My position on anti-CD20 therapies has been criticised, why?

M

Barts-MS rose-tinted-odometer: ★★★★★

I have recently been criticised by a colleague for supporting the DODO (double-dose ocrelizumab study) and the ADIOS (adaptive dosing ocrelizumab study) studies. How you can I on the one hand support more ocrelizumab and on the other hand suggest reducing the dose in the longterm. I responded that it is all about timing and how you use anti–CD20 therapies.

You need higher doses of anti-CD20 therapy initially as an induction strategy to purge the various B-cell compartments of memory B-cells, which I hypothesise house latent EBV and the highly autoreactive population of B-cells that drive and maintain the MS-state. This population of cells may reside in the deep tissues and/or the central nervous system, which is why we are also testing CNS penetrant anti-B-cell strategies, simultaneously. 

However, once you have purged these compartments say after 2 years of treatment you don’t need to maintain such high-doses of anti-CD20 therapies that are then suppressing normal B-cell biology and immune responses, which result in longterm complications. This is why we want to test using ocrelizumab as an immune reconstitution therapy, i.e. high-dose upfront followed by no treatment and wait to see if MS remains in remission or disease-activity returns requiring additional courses. The latter is one of the arms of our proposed ADIOS study. 

In reality, if I could convince a national funding agency, a pharma company or wealthy philanthropist I would use anti-CD20 therapy as part of an induction-maintenance protocol. After two years of induction therapy with high-dose ocrelizumab, I would test different maintenance strategies in parallel. My agents of choice would be teriflunomide, leflunomide, IMU-838 or vidofludimus (selective second-generation DHODH inhibitor,) HAART (highly-active antiretrovirals), famciclovir or another anti-EBV viral agent. The hypothesis is to allow B-cell reconstitution after anti-CD20 therapy in the presence of ant-viral agent to prevent EBV reactivation and reinfection of new memory B cells. By doing this you will be derisking the long-term immunosuppression associated with anti-CD20 therapies and you should prevent the development of hypogammaglobulinaemia. 

The problem with this trial proposal is the outcome measure; the power calculations are not trivial and the study would have to be very long. I also have reservations about whether or not the regulators will accept the induction maintenance strategy. Maybe we can sell it to them on safety, i.e. to prevent the development of hypogammaglobulinaemia and infections rather than on efficacy? If we go this route then there is only one agent we can use and that is teriflunomide, which is licensed to treat MS. As teriflunomide is coming off patent there is a chance the  NHS may be interesting in funding such a trial; i.e. it would save them money. This is something I need to explore (another task for my expanding ToDo list). 

The good news is that Roche has bought into, and run, with the principle of the DODO study and announced at MSVirtual2020 two high-dose ocrelizumab trials (see below). These trials up the stakes in the anti-CD20 wars and I am confident that we need higher doses upfront to purge deep tissue and possibly CNS pools of B-cells. Please note that you don’t need higher doses of anti-CD20 therapy to suppress relapses and focal MRI activity you can do that with current or lower doses. I am confident both these studies will show that higher-dose ocrelizumab is superior to standard dose ocrelizumab on disability progression or smouldering MS, but not on focal inflammatory events. In relation to the latter, we have hit the ceiling already.

You need higher doses up-front to target the drivers of smouldering MS; i.e. disease progression independent of relapses, accelerated brain volume loss, slowly expanding lesions (SELs) and the subpial cortical lesions.  If these higher-dose studies are positive it will put clear daylight between ocrelizumab and the other anti-CD20 therapies and it would mean the ofatumumab and rituximab are currently being underdosed, at least initially in the first two years. 

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.

33 comments

  • Dear Dr G.

    English is not my native language.

    I’m on Ocrelizumab. Last march 27th I was scheduled for my 4th dose. But because of Covid my neurologist and I decided that it was safer for me to postpone that dose.

    We did a 4 week bloodtest to see if Ocrelizumab started to become less efective.

    March b-cells <0.001
    April b-cells 0.008
    May b-cells 0.014
    June b-cells 0.022

    June 6th I had my dose of Ocrelizumab 2.5 months after the initial date. Actualy if it was up to me I wanted to postpone even longer with this data, but my neuro team insisted that I took my dose in June.

    So instead of 6 months I had my dose after 8.5 months and looking at the data it could even be longer to my opinion.

    I hope this info is of use for your team.

    I have one question. What is the difference between CD19 and CD20?

    Best regards
    Roger

    • Dear Rogier
      Your English is perfect.
      CD19 = CD20 + some pre B cells and some plasmablasts so it is present on a greater range of B cells than CD20, but you dont look for CD20 because the CD20 sight could be blocked by the ocrelizumab and so it would seem like the cell was not there, but it would be seen by the CD19 antibody. I think the B cells returning are not ones causing MS, but your story further supoorts that in most people it is OK to delay dosing. I am convinced that 6 monthly dosing is more often than most people require, but that is the approved dosing schedule. We needs a proper study to show this but thanks for your info

  • A pathogenic and clonal expanded B cell transcriptome in active MS. Ramesh et al PNAS August 28, 2020.

    re CSF and blood, ‘B cell subsets were sorted directly into lysis buffer, Naive B cell subsets (N;CD19+IgD+CD27-_), Unswitched memory B cells (USM;CD19+IgD+CD27+), switched memory B Cells (SM:CD19+IgD-CD27+), double-negativeBcells (DN:CD19+IgD-CD27-), CSF plasma/blast/plasma cells (CD19+IgD-CD27hiCD38hi) and blood plasma blast/cells
    ……representing classic B cell subsets………..

    Tested for viral transcripts……

    No human virus transcripts, including EBV transcripts, were detected…….despite detecting EBV transcripts in positive controls.

    We did not find evidence that CNS B cells harbour neurotropic virus.

    • I know about this if you watched the journal club you can see I asked ProfG to address this…..However just because the cell does not have EBV in it does not mean that their mother, gran mothers or great great grand mothers were not infected with EBV.

      • Wow! A classical example of the special pleading that, for me, seriously questions the fundamental hypothesis that EBV is the B cell driver of the inflammatory mechanisms of MS.

  • “In reality, if I could convince a national funding agency, a pharma company or wealthy philanthropist I would…”

    No idea why you need so much money to do this…Pender started with a 10 subject study and
    1 million from MS Australia.

    Question remains is why Rituximab has been trialed since year 2000…and no-one tested this because all they were looking at was MRI machines and not at all their patients who were
    converting to secondary progressive…anyone looking at to the natural history studies could see the disability came not from initial relapses/lesions but all the b cell follicles
    that accumulated in the brain over the next 20-30 years…Not sure this will stop that process as the mab molecule is too large to get into the brain to go after the b cells that do get in the brain.

    • Anoymose Re
      ‘…Not sure this will stop that process as the mab molecule is too large to get into the brain to go after the b cells that do get in the brain’

      🤔 It seems like if dose is high enough then yes they do? No, I don’t understand it either…

      And what allows B cells through in the first place?

          • I understand their, and indeed any drug maker’s concern given that for licensing you’ll need phase III evidence, and with the likely add-on effect of drug II being relatively small compared to drug I, sample sizes will – as you stated above – be substantial. Conditional license based on phase II data would change the game. Are there examples from other diseases?

          • … but if they would be on board, would you do the same trial with cladribine (double dose cladribine, that is)?
            Maybe you don’t need Clad double dose at all and just look at the subset of ppl on Cladribine that depleted more than the average and just see if they do better over years than those that depleted less. No new trial needed.

          • Not sure about cladribine as it is CNS penetrant and gets into the spaces antibodies don’t. What is important is to allow B-cell reconstitution to occur on a background that inhibits EBV.

  • This is a really interesting proposal, but long term famciclovir results in diarrhoea which settles a few days after stopping it and restarts 24 hours after trying again. There are manufacturing problems with Valaciclovir, so that’s hard to obtain. I read a study that healthy volunteers would need to take Valaciclovir 1g od for 16 years to purge EBV completely, but by definition pwMS don’t have a healthy immune system, otherwise the EBV would not have caused MS like 99.9% of people with EBV. Do you think the use of anti-CD20s would reduce the time antivirals are needed? Are there any other suitable antivirals that don’t rely on thymidine kinase inhibition?

      • Prof. G – I continue to struggle with how to test the effectiveness of this approach? I agree with you 100%; however, are the end points the same as with all approaches…i.e. relatively stable EDSS, no flair ups or new lesions?!? There has to be a better way to determine the efficacy of a particular treatment approach. I know you and your team share the same frustrations. Would the following factors provide any insights: Gray matter changes? CNS Nfl? CNS t/b-cell levels? Circulating t/b-cell levels? Losing EVB tiers? I probably already know the answer to my question, given what I read on this blog. Thank you for sharing your insights.

        • Yes, we can use all those biomarkers. But to get this strategy registered as a therapeutic option you have to have a clinical outcome. Therein lies the problem.

          • If any of those markers was validated, could it be used as a predictor/surrogate for clinical outcomes? Some biomarkers would probably change earlier than the clinical observations become evident. If so biomarkers would be able to shorten the clinical trials duration. If this is accepted, it would turn into shorter trials, faster drug approvals, lower drug cost for pharma and finally lower prices for patients.

  • Dear Prof, can i just test my understanding of your hypothesis. You talk about high dose over a 2 year period but presumably, if someone who has just started Ocrevus (me!) were to maintain the current approved dosing and switch to the higher dose later (i.e. if the results of the DODO trial are found to be positive) then this would yield the same rewards, albeit further down the line and with MS smouldering away longer than it may need to if you were to participate in the trial?

    I know this sounds a bit selfish….. sitting back whilst other trialists take the risks. However, in my defense, i am only 4 weeks past my first 2 half doses and have felt rubbish ever since. I actually think i am starting a relapse right now so im not convinced that Ocrevus agrees with me!

    Either way….i hope that you’re proved to be correct!

    • I too felt awful after my first two half doses. Horribly fatigued, no energy whatsoever – lasted over a month, then started to improve. Speaking to other Ocrelizumabers, some of us do feel like that. The first full dose wasn’t as bad, in my experience. Hope you start to feel better soon.

      • Thanks Hannah. I have heard similar stories on the Facebook group and wasn’t too worried about my post infusion ‘flare ups’. The fact that they subsided and then have now returned is more worrying but I guess it takes time for those B cells to deplete…..here’s hoping

    • Similar question — what about someone who is several years into rituximab

      Will a higher dose at this stage have the same effect?

  • Food for thought…
    1. Could a similar line of reasoning also put some perspective on the long-term use of DMF?
    2. “The hypothesis is to allow B-cell reconstitution after anti-CD20 therapy in the presence of ant-viral agent to prevent EBV reactivation and reinfection of new memory B cells. By doing this you will be derisking the long-term immunosuppression associated with anti-CD20 therapies and you should prevent the development of hypogammaglobulinaemia.” Similarly, would you expect EBV reactivation to become more likely after long-term use of DMF?

  • Prof G,

    The MS patient in the future will have a minefield of options to work through:

    Induction approach
    Maintenance approach
    Induction / maintenance approach

    If ocrelizumab double-dosing is successful, they will need to select a maintenance therapy (you list quite a few options). What if a remyelination therapy shows benefit. Will the patient add this to the list of therapies they want to have? The patient will end up like a modern day Oliver – please sir (neuro) can I have some more! The funding body (NHS) won’t be too happy. We could have an MS supermarket where MSers select some strong dose ocrelizumab, 3 years of HAART drugs and a mega pack of metformin!

    And I can’t see why Roche wants to sell less of an expensive drug ie only two doses of ocrelizumab rather than a dose every six months…..

    Please bear in mind that the thing all patients want is not to become more disabled ie to stop progression. If DoDo does this (or pretty much does this) then all the other c.20 anti-relapse drugs will have had their day. You may end up being even more unpopular with your MS colleagues! But a hero to the hundreds of thousands of MSers who just want stability in their lives. Good luck.

    • I think the angle is right, the rationale is correct but maybe the means are flawed…I agree we need to wipe off the B cells and the learning they had in the past, in an aggressive and effective manner (maybe include cd19 in the discussion) and probably keep them calmed in their future education…. maybe a small dose of anti – cd20 or cladribine would do this in the future after an atomic induction …I like Teri but my female patients hate it because of the hair problems or pregnancy issues….

  • Where does this leave those of us who are already past the first two years? I´ve had 7 doses and am a light weight- 110-115 pounds (not kg:)). For a person that size, could the regular dose fall into the category of induction?

  • I think this is 100% the right approach. Clear pathogenic immune cells as efficiently as possible and follow up directly with anti ebv drugs to stop reinfection and break the cycle.

    I really hope you’ll get your funding somehow. What do you estimate a study like this costs?

  • Dear Prof G

    You mention 2 years of higher dose. Does the 2 year timeframe have any specific reason behind it?

    Can I guess that 1 year for someone of a BMI 22 on a normal dose will not have the effect you mention?

  • Dr G et all..
    where the heck the EBV infection sits, if it gets reactivated even 4 years after AHSCT (CTX-ATG)?
    I thought that I have caught the EBV again, so tested the levels to find out that I still do have high IgG (171U/ml) and low IgM ( <10).
    Does it means that chemotherapy hasn't cleaned the B memory cells from acquired immunity, but also from infection itself?

    • Great question Mike. Thank you for sharing.

      Prof G. – I wonder if the use of a DMT with anti-viral aspects would help after AHSCT? If EVB was able to get onto the surface of repopulating t/b-cells, even after aggressive chemotherapy, this would suggest the need to use anti-vitals after depleting the immune system. Seems like testing for EVB before and after depleting might be beneficial?? Add Teri to the mix and see if it keeps EVB away.

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