Should we abandon the ADIOS study?

S

Barts-MS rose-tinted-odometer: ★★★

If you have been on ocrelizumab for two years would you be prepared to participate in the ADIOS (adaptive dosing ocrelizumab study)? One of the study arms would mean that you would not receive any ocrelizumab until you had a relapse or new MRI activity. In other words, we would be using ocrelizumab like we use alemtuzumab or cladribine, i.e. as an immune reconstitution therapy (IRT). 

Some of our colleagues doubt whether people with MS would volunteer for such a study. I personally think they being affected by their own preconceived biases. We don’t know if we can use ocrelizumab or other anti-CD20 therapies as an IRT, which means we have equipoise. It is clear that using anti-CD20 therapy in this way will be safer, i.e. you would be less likely to develop hypogammaglobulinaemia and infections as a complication of continuous therapy. Similarly, the risk of secondary malignancies should be lower and you will be vaccine ready. The latest paper below shows that the time from the last dose of an anti-CD20 therapy predicts seroconversion after a COVID-19 vaccination; i.e. the longer you wait after a dose of rituximab, and probably ocrelizumab, the more likely you are to seroconvert after having the COVID-19 vaccine. I suspect going forward people on anti-CDC20 therapy may have to take drug holidays anyway to make sure they respond to vaccines. In fact, I was on a Medscape recording yesterday with a colleague from UCSF and a vaccinologist and they both said that most MSologists and rheumatologists in North America are already doing this. At the moment I have been saying get #GetVaccinatedASAP and cross the vaccine-readiness bridge when the boosters arrive. We will also have evidence, such as below, to guide us in the future.

Deepak P et al. Glucocorticoids and B Cell Depleting Agents Substantially Impair Immunogenicity of mRNA Vaccines to SARS-CoV-2. MedRxiv https://doi.org/10.1101/2021.04.05.21254656.

The following data from Anat Achiron will hopefully be out as a pre-publication this week.

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Disclaimer: Please note that the opinions expressed in this blog post are those of Professor Giovannoni and do not necessarily reflect the position of the Barts and The London School of Medicine and Dentistry nor Barts Health NHS Trust.

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Prof G

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

26 comments

  • How would you convince an ethics committee? This will be a tricky one.

    The concerning part that stands out to me is “retreatment if relapse” – a relapse could be very debilitating and not something I would personally want to risk.

    Also, how is there equipoise if it has already been proven that Ocrelizumab is effective every 6 months?

    I’m assuming it is only RRMS patients that would be enrolled?

    Final question, what would happen to participants on the IRT arm once the trial ends? Back to 6 monthly infusions?

    Also, blunted vaccine response would not convince me to do the trial. A blunted vaccine response is better than no response and we will eventually move to a stage of herd immunity once most of the country is vaccinated.

    • You need to study how cladribine became an IRT to understand the logic. I don’t think there will be a problem with ethics. Outside of MS clinicians are using rituximab like an IRT.

      • I’m not sure if I buy into cladribine being a treat-only-once therapy. There is enough anecdotal evidence floating around social media indicating that people get disease activity after 4-5 years if they don’t take some sort of maintenance therapy. I’m very concerned, and surprised, that Merck has not come up with guidance yet on both re-treatment and maintenance therapy options. The downsides with IRTs is that it is kinda like going untreated; the strategy is basically just waiting for more end organ damage. As a minimum a plan for maintenance therapy should be offered. Unfortunately the options would be crappy and dangerous drugs, such as Aubagio or Tecfidera giving most people side effects which lowers QoL significantly, or Gilenya etc which results in risks of huge relapses if having to change treatments.

        Come on Merck!!!

          • Of course they fail. The question is how and when, so that strategies for re-treatment or alt. theraphies can be planned for and started, BEFORE any more brain damage occur.

    • Data…There is rituximab and the data from the covid-induced delay with ocrelizumab and data of 18 months post treatment in the phase II extension study based on a large group of people

  • I would do this. After 4 years of Ocrevus infusions, I’m getting more and more infusion reactions (specifically, a surge in heart rate the evening after my infusion). Add that to vaccine stress, and I’d be happy to come off of Ocrevus under the close supervision of a clinical trial.

  • Hi. I’m in the US so cannot help with the study. But I am happy to give you my experience. However, I’ve been saying this is how Ocrevus should be used since 6 months in to receiving it. I received my 1st Ocrevus 2part infusion in mid July 2019. January 2020, I became severely ill w/respiratory infection, started to feel better for a couple days & then my daughter who was in & out if Nursing home for her Clinical for school and in & out of gymnasiums for her wrestling tournaments, caught Flu Virus type A & within a couple days, I had it. So my 6 month Ocrevus infusion was delayed a bit after that. My bloodwork was drawn at time of infusion. My CD19 showed ∅. I was shocked! Did I really need the Ocrevus so soon? And soon after started w/pre-cancerous skin spots having to be removed, felt horrible, a lot of hair fall, took me quite a long time to even feel human again. It’s hard to explain but I felt something wasn’t right… Like the Ocrevus was toxic to me. Come July 2020 when it was time for my next infusion, I declined. I couldn’t go back on other meds due to side effects, other health issues being a contraindication, etc. So my bloodwork was drawn to see where I was at end of July 2020. It had been 6 months. My bw showed zero CD19 again. I felt like I was being overdosed on the Ocrevus. Last med I took was the Ocrevus end of Jan 2020. Just had my bw done again March 2021 & my cd19 is finally coming up. It is now a low normal. No relapses but I don’t have relapses. I’ve just become slowly more disabled. I was also tested negative for Covid antibodies & now awaiting to get the Covid Vaccine which will either be Moderna, Pfizer or J&J (we don’t have a choice, we have to take what they offer) after my 2nd vaccine dose, I can get tested a month later to see my protection. I can also report back for your study if I’ve had any relapses & any further treatments albeit Ocrevus or another.

  • I think the point is: how do we say you can be off and safe? Is there any marker of this? Should we develop first markers and then do the trial?
    Personally, I would not feel safe to come off the treatment without a way to predict disease activity and recurrence before damage happens. When damage happens it would be too late. I think there should be several indicators beside MRI combined together and some of them must track immune system and brain damage.

      • When MRI detects something it’s late.
        NFL are an option… but if the goal is to monitor for relapses then I would check CD19+ CD27+.
        If the goal is to go to remission then these tests are not sufficient and we need something else. I think more on monitoring NFL, CD4/CD8 ratio, OCB (invasive!), SEL, and microglia activity by PET if the Finnish study will be successful. I think that then we have a composite panel that could tell us what ous going on.
        Also, on ocrelizumab as far as I know, CD4/Cd8 ratio does not go back to normal.

  • I was on ocrelizumab for 2 years. I opted to stop taking it to prepare to get a covid vaccine, so it has been about 13 months since my last dose. I tested B cells in October or so to make sure they were still very low. I’ve now had one dose of moderna, and in another 6 weeks I will start on kesimpta.

    But here is the thing, by the time I had an mri and MS was diagnosed I was already clearly very progressive. I have advancing disability, which continued on ocrelizumab, and I have an MRI full of confluent lesions and black holes, but my MRI is pretty much exactly the same as it was before my first dose of ocrevus. I have never had a relapse. So did ocrelizumab reconstitute things for me? I’d be happy to join such a study, but I have no evidence ocrelizumab did anything for me, or that such a study would actually connect with my MS. I don’t like being on a therapy that compromises my immune system, I don’t like risking more accelerated disability, but I also have no evidence that ocrelizumab is doing anything because my mri was already stable when I started it and my disease still progresses.

  • Something I’ve always wondered Prof G and team… is the hypogammaglobulinaemia permanent once it is detected? Or will it require IVIG to replenish?

  • Why put so much effort into B cell therapy when we know its not effective as Alemtuzumab or HSCt, when there’s breakthrough disease activity while taking thesr therapies. Meaning it does not stop brain atrophy and when inflammation is reduced to zero. Why is research going around in circles? Ocrelizumab and other B cell therapies only address part of the MS problem. Just recently machine learning has discovered 3 new subtypes of MS. Why hasn’t this been reported on this blog? Dare I say it when Machine learning and AI become self aware, are these new form life going to experience the same prejuidices experienced by ethnic minorities ?

  • Bring back MD! Ocrelizumab might blunt vaccine response but MD was blunt because he obviously cares about the people and is frustrated at the bureaucracy of MS research. I am offended by the number of Vit D and face mask trials rather than his post’s title.

    • That there Steve, you hit the nail on the head! MD is very honest and blunt. That’s what peaked my interest in this blog in the 1st place. I could always come on hear for honest updates on these meds & other research & that my MS friends is what we really need. If I wanted people to pat me on the back & tell me everything is going to be okay because they have new meds out there now that work great, I can go ask the masses of people out in the world watching the annoying MS drug commercials NOT showing people the truth of MS progression & disability (no one gets that not everyone can take all of the meds, or that they “may” help with no guarantees or that they do some serious damage by trading one health issue for another). So I for one would rather read MDs blunt blogs that speak to us with the same frustration that we live with every day. Isn’t honesty actually refreshing. MD please bring your brilliance, your honesty, and your will to question science for the greater good back here.

      • I completely agree. Although I didn’t read the post in question, I strongly doubt it was intended to offend. The fact that Mouse Doctor has devoted so much of his time to this blog demonstrates that he truly cares about PwMS. He’s also willing to call out the garbage studies that are being published (not unique to MS). I find his posts refreshing.

  • The proposed study has equipoise and the data generated will be important as more and more PwMS choose treatment with ocrelizumab. I fear the biggest barrier to recruitment will be the physician not the patient.

  • Roche came up with the 6 monthly dosing schedule for ocrelizumab to improve their profits, not for scientific reasons. Pharmacological science always needs to be considered in the context of profits.

    • Jimmy Hill I agree. But I also know that they had to come up with some type of dosing schedule to get approval. But many can take up to years for their B-cells to come back up so to me it would make sense for Drs to draw blood at 6 months and determine if they can put off the next infusion longer to keep side effects to a minimum. Look at my experience with Ocrevus above in comments. Maybe I’m not the norm as my MS & disability is progressed & I’ve also had T1d (Type 1 diabetes) another autoimmune disease for 41yrs of my life since early teen. Look at Tysabri.. it started off as an infusion every 4 weeks. Now they are doing many at every 6 weeks without issue in an effort to curb jcv levels rising & PML.

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