Anti-CD20 Derisk Study

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Barts-MS rose-tinted-odometer: ★★★★★

Did you watch the anti-CD20 debate on the triMS-online platform yesterday? The question that was asked was ‘Can we use anti-CD20 therapies as immune reconstitution therapies rather than maintenance therapies?’. I am not sure the debaters answered the question. 

When I asked Anders Svenningsson, who is probably the world’s biggest adopter of anti-CD20 therapy as a treatment for MS, whether or not someone with MS could stay on anti-CD20 for life, he hesitated before saying ‘YES and NO’. His reason? SAFETY. He described things they were doing to try and reduce the risk of hypogammaglobulinaemia and infections in their patients on longterm anti-CD20 therapy. I am not sure it will work. Interestingly, he suggested stopping  anti-CD20 therapy when pwMS get to 55-60 years of age when the risks of treatment outweigh the benefits. In other words, Anders Svenningsson is saying we can’t leave pwMS on anti-CD20 lifelong. 

I have been making this exact point on this blog for several years and that is why I have proposed the ADIOS and iTeri studies as ways to derisk long-term anti-CD20 therapies. However, I have been thinking are there any other DMTs we could use after anti-CD20 that would potentially work to derisk the hypogammaglobulinaemia and tackle the cause of MS. I suspect yes. Fumarates, as monotherapy, or in combination with a neuroprotective therapy, also makes sense. The difficulty is what will be the primary outcome of such a trial and how would you do power calculations? 

Maybe we could use a non-inferiority design and make safety the primary outcome. Would regulators buy that in addition to non-inferiority as a secondary outcome?

There are not many companies who have the resources, motivation and know-how to do such a study. Roche-Genentech and Novartis would not as this would eat into their franchise. In my opinion, the only company with big enough bollocks and know-how to take this on would be Biogen. Would they be interested?

This is potentially an opportunity for them to come up with a new combination pill of one of their fumarate formulations with an add-on neuroprotective. DMF will maintain MS in remission post-anti-CD20 and the neuroprotective will tackle smouldering MS, which is something anti-CD20 therapies don’t do. A fumarate-neuroprotection combination may actually not only show improved safety but superiority on end-organ damage markers (brain volume loss etc.). 

The hypothesis is that if B-cells and in particular memory B-cells are driving MS then starting DMF for example before memory B-cell reconstitution occurs may actually make MS more responsive to fumarates. Add in a combination, to generate new intellectual property (Biogen need this as their fumarate patents are being challenged) and you have a new DMT.

If successful this new combination pill will probably become the most prescribed DMT in MS. Why? To quote Anders Svenningsson you can’t really remain on anti-CD20 lifelong so if you have to derisk an anti-CD20 at some stage. So why not do it before you develop hypogammaglobulinaemia? As more than 50% of MS patients will be treated with anti-CD20 therapy in the near future this combination therapy could potentially capture more than 50% of the market.

If you are on an anti-CD20 therapy (ocrelizumab, rituximab or ofatumumab) would you volunteer to participate in the DERISK study below?  

CoI: multiple

Twitter: @gavinGiovannoni      Medium: @gavin_24211

About the author

Prof G

Professor of Neurology, Barts & The London. MS & Preventive Neurology thinker, blogger, runner, vegetable gardener, husband, father, cook and wine & food lover.

11 comments

  • Where do I sign?

    Tecfidera was the only treatment with which my symptoms improved, along with clear MRI and no relapses. I saw improvement particularly of fatigue and loss of concentration. There is some speculation that Tecfidera has an anti-inflammatory effect.

    Sadly I ended up developing lymphopenia – is the dose perhaps too high for some patients? My neurologist told me that lowering the dose wouldn’t improve the lymphopenia and meant the medication wouldn’t be effective. I’d love to go back on Tec if it was safe to do so. I’m on ocrelizumab now and MS is definitely smouldering with gradually worsening symptoms…

  • Hi Prof G, I would sign up too! I’m currently on ocrelizumab – only newly prescribed and my first full infusion went ahead in June this year. Prior to that I was on Tecfidera for 18 mths but had to come off it due to low lymphocytes. I was then given an option of a low effective modifying treatment, which I tried but as it was an injectable that I had to do myself. I found this very hard to do and requested if I could be considered for a higher DMD that wasn’t so disruptive to my family life at the time. The drug ocrelizumab seemed to fit, although I have had 6 infections and I am constant antibiotics combating, we think a UTI! I have also developed lower limb edema and I have been given more meds (water tablets) to try help alleviate the symptoms. They don’t seem to be working and my GP is at a loss what to do! My neck also feels like it’s inflamed (strange to describe) but it is there all the time and I’m not sure if this is just me, my MS the medications or something else! See where I’m going with this…Why is it that no-one in my part of Berkshire (Surrey borders) seem to have the time to ask and at least put my mind at rest. If it is the therapy – may be it is not agreeing with me – help me find one that might. Or, at least help me navigate through all the infections and let my Urologist know that and to help with a plan to treat me, without daily antibiotics (I’ll be susceptible to all sorts in the future – I’m sure of it!).

    Lastly, my age, my sex, my current situation all have a bearing on when this therapy should be prescribed and how long I can have hope that my MS is under some sort of control. Ideally with a drug that treats the smouldering side of the MS (burning pains, neurological pain and constant feeling of decline) along with combating the disease is a mighty drug, we all want and ask for.

    Well done for all your questioning and I hope this request is met with treating the disease and ultimately stopping it progressing and not just greed and brand promoting.

    All the best,
    Jane

  • Radiologically stable on ocrelizumab (1st line) so far but sensing smouldering/PIRA, I would consider taking part in this.

    I think my requirement would be to be eligible for alemtuzumab or HSCT in case of a relapse or clear progression, though (in my country, being on DMF would not usually allow for that).

  • Why not a *brutinib?
    I am on ocrelizumab, just first two half doses, but I am wondering about those people that are fine after years (up to 8 according to a previous post) they stopped rituximab or the single case report of the single high ocrelizumab dose. What do these people have in common (biologically)? What happened to them?
    Also, we say memory b cells drive the disease, but we also say antibodies should not be in the brain and we have not yet decided if microglia is good or bad. So, before participating to the derisking of anti cd20, I would volunteer in studies that aim to the other two points that may have broader impact on the disease sizomus or dodo.
    Another point: if people develop hypogammaglobulinemia in the blood with anti cd20, isn’t it possible that they will develop “hypogammaglobulinemia” in the brain at a certain point? 🙂

  • Prof G,

    “This is potentially an opportunity for them to come up with a new combination pill of one of their fumarate formulations with an add-on neuroprotective. DMF will maintain MS in remission post-anti-CD20 and the neuroprotective will tackle smouldering MS, which is something anti-CD20 therapies don’t do.”

    1. Does this add-on neuroprotective exist now? Would the combination pill also work for those who can’t have Natalizumab anymore or those who have had Alemtuzumab?

    2. I’ve lost track of the various studies you have proposed: ADIOS, iTeri, DODO…. are any of these actually running or just ideas?

    • DoDo (Double dose….Ker Ching Study) is going ahead if you look at ECTRIMS the details were there….P0230 – Rationale and design of two Phase IIIb studies of ocrelizumab at higher than the approved dose in patients with RMS and PPMS.

      I doubt it is called DoDo….It’ll be Operetta, Gilbert and Sullivan or Aria I & II, the “three tenors” or maybe it should be….three thousand tenners…closer to the cost:-(

    • Yep HSCT verses Alemtuzumab/ocrelizumab (initially called Zeus by ProfG) it has a another name….DoDo…dont know the name

  • Yes , I’d sign up, having turned 54 yesterday and having had first full dose of ocrevus last month and still feeling as I did 18 months ago , possibly worse , hard to tell under lockdown 🥴 I’m worried that I’m running out of drugs to try. I was diagnosed 20 years ago, had betaferon, cops one , tecfidera and now ocrevus , I don’t care what you call it , smouldering, secondary progressive , fairy wings , I just want to carry on keeping the worst at bay.
    Where do I sign ….

  • A couple of patients here commented feeling better on previous DMTs and not as good on Ocrelizumab. Could it be simply the previous DMTs haven’t stopped progression (or damage on neuro reserve), and Ocrelizumab is taking the blame? What if Ocrelizumab was used as the first DMT?

    I’m convinced CD20 therapies are not suitable for life-long and would love to see de-risking projects to go ahead. But I would not have the gut to come off CD20 therapies as it shows benefit to progressive MS while other none IRT-DMTs have not.

    • I am on ocrelizumab as first line DMT. Less than a home run so far but sadly it took forever for me to get diagnosed (at 3ish EDSS).

      As for the ocrelizumab helps PPMS ans others do not, my suspicion from reading the study is that Roche was just very good at picking patients with relatively good Prognose.

      • Siponimod/Norvaits seems to fit in this description more. Evidences for OCR on progressive MS seem stronger and have legs to me.

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