The 1st anti-plasma cell drug in MS. What should you ask?

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SIZOMUS is a short name for “Safety of IxaZOmib targeting plasma cells in MUltiple Sclerosis”

I first became the study Clinical Research Fellow on the “SIZOMUS” clinical trail last year. Instantly my brain filled up with questions. I thought I’d go straight to the horse’s mouth for the answers and sought out the two lead study investigators – Prof Giovannoni (aka Prof G) and Dr Gnanapavan (aka Neuro Doc Gnanapavan). I’m sharing these with you below – I hope you like it!

I guess I’ve touched only the tip of the iceberg here and will have many more questions in the future. If you have any questions please comment below, and I will try to answer them or ask our two experts! It has been always been said that “The art and science of asking questions is the source of knowledge”

If you are interested in participation in the SIZOMUS study or would like to know more, please contact me:
Dr. Mohammad Abouwafa (Wafa), Clinical Research Fellow for SIZOMUS; mohammad.aboulwafaali@nhs.net

About the author

Dr Wafa

42 comments

  • Why is SIZOMUS only a phase I trial? Hasn’t the safety profile of ixazomib already been established? Why not go straight to phase II and cut down on the time it will take this treatment to get through the clinical trial pipeline?

    • One cannot make assumptions on safety when the populations have different immune backgrounds.

      Example: highly unlike but tempering plasma cells could cause MS worsening for mechanics we don’t fully understand.

    • I double on Karage’s comment.

      It is first to be trialed in MS and this is a different population than myeloma patients.

    • The sample size in the study is sufficient to be also considered a Phase II study 🙂

      • Out of curiosity, if this trial showed obviously good results in terms of slowing or stopping disability progression, do you think Takeda would proceed straight to phase 3?

  • Hi Dr Wafa, silly question, if we assume plasma cells are what to look for, would OCB-negative pwMS benefit from Ixazomib? Or a slightly different question, I see an updated CSF for enrolments for someone diagnosed few years ago is not required, why is that?

    • I would say this is a smart rather than a silly question really!

      For SIZOMUS we do require OCB postitivity for enrollment.

      I belive plasma cells are there weither OCB is present or not, but OCB would provide to us a potential objective treatment target.

    • Hi Karage,
      Patients with established MS generally develop OCBs over their disease course. I always think those who are still negative 10 years after MS diagnosis and not received treatment that can affect antibody production probably do not have MS!
      This is also why a historical result is acceptable at screening, but we do repeat the LP for OCBs at baseline for use in the study analysis.

      • Hi NDG and Dr Wafa,
        Thank you for replies!

        I was thinking on an article MD shared that some DMTs (OCR) may clear OCB for a portion of patients after few years, so a LP check would be necessary.

        On OCB-negative MS, I talk to Asian patients and clinicians. The OCB prevalence is nowhere near it can be seen with Caucasians, I understand that MS can be different to the populations (or even could be different diseases), really interested in the true reason behind the difference.

      • Firstly, thank you for your continued research into progressive MS!

        I was diagnosed 12 years, have never been on any treatment (long story) and my mobility is continuing to decline but I had a negative LP last year showing no OCB so I am very surprised by your comment above.

        Could you please give some advise as to what else you think it could be or whether I should seek a second opinion?

        Thanks you!

  • ixazomib is used for multiple myeloma. Are there any case studies of patients with MS who also got multiple myeloma and were treated with ixxazomib ie any indication that the treatment had any impact on their MS?

    If ixazomib was successful at getting rid of OCBs. what would this mean for an MS patient ie would it show that the smouldering MS has been put out as the antibodies produced by the plasma cells had stopped?

    If the slowly expanding lesions are stopped ie the microglia activity around the edge of the ring is stopped, what happens to the lesion? Will there be some remyelination of the lesion?

    • Hello Anon

      Very good questions!

      To my knowledge there is no case reports for use of Ixasomib in MS, but we should definitely keep an eye on that.

      Plasma cells are found in abundance around chronic lesions, it is compelling to know whether anti-plasma cells will shut down the smouldering process. It makes sense theoretically but needs to be proven at the end through clinical as well as pathological studies.
      Remyelination takes place as a natural recovery/repair process, but not for always, smoe chronic inactive lesions do not remyelinate and other myelinate partially.

      • Could a phase 2 trial start for this class of compounds within the next 2 years or will it take more time ?

  • Hello Dr Wafa, I may have misunderstood the question and answer from NDG on vaccines. I understood that under ixazomib there will be no impact on vaccination because there will be a memory b cell pool from which plasma cells can repopulate. People on Anti-CD20 may not see this because both memory and plasma cells pools will be under depletion. So I was wondering if you are going to track this in your study. If I think to my blood tests I would check VZV IgG (~500) and HBVs IgG (>1000) because of their values that could mark decreased response and the extent. In case there will be an impact will you suggest to vaccinate again?
    Another question, I remember the study was going through first safety committee review in may. I guess everything is fine and nothing new happened both in terms of side effects or disease activity/worsening. Please keep us posted, there is a lot of interest for this study.
    Thanks a lot!

    • We are checking VZV IgG prior to starting treatment and patients are being advised to vaccinate before commencing the study. Those who have had previous hepatitis exposure and TB exposure are naturally excluded from the trial.

    • Thank you Fabio and NDG!

      We had a trial steering comittee review in May as per our protocol. Steps are running forward smoothly. We are expecting to proceed with the next recruitment phase very soon.

      Thanks for your follow up 🙂

  • Please can you toughen up the cartoon showing ixazomib – it looks like something from the Bristol Stool Chart! We need more than poo to beat progressive MS!

    • I thought it was the famous Mr Hankey, Sid.
      According to some of the more credulous persuasion, poo is the answer to everything……………………….

    • Well from a design point of view, your opinion is absolutely valid! Me (and Tekeda as well) should consider this in future pill outline LOL.

      But from a scientific point of view, I disagree. Stool may really help MS

      HAVE A LOOK AT THIS
      https://clinicaltrials.gov/ct2/show/NCT03975413

      THANKS for your comment Anon and Mousedoctor…I laughed a alot. 😀

      EDIT: Sorry this is me Wafa, but this comment was from a log off view to the post. 🙂

        • “THANKS for your comment Anon and Mousedoctor…I laughed a alot. 😀”

          Remember that my jokes are free, MD2 is paid huge sums by the tax payer.

          I’ve put the MDs forward for the Fecal Microbiota Transplantation study. They will act as donors as most of their research churns out crap (only joking MD2).

          • “Remember that my jokes are free, MD2 is paid huge sums by the tax payer.”
            Not any more Sid (not joking).

            Personally, I’m looking forward to a visit to Sid’s, vinegar factory, sourness guaranteed for over 50 years 😉

  • Thanks for this post Mohammad, a bold new first and exciting phase 1 study of this drug in MS!

    Out of interest, first licensed in Europe 5 years ago in November 2016:

    https://www.ema.europa.eu/en/medicines/human/EPAR/ninlaro

    https://bnf.nice.org.uk/medicinal-forms/ixazomib.html

    Orphan drug, NHS cost around £6k per cycle from cancer budget, have Takeda donated it for trial?

    How many participants do you need? I’d volunteer now, but you’d laugh if you
    saw my blood counts 😉 hope you get a great response!

    Huge thanks to the trial team and all volunteers 🙂

    • Hi Annonie Mouse,

      Yes Takeda are donating the drug for free for this trial. It’s possible if the drug is effective in clearing the OCBs the dug will not need to be given again!
      There will be 76 participants in the total study (RRMS, SPMS and PPMS!).
      And thank you for your support 🙂

  • Between this, the anti cd20 + TAF trial and BTK-inhibitors it seems we finally have a few new approaches being tested.

    I wish you the best of luck – would sign up if I was in the US.

    • I’m sorry, but most of these responses are way over my head or not what I am closely following. But you mention signing up in the US, so can you point me in the direction of such a study(s) in the US so I can review? Who knows???

  • Dr. Wafa..you should have tested in this in other diseases concurrently RA and SS…lost opportunity.

    You are aware all these AI diseases are EBV controlled.

    “whether EBV-infected B cells and plasma cells in the CNS in MS are autoreactive, as are EBV-infected plasma cells in the target organs of rheumatoid arthritis77 and Sjögren’s syndrome;78”

    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5292561/

  • Dr. Wafa..you should have tested in this in other diseases concurrently RA and SS…a lost opportunity.

    You are aware all these AI diseases are EBV controlled..? So it it works in ms it should work in the others.

    “whether EBV-infected B cells and plasma cells in the CNS in MS are autoreactive, as are EBV-infected plasma cells in the target organs of rheumatoid arthritis77 and Sjögren’s syndrome;78”

    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5292561/

    “CD8+ T-cell deficiency is a feature of many chronic autoimmune diseases, including multiple sclerosis, rheumatoid arthritis, systemic lupus erythematosus, Sjögren’s syndrome, systemic sclerosis, dermatomyositis, primary biliary cirrhosis, primary sclerosing cholangitis, ulcerative colitis, Crohn’s disease, psoriasis, vitiligo, bullous pemphigoid, alopecia areata, idiopathic dilated cardiomyopathy, type 1 diabetes mellitus, Graves’ disease, Hashimoto’s thyroiditis, myasthenia gravis, IgA nephropathy, membranous nephropathy, and pernicious anaemia. It also occurs in healthy blood relatives of patients with autoimmune diseases, suggesting it is genetically determined. ”

    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3270541/

  • Hello – I am very keen to take part in this trial I have Primary Progressive MS – however I am 65 years old 66 in November – I know 65 is the cut off age – should I still apply ?

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