is why we gave two infusions of 300mg every 6 months and not one infusion.."

      Does one 600 infusion dilute more over time..so 2 300 infusions gives stronger effect..?

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  4. I tought you said that Ms is just ONE disease

    In that case why you thing Rituxan should´nt work in PPms?

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    1. It didnt work in PPMS, maybe because it wasnt loaded with young active PwMS

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  5. It is interesting to see the spectrum of opinions about ocrelizumab treatment of PPMS.

    Yes, except from a patient's point of view it is not interesting at all, it is just maddening. And all it shows is that neuros really have no clue and make it up as they go...

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    1. They don't make it up. As individuals they simply have different world views and prioritise different bits of information.

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    2. I'm sorry, how is not knowing the difference between 2 drugs you are proposing prescribe a matter of opinion etc?

      Once you know the science, and are forming opinions and prioritising different bits of info, - fine.

      But the way you have described the story, neuros don't seem to know the difference between 2 drugs: rituximab and ocrelizumab.

      If you are prescribing those drugs, then you shouldn't be forming opinions and prioritising different bits of info until you understand the differences.

      It's not like there are 12348875 drugs out there to prescribe to ms patients.... there are, what, 12? and neuros don't appear to know much about many of them (outside of what the pharma advertise to neuros).

      This is like my HSCT experience.

      Neuro: don't do HSCT. We don't know if it works and it can kill you.
      Me: oh ok... what about the different agents used... cyclosphaaa something?, raTG - what does it all mean?
      Neuro: I'm not sure....

      This rituximab/ocrelizumab thing is bloody similar. If I, a laymen who doesn't practice neurology, thought to ask 6 months ago - what is the difference between ocrelizumab and rituximab - then why can't the neuros ask the question before they form opinions?

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    3. They all work the same way ecept natalizumab, they all deplete memory B cells, some do it better than others. Think this way and choices are easier, however this is not what pharma want you to think:-(

      Neuros do not do HSCT

      Saddly they also often don't do Reading........and in some instances they don't do thinking:-(


      What is the difference between rituximab and ocrelizumab ...a patent and about forty thousand dollars a year:-)

      The rituximab informed the ocrelizumab trials. We learned from our previous mistakes, you want a positive rituximab trial you do it again and learn from ocrelizumab...Who pays for this study? Why would you do it?

      P.S. POCORI are funding trials of rituximab in MS.

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    4. MouseDoctorWednesday, May 24, 2017 8:49:00 am - "What is the difference between rituximab and ocrelizumab ...a patent and about forty thousand dollars a year:-)"

      Gavin Giovannoni "I have recently learnt that ocrelizumab is a much more potent B-cell depleter than Rituximab, i.e. ~10x as potent"

      This is exactly my issue lol.

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    5. MouseDoctorWednesday, May 24, 2017 8:49:00 am
      "Neuros do not do HSCT"

      Then why on earth are they giving advice as experts on its risks??????????

      They are making it up as they go - my original point. These "differences in opinion" are a bit like Chinese whispers.

      I don't know why it is so hard for practitioners to see that.

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  6. ps. the opinions can't all be right. problem seems to be that no one seems to know much about ocrelizumab - which is why opinions form.

    it's not acceptance of innovation either: it's really knowing the difference between ocrelizumab and rituximab.

    I've asked the question on this forum in the past and I've asked it of practitioners directly. No one had a clue. Which is, I guess, understandable (though it does beg the question are neuros just pharma's spokespeople or do they seek out info which pharma doesn't feed)... but there is a huge difference between "I don't know what the difference is" to "I'm going to prescribe abc because *insert my choice of thinking* - that's not cool.

    It means your colleague doesn't know and is making it up as she goes.


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    1. there is alot we want to see published

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    2. Re: "It means your colleague doesn't know and is making it up as she goes."

      I am not so sure. This colleague has a lot of experience of using rituximab in PPMS and is not willing to change their prescribing pattern based on the ocrelizumab data. They have concerns about its safety. The fact that they have been using rituximab and off-label treatment means they are willing to do something for their patients.

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    3. I did not suggest your colleague is unwilling to do something for her patients.

      The fact that your colleague is writing to you in the first place prolly sets her apart from many of her peers.

      But this - "not willing to change their prescribing pattern based on the ocrelizumab data" - is her opinion which is not based on an understanding of differences between ocrelizumab and rituximab AND it's on opinion she is imposing on her patients.

      If her opinion turns out to be right, then her patients will prolly be fairly happy.

      If her opinion turns to be wrong, and her patients could have had better outcomes on ocrelizumab, then they might be a bitty pissy with her.

      How does that not constitute 'making it up as you go'?

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  7. Dr. G, you hypothesize that EBV-controlled B-cells in brain follicles are the driving force or even possibly causing all forms of MS.

    Is there any current evidence that ocrezulimab has any effect on these EBV-driven B-cells? What if it doesn't, then where does ocrezulimab stand in terms of your hypothesis? Possibly just a potent "downstream" anti-inflammatory immunosuppressant that is not actually fixing the cause and propagation of MS?

    Ocrezulimab's rate of disease progression in PPMS is underwhelming (< 25% above placebo). That would argue that it has little to no effect on these EBV-driven B-cells, if these cells were the cause of disease progression, which possibly they are not.

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    1. It is an antibody and so wont get into the brain very well

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  8. Dr. G, thanks for another terrific Ocrevus post. Some of the points you raise do beg some questions, though. All queries proffered with a tremendous amount of respect you and your team…

    – You state that the Rituxamab PPMS trials were a failure, and that the Ocrevus progressive MS trials were a success. While of course these statements are true, isn't it also true that the realities of both studies are more nuanced?

    You have previously commented on the trial design of the Ocrevus PPMS study, explicitly stating that the study was intentionally populated with patients that fit the "responder" profile discovered in the "failed" Rituxamab trials. Namely, patients who were younger, less disabled, had been diagnosed relatively recently, and who had signs of active immune activity in the CNS. You stated that treating patients outside of these parameters might be ill-advised, which would exclude 70% of patients with PPMS.

    Had the original Rituxamab trials been duplicated using this same patient population, might we not have seen results similar to those of the Ocrevus progressive MS trial? It does seem as if the Ocrevus trial was playing with "loaded dice", on a playing field much to the drugs favor. Had the study participants been more representative of the general PPMS population, as it was in the Rituxamab PPMS trials, the results of the Ocrevus trial might not have shown even the moderate effect seen in the trial as it was run.

    Additionally, it does seem suspicious that the Ocrevus trial was underpowered in regards to parsing data by patient subset, thus, a breakdown of the drugs efficacy by patient subset was impossible. This made it difficult for regulators to give the drug only partial approval for the subset of progressive MS patients that are likely responders, rather than the blanket approval it recently received from the FDA. Hopefully further data will be released in this regard, but based on the published data, we can't say for sure that patients outside of these parameters will actually see any benefit whatsoever. Please correct me on any of these points, as I'm playing a bit of the devils advocate here.

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    1. Dear M

      As I am not conflicted, unlike our neuros as they were involved in the ocrelizumab studies..hell they are involved in all studies.

      Anyway I think you are right on the money with an explanation. I was once told (not from anyone in QMUL) that a trial about another drug was done in such a way that the regulators could not use it to hold up a descision of data based on another trial.... So the fact of doing it in an ambiguous way was cunning.

      I agreed the PPMS trial was playing with loaded dice, and done in a way that they obvious question...is it only active ppMS that responds the best... could not be answered...brilliant... it worked they got licence for all of PPMS. Studies tell us that those with active Disease are going to respond the best. However is is this a dis service because does it block the hunt for a true neurotprotective to treat underlying progression?

      The FDA bought it and now, all pwPPMS can get access to treatment. It also means trials for neuroprotectives have got harderas you have to deal with the immune element too..not a bad thing

      Will the EMA buy this?
      Will they pin it on active PPMS?

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    2. Thanks for the reply, MD. Wondering if Dr. G would address any of the other issues I've raised. Hope he's not upset with me over the pharmaceutical company money comments I made previously. As I stated, they were not directed at him.

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    3. i doubt hes upset..skin thicker than a crocodille..just busy

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  9. – As for the lack of studies showing Rituxamab's efficacy in treating progressive MS, the 2016 Swedish retrospective study did include over 250 patients with progressive ms, and did show varying degrees of efficacy in this population, with particular effectiveness in patients with SPMS. I do know that Rituxamab has been used fairly extensively here in the states to treat people with progressive ms, but of course we have nothing but anecdotal evidence to judge the efficacy of these treatments. It does, however, appear that these treatments have been relatively safe. My own neurologist has been using Rituxamab extensively in his progressive patients, and at this point has logged over 1000 patient hours using the drug with no serious adverse events reported, to my knowledge. The Swedish study states that Rituxamab's use across the spectrum of MS patients is efficacious and safe, but it does note a relatively small number of serious infections occurring.

    – Regarding the Ocrevus cancer signal in the progressive MS trials, yes, they may be outliers, but then again, they may not. The fact that about 1 in 45 trial subjects developed malignancies has to warrant caution, and using the PPMS population at large as a giant pool of guinea pigs seems downright frightening given those statistics. Of course, there's no other way to go about it, but it will be calamitous if in two or three years we start seeing hundreds of cancers in treated patients.

    Additionally, the cancer figures cited by Genentech in its relapsing MS trial published data is also somewhat misleading. During the two-year duration of the trial "only" four subjects developed malignancies, but what has been less publicized is the fact that one year later five more subjects developed cancers, putting the cancer rate of the RRMS Ocrevus trial subjects at about 1 in 180. Does this not potentially bode ill for what we might see as the drug enters widespread use in all patient populations?

    – This is the first I've heard of this being 10 times more potent than Rituxamab in depleting B cells. Not quite clear on this, as my understanding is that Rituxamab basically reduces B cell counts to zero within a few weeks after infusion. I personally did one round of Rituxan infusions several years ago, and subsequent blood test revealed that I had no circulating B cells in the periphery for about 10 months after the infusions. Is there any evidence that Ocrevus penetrates the blood brain barrier and gets at B cells or tertiary lymphatic tissues within the CNS? I do know that the NIH did a trial using Intrathecal Rituxamab, which demonstrated no efficacy. I believe the thinking is that the Rituxan was washed out of the CNS before it could do its magic, so not sure whether or not this provides any useful info.

    Given the rather disastrous trials of Ocrevus on Lupus and rheumatoid arthritis, might not this extra potency make the drug less safe, while perhaps also making it more effective? Something must account for the deleterious effects of Ocrevus on RA patients, especially since Rituxamab has been used safely and effectively for the last 10 years on the same patient population (with FDA approval). Clearly, there are differences between the two drugs, but are we sure those differences make Ocrevus the better choice?

    Again, thanks for your continuing updates on your communications with other MS docs, I find these posts fascinating and thought-provoking. You are doing a great service to the MS community.

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