B DayToday

               To Be or Not to Be that is the Question?
                                                                     No it is Not!

                       The Question is Does Getting Rid of the B cells

Inhibit Progressive MS Independent of Getting Rid of Active Inflammation

To (Deplete) B or Not to (Deplete) B that is the Question
(for PPMS)

Efficacy of ocrelizumab in patients with PPMS with and without T1 gadolinium-enhancing lesions at baseline in a Phase III, placebo-controlled trial

Maybe ProfG can post the Answer Apres-ski as I am sure he knows as one of the collaborators

Alternatively Why Not Tweet the Answer.
The Talk is Today.

I suspect the answer is going to be that it does not matter, 
but that would rewrite the history of anti-inflammatories in PPMS
including the rituximab in PPMS conclusion.
We will See. 

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    • Thanks I suspect that something will become available once the talk is live, if you had the slides before hand there would be no point in turning up.

  • Mouse you know that I have been contemplating this issues for years. I hypothesise that we will need to do more than deplete B cells. We need to clear intrathecal plasma cells, render pwMS OCB-free, switch off hot microglia and then add-in a neuroprotectant. As for the apres-ski; it is about to begin.

    • Hi Prof G.

      With a procedural science hat on, I can absolutely see the logic in testing each of these in turn ..

      With an MS'er hat on, and the urgency that comes with that, I'm sure there is an appetite for starting with the Howitzer, and working back.

      How about it, as a crowd-funded trial?

      IV Alemtuzumab (T+B cells) + Intrathecal Elotuzumab (CNS plasma cells) + TLR4 inhibitor like LDN/Valganciclovir or minocycline (microglia) + Simvastatin (inflammatory cytokine release inhibitor from activated microglia). Most of these drugs have already proven relatively safe, at least in isolation.

      Yes, this is throwing the kitchen sink at it, but it gives you a quick answer and potentially a way to be the first to actually stop the beast in its tracks and transform lives. You can then work back and refine it over time whilst (hopefully) hitting the slow or stop button on progression in the meantime.

      Alternatively, if even this doesn't work, it will be just as valuable in terms of what you'll learn about the disease – i.e. the target lies elsewhere. Except, this way, you won't waste the next 2 decades trialling these factors in isolation.

      Desperate times and all that. Thoughts?

      Incidentally, looking online at compounds studied in inhibiting microglia activation, I hadn't appreciated prior that it reads like a who's who of factors that seem to have a hitherto poorly understood benefit on MS (oestrogen, simvastatin, ALA, minocycline/tetracyclines, – and, more anecdotally, LDN). Could the link be that simple?

    • I was asking about the results of the presentation of Prof Wolinsky not your thoughts but thanks for those.

      Results supplied by Prof Wolinsky

    • Re "render pwMS OCB-free"
      What about the 5 to 10% of people with confirmed MS (sometimes quite longstanding MS) who don't have OCBs?

  • If Alemtuzumab depletes B and T cells, why would it not have the same effect as Rituximab or Ocrelizumab on PPMS? It either means that Alemtuzumab doesn't deplete B cells or there is something else going on. I don't understand why this is being ignored or not discussed.

    • it would have same effect but it has not been tested in PPMS it has not been properly tested in SPMS also. If the trial was loaded with active Msers it would work.

      However alemtuzumab does deplete B cells for long and I suspect this is why you get B cell autoimmunities

    • lol. Efficacy of ocrelizumab in patients with/without
      T1 Gd+ lesions at baseline was consistent with the
      overall study population…
      However, the ORATORIO study was not powered to demonstrate
      efficacy differences between these subgroups

    • So it is designed to say approve for all of PPMS and not a subset…perfect for company point of view. This could be the base on which to layer neuroprotectives..We have been saying you need both

    • The cynicism involved in trial design is stunning. Too many conflicts for neurologists to call it out? I thought Wolinksy's two presentations, taken together, very clearly stated that there are problems with the way these trials are structured. I wasn't there so can't tell if, in his tone or demeanor, how angry he was. Informed PPMS patients should be angry, and (as I've said here before) something like an "ACT UP-style" group of patients is needed to protest how these trials are funded and set up is now necessary. Going through Pharma those of us with PPMS now will never see effective treatments in our lifetime.

    • I'm not so sure.Without pharma nothing is going to happen soon.

      To get control of progression you need to control inflammation and protect and repair. You want to protect and repair but you still need to control inflammation. ocrelizumab does will be a good bottom layer. Maybe Roche have some fantastic neuroprotection and repair agents up their sleeve, but until they get into the MS market and making some cash they are not going to go again. They have done three trials in MS and all are positive.

      I doubt Prof Wolinksy is angry he is presenting pharma data..

    • Let's get to the root of inflammation. Is it lymphocyte activation? From the tone of researchers it seems the answer is no. Are hot microglia responding to a yet undefined agent? Until the root cause is known the anti-inflammatory drugs will be incomplete and window dressing. Without a complete understanding of inflammation repair and protection are on hold.

  • I'm really suprised – I thought from this article (which quotes Prof G) that the drug is a miracle about to cure all with MS. http://www.express.co.uk/news/uk/610907/Multiple-Sclerosis-Drug-Ocrelizumab-Treatment-Britain-Gavin-Giovannoni-Nick-Rijke

    I'm also disappointed that there is not a new blog entry entitled "Clinicspeak: reflections on Ocrelizumab after the fallout….." 😛

    Ok, point made, I will move on from snide comments now. Thanks for all the work you do, I am infinitely appreciative of this blog and the efforts that go into it, despite my snide remark!

    • If you are getting your information from the express be warned and papers can take any quote in whatever context.

      However Ocrelizimab has real potential and could supercede Alemtuzumab for RRMS. Therefore why do you need reflections. Do you want to hear him say this is the end of alemtuzumab if ocrelizumab is shown to be an induction therapy?

      What you seem to be concerned about is the effect in PPMS. If you are expecting the history of rixuximab to be altered because it has the same mechanism you are asking too much. Because they have been sensible and worked out how to get a positive where there would be nothing. Why do you need a reflection on that either.

      Next it is a company study that ProfG was involved in, do you think it would be wise to discuss down sides before it is assessed by the regulators but more importantly before it is published.

      We (not ProfG) can do that:-)
      …..be warnhttp://www.express.co.uk/news/uk/610907/Multiple-Sclerosis-Drug-Ocrelizumab-Treatment-Britain-Gavin-Giovannoni-Nick-Rijke

    • Thanks for the response MouseDoctor.

      I apologise my tongue in cheek comment was not clearer. Recently, BBC was criticised for irresponsible reporting on HSCT. Words like "miraculous" and "cure" are often cited as examples of irresponsible reporting.

      Ocrelizimab was called miraculous in the article, a game changer etc. It is a better version of Rituximab. It will not, as has been noted, be the answer to PPMS on its own. The PPMS forums are abuzz with news of this miracle drug. My tongue in cheek comment was comparing the reporting of Ocrelizimab v reporting on HSCT (and v. past reporting of 'miraculous' Lemtrada) – and asking why always such an outcry at the way media sensationalises HSCT but no one talks about media sensationalism in other contexts, including Ocrelizimab and Lemtrada.

    • I disagree on this. OCrelizumab may well be a game changer.
      You have a choice of current DMT vereses something without their side-effects

      I agree with you that the media are universally useless when reporting anything and it is cure this and cure that and this is bad.

      However the HSCT report was from a cuurent affairs/news programme that aims to be quality media rather than some popshow. If it was a report by "Good Mornbing Britain" breakfast TV then it would be par for the course. I dont know the Australian versions of mediaand do not expect you to know anything about Panorama but if the New York Post present like the National Enquirer you are more likely to comment.

      Perhaps you are senstitive to people talking about HSCT

    • No I'm not sensitive to people talking about HSCT, but thank you. I'm sensitive to herding behaviour, which is a different issue. Examples of experts using "herding" behaviour to influence people's choices is when they quote inflated risks mortality risks (such as 2% when the recent literature is littered with 1.3% stat for both meylo and non myelo protocols).

      A drug which reduces the risk of progression by 24% in PPMS on its own is not a game changer. You're right, I didn't even watch the Panorama program, I assumed it was the same as the myriad of other media presentations on HSCT – "miracle" and "cure" come to mind (which neither Ocrelizimab nor HSCT is).

      As a side issue, an Australian neurologist told me that Ocrelizimab is likely to carry a malignancy risk – I don't know how correct that is, but it cannot be that it's ok that Ocrelizimab is called a miracle.

      Having said that, we have now spent 2 comments each talking about a silly tongue in cheek comment which prolly doesn't deserve so much conversation.

      Perhaps you are sensitive to people talking about Ocrelizimab 😉

    • My comment was also aimed a bit more at Prof G rather than mousedocs. In about August last year, I wrote to Prof G and to an Australian neuro Dr Andrew Colin. I wrote to Prof G in his capacity as a member of the board of MS Reasearch. My issue was that the Australian statement on HSCT issued by MS Research Australia was incorrect in places, misquoted statistics which were not supported or reflected in the references in the statement and so on. I had spent about 6 months looking at the statement and going through its references to come up with a 4 page description of what was wrong with the statement. I wrote to Prof G and Dr Andrews to get their views on what I had written before sending what I had written to MS Research Australia. Dr Andrews wrote back to me and agreed with what I had written, said he has nothing to change or add. Prof G wrote back to me and said to the effect that he doesn't know enough about the topic, but he kindly referred me to a colleague who does. As I had what I needed at the time (confirmation that what I had written wasn't mumbo jumbo) I approached MS Research Australia, and after a couple of meetings with their CEO, they have now updated their statement on HSCT, which is much more in line with what you or another mousedoctor wrote in an earlier blog entry. I was and am satisfied with that – with accurate descriptions of HSCT, warts and all. But scare mongering is not cool. Hence my tongue in cheek comment re HSCT v. "miracle drugs" as a friendly dig at Prof G (which I admit, he would have prolly not noticed). This friendly dig has now exploded beyond all reasonable proportion, and I have to point out again that even though we are all human and will therefore never agree on everything, the beauty of this blog and the tireless work you put into it, is that we can discuss and disagree and even get to the bottom of what the disagreements are while I and countless others affected by MS continue to learn 🙂

  • gavin giovanonni on hsct about two weeks ago clamoring for a head to head trial of HSCT vs Alemtuzumab – "You will need to show its better than alemtuzumab, arguably the most risky of the high-efficacy therapies we have. If hsct can't beat alemtuzumab it is going nowhere as a treatment for MS"

    in this blogpost here we have the results of ocrelizumab being trialled against interferon beta, and reporting a heightened malignancy risk.

    not a peep out of him this time asking for a head to head with Lemtrada before its prescribed to RRMS patients.

    funny how his moral outrage evaporates where pharma are involved.

    probably just a coincidence and in no way related to the fact that one pays him and the other doesnt.

    • "Not a peep"…ProfG has been on holiday and no-good internet so unsurprising has been quite and you may notice he has not posted all week.

      There is no proven heightened malignancy and no one is not going to a argue for a head to head yet because ocrelizumab is not licenced yet.
      After that a head to head could occur but onsafety grounds you may argue against it. Furthermore you would have to pay for the drug. E.g. 500 person trial would cost 500 x £70,000 = £35,000,000. Too much for an academic trial.

      Now moral outrage…the point of calling for a trial is that it will challenge people in our profession to confront their bias and it may become accepted if the results are good otherwise it is going to be seen too be a dangerous approach given as a last resort.

      So perhaps think before you troll!

    • "here you are not really arguing against the critique made"

      You are still not thinking. If you cannot digest the response when there is nothing to be said and nothing to post on.

      If and when Ocelizumab is licenced comparisions will be done with alemtuzumab.

      Lack of Pharma involvement in HSCT means nothing concerning the comments made. End of story.

    • hsct is not licensed, ocrelizumab not licensed. so same rules of critique for both please

      one is compared against betaferon and gets off Scot-free on the blog. other gets a diatribe saying the trial is a waste of time unless it's against alemtuzumab

      one lines the pockets of neurologists, the other does not

      will leave you to work out which is which

      not complicated. take your own advice. think.

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