Sunday, 7 May 2017

#NeuroSpeak: more on ocrelizumab in PPMS

An email debate that deserves to be held in the open. #NeuroSpeak #MSBlog

I have started-up another email exchange with a colleague about the ORATORIO (ocrelizumab in PPMS) study. I have asked him/her if we could have this debate in the open on the blog, but he/she has asked to remain anonymous. 


When I respond to MS-related questions that may be of interest to the broader community I prefer to answer them in the open, which is why I have redacted the discussion and posted it below. I would appreciate your thoughts on some of the issues raised. 


The following is are his/her primary questions: 

'You were a co-author on the ocrelizumab in PPMS NEJM manuscript, which didn’t really address the issue of age/inflammatory activity as markers for treatment response. Both the rituximab data in OLYMPUS and the Gadolinium data in the supplement of the NEJM article indicate that the population that benefits is the young patient with inflammatory activity. B cell depletion is not benign, especially in the older population, and the ocrelizumab manuscript infers that all PPMS patients should be treated with ocrelizumab. Are you really treating all of your PPMS patients with B cell depletion, and, if not, why didn’t you push for more discussion about this issue in the NEJM paper?'


My response: 

We tried to restrict the trial population as much as possible to mirror that of the responder subgroup in OLYMPUS (rituximab in PPMS) study. Please note the following specific inclusion criteria for the trial:
  1. Age cut-off of 55 years of age
  2. Disease duration of symptoms of less than 15 years in patients with an EDSS score of more than 5.0 at screening or less than 10 years in patients with an EDSS score of 5.0 or less at screening
  3. Documented history or the presence at screening of an elevated IgG index or at least one IgG oligoclonal band detected in the cerebrospinal fluid
​The presence of absence of Gd-enhancing lesions was not part of the inclusion criteria and hence should not be used to select patients for ocrelizumab treatment in the real-life situation. The detection of Gd-enhancing lesions also depends on the frequency of imaging. If you are going to select patients for treatment I suggest you use the the three inclusion criteria above as your guide. I predict that these will probably exclude 70% of a typical PPMS clinic population. 

Please note that the trial population in the ORATORIO study was not typical of other PPMS trials; the population was younger, less disabled, had higher proportion with Gd-enhancing lesions at baseline and higher on study number of relapse​s. As I have said before there were strong trends in both the Gd+ve and Gd-ve cohorts, therefore, we shouldn't limit treatment to patients with Gd-enhancing lesions only. If we did this we would be denying many patients access to an effective treatment.

I personally don't buy into MS being 2 or 3 diseases. MS is one disease and PPMS is simply more advanced MS; if patients are active they should be offered treatment regardless of their presenting clinical phenotype.

Regarding my own practice. We can't use rituximab in the UK; the NHS won't pay for it and are unlikely to pay for ocrelizumab either. NICE will assess the cost-effectiveness of ocrelizumab based on its price for relapsing-forms of MS and in PPMS ocrelizumab will be compared to best-supportive care. The latter means ocrelizumab is unlikely to pass the NICE cost-effectiveness threshold. I am hoping that Roche, who will be marketing ocrelizumab in Europe, approach NICE and the NHS to discuss differential pricing and to offer ocrelizumab at a cheaper price for patients with PPMS. Differential pricing is a 'hot potatoe' and I am not sure the NHS is ready for it; but I live in hope for my patients. 

Please note ocrelizumab has yet to be licensed in Europe and we can't assume its license will be the same as the US. 

At present we offer our patients with active PPMS off-label cladribine, a relatively cheap B-cell depleting agent. Like all DMTs it is a choice and not all patients take-up the offer. I am also aware that in the US a large number of neurologists are still using low-dose methotrexate in PPMS. 

I am not sure we have enough data on B-cell depletion in PPMS to make a call on whether it is benign or non-benign. Hopefully, good quality safety data will emerge from post-marketing surveillance studies. I suspect as with all immunosuppressive therapies it won't be benign. I would recommend telling all your patients about infusion reactions, the herpetic infection risk, the possible malignancy risk and the likelihood that in time they may develop hypogammaglobulinaemia and need Ig-replacement therapy. Please note we have a large amount of clinical experience in children with agammaglobulineamia and these kids do well long-term, as long as we keep the Ig levels normal.

I am not sure you are correct in suggesting that we are recommending ocrelizumab for all-comers. The trial population defines the group we are advocating its use in. I am surprised the FDA did not include the CSF findings in the label. If I was a regulator I would state that CSF-ve PPMS should not be treated with ocrelizumab.

Regarding discussion in the NEJM paper; the editors of the NEJM essentially cull all speculative discussion and limit the discussion to issues in the trial. NEJM editors are renowned for rewriting submitted papers to keep them consistent for style. The NEJM article is not the forum for the kind of discussion you want to have. I suggest we have this discussion on the blog.

His/her response: 

'Thanks for your prompt and thoughtful response. It was very helpful. When do you think we’ll be able to see the age cutoffs for the study? Given that the average age for the study was 45 (and for OLYMPUS it was much higher—about 50), there should be enough patients who entered the study between 50 and 55, to know whether the relatively small treatment effect in the whole group was made up primarily of those under 50. I would certainly like for my older PPMS patients to avoid the potential adverse effects of this drug if there is no clear benefit for this group. 

I agree with you about MS being one disease( except possibly for unusual outliers, like the NMO story). So, wouldn’t you expect B cell depletion to work for the younger, more active SPMS patients, too?'

My second response:

There are numerous post-hoc subgroup analyses that are ongoing. I will ask the trial team to include your question about age on the list.

Regarding SPMS; yes, I would expect B cell depletion to work for SPMS as well. I wouldn't limit it to young, or early, SPMS either. Based on our length-dependent axonopathy hypothesis I would even expect patients in wheelchairs to benefit, however, the benefit will be limited to arm and bulbar function. The latter is why we are lobbying Roche to do a trial of ocrelizumab in more advanced MS, with the primary outcome being upper limb function. 

CoI: multiple

16 comments:

  1. This was so informative and a conversation I have never had with my neuro. I am 52 and have had MS for 12 years with an EDSS of < 1.0. No idea about my IgG status. My Neuro is gung ho to transition all of his JCV + tysabri patients to Ocrevus of which I am one. Having read your post this a.m., I think we have a few more steps before I make that decision.

    One of my concerns is that for each of these more sophisticated therapies there is no easy turning back.

    As always, your blog is my first read in the morning and puts my mind at ease.

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  2. "PPMS is simply more advanced MS"

    Clearly it is..question is why does PPMS do so poorly in HSCT.
    It works only in a small percentage to stop progression
    but after 3-4 years it doesn't even do that and progression resumes.
    Secondary progressive hsct results in 40% stopping progression.

    Does PPMS just have more memory B-cells hiding in the brain and
    producing antibodies?

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  3. Might I have your permission to reprint this article on my blog (Wheelchair Kamikaze)? I believe the information contained within is extremely valuable, and of course I would give you and your blog full attribution.

    I might add a simple paragraph explaining some of the more technical terms being thrown about, but otherwise would leave your article to speak for itself.

    Hoping that you will agree to this, as my blog reaches thousands of patients, many of whom are wrestling with the Ocrevus question.

    I hope I'm not stepping out of bounds here, and if you decline I will fully understand. But, in the interest of getting this info out to the most MS patients possible, please do consider this request.

    Thanks for all you do, and for this blog, in particular.

    Oh, one additional question: would you consider the same prescribing restrictions (younger age, less disabled, positive CSF results) when prescribing Rituxan (if you could)? My neurologist is a big advocate of Rituxan, and has many patients on the drug. Just wondering if the same criteria should apply?…

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    1. Yes, you are welcome to reproduce the post, but the conversation is ongoing.

      In relation to anti-CD20 therapy I would definitely make sure pwPPMS have an abnormal CSF. We have not data to support it effectiveness in CSF-ve PPMSers. I think the latter cohort have another disease, i.e. not driven by B cells.

      Regarding age: I won't use age as a strict cut-off. Some people are biologically young despite being old and vice versa. All I would look out for is signs of activity, i.e. recent evidence of progression (last 12-24 months), and/or MRI activity and/or a raised CSF neurofilament level. You have to something to measure.

      Re rituximab: it works in the same way as ocrelizumab. The difference between the two relate to NABs and how they kill B-cells. I have discussed this before in the past.

      I want to reiterate that not all PPMSers are eligible for ocrelizumab.

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  4. Dr. G, why do you support Ocrevus in treatment of progressive MS? Is it because currently it is the only thing that makes a slight dent on progressive MS?

    You seem, for good reason, to believe in EBV controlled memory B-cells contained in brain follicles, which may cause or lead to all forms of MS, but these are not affected whatsoever by any current treatment marketed for MS, including Ocrevus or even HSCT? Does Cladribine effect these EBV induced memory B-cells? How does one measure these EBV-controlled B-cells? Why do you not throw much support behind the small Australian trial with infusion of reactive CD8 cells that destroy EBV driven B-cells, as this seems to fall more in line with your hypothesis?

    All current immunotherapies are very high risk treatments (i.e. malignancy and immunosuppression related infections) for drugs with very little efficacy (~25% above placebo) that is still not addressing the cause/trigger and progression possibly of MS. You may, in progressive patients, very slightly slow down the disease but you are inevitably still going to worsen.

    I guess that I am having trouble wrapping my head around your support of Ocrevus in progressive MS, or any other immunotherapy for that matter, that does not at all address the "black swan" of EBV controlled B-cells in these brain follicles that you hypothesize about?

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  5. I don't think we can generalise the outcomes of a single phase 3 outcome to an entire generation of PPMS. What would you do if it doesn't work, how long would you treat for? -these are questions which EMEA, NICE should ask. We need more real evidence in tandem with randomised controlled trials.
    The restriction of a potentially useful therapy in one part of the world/country compared to another has always left me with a bad after taste. NICE would be aware of the potential backlash in their assessment. It may also allow them to consider biosimilars in the best interests of NHS longevity.

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  6. "....why do you support Ocrevus in treatment of progressive MS? Is it because currently it is the only thing that makes a slight dent on progressive MS?"

    https://www.nytimes.com/2017/03/28/health/fda-drug-approved-multiple-sclerosis-ocrevus.html?_r=0

    Every PPMS should be given option of Ocrevus..because the patient is best judge if it works for them or not. This woman was in he trial and is
    seemingly A+ candidate/responder 51 now 6 years of disease and been treated for 3 years..states progression went from "Bullet Train" to a "local train". At first she hoped she was a placebo cause she felt
    the slowdown but she wanted more to get back her loses but now she's thankful she might have bought more time..Is she aware that Rituximab was approved for medical use in 1997. Seems like RA Lupus MS should have
    been boxed up and FedExed over to Oncology Dept.

    People write that they want Ocrevus to stop secondary progressive but if it
    doesnt stop progression in PPMS it likely won't do it in RRMS.
    It's a progressive disease..stop progression and you have a cure.
    But that's asking alot out of a 20 year old Cancer drug.

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  7. Okay I'm confused? What conversation? Team g are doing all the talkng? Do team g really need validation from anonymous neurologist? A anonymous neurologist keeping his/her answers short? What is the point of this post????!!!!!

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  8. Ok. Now I understand. The reason why team g is taking care to respond to participants on this site it's to measure cognitive decline. You really don't have time for us it's a research website. Measuring cognitive decline. Shame on you. And goodbye. I'm no one's botch. I dare u to post this and goodbye

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    Replies
    1. Amazing what some can read into a post, isn't it?

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  9. Finally posted your dialogue to Wheelchair Kamikaze. Sorry for the delay, had kind of a rough week disease wise. MS sucks.

    One question regarding IgG deficiency in ocrelizumab treated patients. Has this been seen in patients treated with rituximab for MS and other autoimmune diseases? I don't think I've ever encountered any reference to this in any of the papers I've come across regarding rituximab in the treatment of AI diseases.

    Here's the link to my blog post, I couldn't help but add my two cents on some of the issues raised. Hope you don't mind.

    http://www.wheelchairkamikaze.com/2017/05/ocrevus-dialogue-between-two.html

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    1. In the 2-years of the OPERA and ORATORIIO studies IgA and IgM levels dropped, but not IgG. Only IgM levels went below normal. Please note that plasma cells have a long half-life so the fact that IgG levels are preserved is not surprising. However, with long-term use these levels will drop. Hypogammaglobulinaemia, with infections, is a well described complication of long-term Rituximab use and will almost certainly occur with ocrelizumab.

      Maintenance immunosuppressants accumulate risks over time. In comparison PIRTs (pulsed immune reconstitution therapies), for example alemtuzumab, cladribine and HSCT, front-load risk. The latter is one of the reasons why some pwMS choose a PIRT.

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    2. Thanks for that explanation, Dr. G. Makes perfect sense, of course. My own neuro has many patients on Rituxamab, and has been suggesting it for me. I'll have to check with him on this issue. He's decided to withhold Ocrevus for patients seen at his clinic, due to his concerns over the cancer signal.

      I sincerely hope you didn't take offense at my little "cures, not treatments" diatribe at the end of my blog post. Was most assuredly not directed at you, but rather at US neurologists who literally make more in pharmaceutical company monies than they do in salary. In some cases, many times more. These doctors are not receiving these fees for research purposes, rather they are, in effect, acting as paid spokespeople for the pharmaceutical companies in question.

      I believe this problem is much more widespread in the US than in countries with national healthcare systems, where drug prices are far less than they are here in the states. The situation in the USA is almost beyond belief, from every other TV commercial being for a prescription medication to doctors being paid, in some cases, hundreds of thousands of dollars over 18 month periods in "consulting fees" and "honoraria", which have nothing to do with research but everything to do with pharmaceutical marketing.

      If you're interested, you can have a look at what's going on but utilizing the Dollars for Docs website, which allows users to search a database of pharmaceutical company payments to doctors (excluding those payments made for legitimate research purposes). Searches can be made on individual doctors, and I bet you'll be surprised at some of the amounts many of your US colleagues have received.

      Here's a link to the Dollars for Docs website:

      https://projects.propublica.org/docdollars/

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    3. Thanks
      Luckily for ProfG and DrK the Europeans haven't done this yet:-).
      It's coming.

      P.S. Love the rant.

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    4. MD, you are welcome, and thanks. Glad you enjoyed the rant.

      Don't know why the link I posted isn't working, the URL is correct. In any case, you can Google "Dollars for Docs", and the website should show up at the top of the list. It's maintained by Pro Publica, an organization dedicated to freedom of information. The actual statistics are compiled under the order of Obamacare, so once the current government does away with the Affordable Care Act, I'm not sure the site will survive…

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