Derisking anti-CD20: the ADIOS-IM study

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Barts-MS rose-tinted-odometer: ★★★★★ (a London Grey day #666677)

Can we use an anti-CD20 therapy as an immune constitution therapy (IRT), i.e. 2 years of treatment followed by no treatment unless there is EIDA (evidence of inflammatory disease activity)? This strategy is not new to the field of MS; this is how we use alemtuzumab, cladribine and AHSCT. So why not with ocrelizumab, ofatumumab or rituximab?

The anti-CD20-IRT question really needs an answer. However, many of my colleagues are nervous about not treating pwMS continuously and would therefore prefer to use adaptive dosing of anti-CD20s based on B-cell, or memory B-cell, reconstitution. This is why we proposed doing the ADIOS study (adaptive ocrelizumab dosing study) in 2019 and were in the process of getting this study designed and funded prior to COVID-19. 

However, since COVID-19 and the introduction of COVID-19 vaccines have spotlighted the long-term safety signals associated with continuous anti-CD20 therapy and their associated poor vaccine responses we now want to redesign the study. We now want the study to be focused on safety and to add another arm to test using anti-CD20 therapy as induction therapy for 2 years and then following it with a derisking strategy using one of the licensed immunomodulatory or low-risk maintenance therapies, i.e. interferon-beta, glatiramer acetate, teriflunomide or dimethyl fumarate (DMF). This is the so-called IM or induction-maintenance arm.

The proposed primary outcome will be serious Infections, which are those requiring hospitalisation. Secondary outcomes will include the development of hypogammaglobulinaemia, antibiotic and antiviral drug usage as a surrogate for infections, vaccine responses, days off work and healthcare utilisation. With regard to efficacy, we propose assessing change in T2-lesion volume or number and relapses for inflammation and brain volume change and disability progression as end-organ damage markers. 

This study will need to be pragmatic and run through a registry, for example, the UK’s OPTIMISE pharmacovigilance platform. We also propose doing some nested or add-on studies in cohorts to do specific vaccine, biomarker, immunology and virology studies. These add-on studies will provide more data on each of the arms being used in the ADIOS-IM study.

Some questions for any readers who are anti-CD20 therapies. Would you volunteer to participate in this study? If there are any HCPs reading this post do you think we have clinical equipoise to do this study or have you already adopted one or more of these strategies to derisk anti-CD20 therapy already in your clinical practice? 

Another potential advantage of this study, apart from making your MS treatment safer, is the potential cost-saving in the long term for the NHS or your health insurance provider.

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General Disclaimer: Please note that the opinions expressed here are those of Professor Giovannoni and do not necessarily reflect the positions of the Barts and The London School of Medicine and Dentistry nor Barts Health NHS Trust and are not meant to be interpreted as personal clinical advice.

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.

29 comments

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  • Being honest, i would not be falling over myself to participate in this study. When looking at clinical trials the main goal of patients (i expect) is to try and improve their own outcome / situation. This study carries more risk than benefit in my view and is more likely to be met with a ‘I will see how it pans out for others’ attitude. Sorry, i know that sounds selfish but i expect it is the reality for most. With so many DMT options on the table now, the option of an untested IRT doesn’t seem all that appealing

    • Aaaand this is way many clinical trials are flooded with poor people, often with several other health issues and lifestyle problems. Meaning the results cannot necessarily be generalized to an average population group. On the bright side, it does provide poor people with access to DMTs they otherwise would not get a hold of (particularly in the US).

      Personally I would much rather see a trial which found a good (effective and safe) IRT/maintenance drug combo which includes the DMTs already classified as IRTs. Take cladribine for example, the effect seems to wear off over time, for a significant amount of people. However there is no strategy for how to tackle this, and prevent disease activity from happening. Should more courses of cladribine be given after the 4 year treatment period? Or is there another maintenance drug which for most, say 90% of patients, keep disease activity at bay? What are the different routes to chose between?

      There are enough pwMS on both alzemtuzemab and cladribine (and HSCT for that matter) which experience disease activity after a while, for me to «hope for the best» and not do nothing.

      I cannot believe why this is not more of a topic!!!

      • Sadly for cladribine there was no follow up because the trial was stopped.for.alemtuzumab you get extra doses 3 cycles blockbrelapses for.most people

  • “Not another study proposal?”

    I was thinking the same thing – DoDo, DILDO, FIDO, MUMBO-JUMBO…. Do any of them make it to the finish line (or start line)?

    Under Myers-Briggs you wouldn’t be classified as a “completer finisher”.

    Please focus on a small number of doable studies (preferably anti-viral) and deliver some results!

    • Dear Anon
      You sound.like SID, dlido indeed. I have just had meeting with profG about this, he does think it the output is that bad

  • I would be willing to participate in this. However, I’m struggling to get treated with Ocrevus in the first place.

    Given the risks of long-term immunosuppression I don’t really want to be on it longer than is necessary so had hoped that after a few years, assuming no disease activity, I would be able to discuss stopping treatment or switching to one of the less risky DMTs. Whether that would be agreed to or nowt I don’t know.

    There must be many people who have started on anti-CD20 and have stopped for lifestyle reasons, particularly with Covid. Is there information on how these people have fared?

    • Dear Anon
      You sound.like SID, dlido indeed. I have just had meeting with profG about this, he does think it the output is that bad

  • One can’t argue with the statistics, but I find it hard to mentally accept all this talk of derisking Anti-CD20

    Because my experience with Anti-CD20 has been almost entirely positive.
    And the Covid-19 vaccine has worked

  • Can you explain how the IRT arm would achieve equipoise?

    As patient, I *might* go for continuous 6 month dosis vs IRT with maintenance RCT but I really doubt I’d be willing to ocr IRT without maintenance.

    Would most likely depend on my eligibility for a switch to alemtuzumab or cladribine, too.

  • I have been on Ocrelizumab for 2 years and I work in a school. I would be interested in taking part in a study like this. Being permanently immunosuppressed during a pandemic has hugely increased my anxiety, I wear a mask every day now (FFP3) to work to try to just get on with things. I didn’t factor in a global pandemic when choosing my DMT and I feel there is now a whole other side of things to consider. I realise everything is a balance of risks both with MS and Covid but if things can be carefully managed rather than blindly infusing on a 6 month basis it sounds like an interesting option to explore.

  • I was on Ocrevus for almost two years. The prescribed dosing was to aggressive for my immune system, my lymphocytes never were able to recover between doses and by the end of my time on Ocrevus, they had dropped dangerously low. I’ve been off Ocrevus for almost nine months and I’m back on Glatiramer Acetate after being on it for 19 years before starting Ocrevus. So I guess, in effect, I am participating in the described trial. Given my immune reaction to Ocrevus, COVID and my lack of antibody response after two Moderna doses in March, my doctor and I felt like this was a sound approach. The nice thing about Ocrevus is that I can always go back on it down the road if my situation warrants. As an immunosuppressed individual in the US, I am eligible and received a third dose of the Moderna vaccine. I have not yet mustered up the nerve to get another antibody test. We will see how things work out.

  • Have done and would continue anti-cd20 therapy in IRT style, but not on schedule or means of administration you outline. My rationale is based upon the possibility that MS is caused by an infectious agent taking up residence in primarily CNS b-cells (much like the hypothetical recently and in 2012 discussed on this blog). The aim is to knock down/out the infection and retreat once it seems it may have re-established itself. Hopefully the immune system will better manage the suspected infection between cycles. First and second rounds are separated by 5 years (a number based upon observation of mean time period in anecdotal reports of if/when HSCT fails). The protocol is 4 weekly rounds of iv and it rituxan, similar to how resistant EBV-related CNS PTLD has successfully been treated. I’m 8 years in w no noticeable progression, some improvement, minimal MRI activity (after 5 years), BUT significantly higher number of OCBs. I believe some OCBs may be reactive towards elements of the rituxan itself, not just more of my brain widgets (spinal fluid collected in second week of second round). Would love it if an actual scientific study would be done w iv/it anti cd20 for RRMS. Would be a bit pleased with an IRT study too.

  • I like the idea of an IRT (Cladribine) followed by a mild daily anti-viral with a good safety profile (Valaciclovir).

    Honestly, I would prefer another pulse of Cladribine, if needed, but the manufacturer has yet to get off their bums and conduct a safety trial. No need for a placebo arm, just give a third round and monitor for safety/efficacy. Oh well, waiting for the next relapse or lesion is how all the DMTs are assessed for switching, so making that a risk unique to CLAD would be a bit flawed. One would think the positive Covid vaccine response data associated with CLAD would be good motivation for EMD Serono to get this trial done.

    My DMT history has been a bit abnormal, as I started with three full cycles of OCR (2yrs), followed by TERI (6 months), and then CLAD.

  • I would be happy to be in this trial. I’m on ocrelizumab and spend most of my time wishing I wasn’t! It may have stopped my relapses in their tracks (I only ever had one) but it has affected my work (healthcare) and general confidence all due to covid. So bloody typical it’s the worst one to be on for a vaccine response too 🙁

    I delayed it once for my vaccines last year and now I am delaying it again for my booster. I haven’t decided how long for yet.

    Question – I had an antibody response post two vaccine doses, if I now have a booster and am only approx 4-5 months post-ocrelizumab, will it make any difference? Am I less likely to get a response anyway, or is it more likely if I have some antibodies there from before? Thanks

    • If you have response you are more likely to boost it I suspect However if you can monitor your CD19 levels it may give you a clue, once they start to increase you can make a response. 5% of people have 1% Bcells at 6 months
      50% at 9 months 90% at 12 months based on phase II data, 2% is less come and 3 % less common

  • I suspect I would get excluded as I switched to ocrelizumab with low lymphocytes after DMF (although they are still low now). In principle, I think it would have been of interest to take part as it’s important to have the research to try and de risk the treatment. But the thought of being in the arm that switches to a needles based maintenance treatment would have put me off. I like ocrevus (before covid) as it was nice to ditch the twice daily reminder of having MS when taking pills.

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