Anti-CD20 vs. Teriflunomide

A

Barts-MS rose-tinted-odometer: ★★ (seeing blue)

When I state that the real MS is smouldering MS and that relapses and focal MRI activity are not the disease I really mean it. 

PwMS who are NEDA-2, without relapses and with no new MRI lesions, but getting worse must have something going on in their brains and spinal cords. This is why we need to go beyond NEIDA (no evidence of inflammatory disease activity) as a treatment target in MS and focus on protecting the end-organ so that pwMS can have enough reserve to cope with normal ageing when they get older.

One example or ugly fact to illustrate the disconnect between inflammation (relapses and focal MRI activity) and the end-organ (brain volume loss) is the recent ofatumumab vs. teriflunomide trials. 

Gd-enhancing lesions (↓~95%): Ofatumumab >>>> teriflunomide

New T-2 lesions (↓~83%): Ofatumumab >>> teriflunomide

Relapses (↓~55%): Ofatumumab >> teriflunomide

Disability progression (↓~33%): Ofatumumab > teriflunomide

Brain volume loss (↓~0%): Ofatumumab = teriflunomide

If ofatumumab is so much more effective as an anti-inflammatory than teriflunomide why doesn’t it protect the end-organ more than teriflunomide? I don’t know but is clear, at least to me, that there is something else going on that is driving the end-organ damage in MS that is not linked to focal inflammation. Could something about teriflunomide’s mode of action that is downstream of focal inflammation be telling us something fundamental about the cause of MS?

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Preventive Neurology

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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.

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.

24 comments

  • Maybe a silly question but is there a relationship between number and volume of lesions and BVL? For instance, would a patient with predominantly spinal disease be expected to have less brain atrophy? Or are these separate issues in your view

  • It will be interesting to see how my metrics progress after a course of Cladribine.

    By chance, I was able to get OCR first line. Had four treatment cycles, yet became “allergic” so I switched to Teri for eight months. Experienced some adverse side effects from Teri, so now I am staring year one of Clad.

    Obviously, the severity of my disease course justified the use of these DMTs; however, I am hopeful my DMT journey will be successful at addressing all aspects of my MS…..OCR did a good job with the initial inflammation in my brain/cervical spine, Teri has antiviral aspects so it possibly eliminated those nasty EBV cells, and Clad is very effective at penetrating the CNS and attacking MEMORY b-cells.

  • I completely agree with this study. Smouldering MS is the real villain. I have had 5 Ocrevus infusions. Although my MRI shows stability and no new lesions, I have consistently had a new set of symptoms for 15 months which my MS Nurse cannot explain and has not put in my records. Keep up the excellent work Prof G 👏👍👌

  • When people with MS display no MRI activity, but get worse physically, are they usually classed as secondary progressive?

  • Professor Gavin when is your famciclovir trial targeting ebv for ms expected to have the results ?

      • Are there any pharmaceutical companies interested in funding a trial targeting ebv within the next 12 months using other compounds ?

          • Only testing this in rrms…shows they lack confidence…how can you tell if it works unless you trial it on sp and pp as Atara is doing. If it works in progressive ms you can assume it works in rr.

          • Hi Prof G, I have read before that you think mS should be hit hard from diagnosis and ‘watching to wait and see’ is no longer the approach that should be taken.

            With this in mind I was confused why this would be the approach if the real MS was unaffected by DMT?

            And if DMT do not work with smouldering MS what would?

  • Why is cladribine being funded for progressive ms if it is not that effective for brain volume loss in the later stages after CIS ?

    • Due to CNS penetration. It is never too late to tackle MS. Please note in CIS BVL loss on cladribine was less than 0.2% p.a. It is therefore about timing.

  • “When I state that the real MS is smouldering MS and that relapses and focal MRI activity are not the disease I really mean it.” I thought you were joking🙂

    But what are the most promising drugs currently in trial which address the real MS rather than relapses / focal MRI activity? I’m talking drugs that would benefit a patient who has had MS for 10, 15 years.

    Which trials should such a patient sign up to? Octopus, SIZOMUS, the remyelination trial (metformin) at Cambridge? I’m guessing most of us buy into the smouldering MS position, but as patients want some direction on how to maximise our chances of reducing any more brain atrophy.

    If ebv is the culprit, I’m guessing an anti-viral might be the best weapon against smouldering MS. As a layman, I can’t really see how remyelination therapies address smouldering MS.

    • “I can’t really see how remyelination therapies address smouldering MS.”

      No.. remyelination is for repair only..unfortunately where there is the most disability is
      where the nerves are permanently damaged. But if there is no nerve..there is nothing to remyelinate. If someone is fine at 75 degrees but has heat sensitivity at 90 degrees then
      remyelinate could likely help in that situation.

      “If ebv is the culprit, I’m guessing an anti-viral might be the best weapon against smouldering MS.”

      Problem is there is no antiviral that can remove ebv from latent infected b cells…and
      neurologists are not really trained in virology. CD8+tcells is how healthy humans control
      and kill EBV cells…So for the past 25 years oncologists have been useing tcells to stop
      EBV cancers…google CD8+ t cells kill EBV…this is the only way for now.

      Prof G and Julian Gold tried antivirals with Raltegravir..and this is how that went down:
      https://pubmed.ncbi.nlm.nih.gov/29990894/

      “Maybe the most important reason for the failure of antivirals for infectious mononucleosis therapy can be ascribed to the fact that the symptoms and signs of the disease are not the consequences of viral replication but the immunological response to EBV-infected B-cells that circulate in the blood and infiltrate the tissues of different organs. ”

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6429425/

      • Re: “Problem is there is no antiviral that can remove ebv from latent infected b cells…and
        neurologists are not really trained in virology.”

        Not sure this is correct. EBNA-1 blockers may be able to do this so can HDAC inhibitors. We are thinking of getting these into MS as well.

      • Doing the tenofovir alafenamide trial in rrms is not from lack of confidence. We know their is a significant decrease of ms cases in the hiv population which also uses antiretrovirals. Furthermore we know from in vitro studies that they are potent against ebv and there were studies done that were looking at the viral load of ebv using some of these antiretrovirals in the hiv population and their was a 16 fold decrease of ebv viral load after 96 weeks. In essence it does seem to work against ebv. The longer the use of these antiretrovirals the greater the decrease of ebv viral load.

        Let’s say I will trust the Harvard Medical School ( the sponsor of this trial ) over this lack of confidence you expressed.

        • “I will trust the Harvard Medical School ( the sponsor of this trial )”..

          Why..? How many trials has Harvard pulled off that led to therapy..?
          Probably not enough to just reduce viral load.
          They should be testing this in sp and pp to see if they can reduce edss..and in 6 months you know if it works. What
          do they expect to achieve/learn with another rr trial..?

  • I want you to retitle this article:
    We don’t know.
    So as my old school Generic Copaxone Glatopa sits out to warm up,
    I am reading how even the new and improved immune modulators
    May not help our smoldering burn 🔥
    I see The Burn, can You?
    Thinking the protein soup I will inject might be the best bang for the $6,000 a month club.
    Maybe feeding my immune system is better than, or at least as good as,
    Trying to Tell my immune system how to behave.

  • “If ofatumumab is so much more effective as an anti-inflammatory than teriflunomide why doesn’t it protect the end-organ more than teriflunomide?”

    I thought Prof G said BVL is due to damage done few years back, so 2 years is too short to judge the efficacy of drugs on BVL. And I hope the ofatumumab vs Teri is not the reason why Teri is rated higher for long-term efficacy than CD20+s and S1Ps in the DMT selection tool (beta) 🙂

  • “the real MS is smouldering MS and that relapses and focal MRI activity are not the disease”

    Don’t think this is anything new with this..people have known from natural history studies that relapses weren’t resulting in long term disability but it was the progressive damage…and brain atrophy in spms
    that was at fault.

    Similarly no relapses and no mri lesions in ppms made some realize this was the real
    form of ms…take out relapses and inflammation and you get the real ms which is ppms. Spms can
    have some inflammation/lesions so it’s not quite the same. Solve ppms and you solve your smoldering ms.

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