Goalposts

G

We need to keep pushing the envelope and moving the goalposts in terms of our treatment targets in MS. 

As MS advances innate immune activation with microglial and astrocyte activation occurs. However, the latter may be adaptive in response to damage and hence a good thing, which is why I am sceptical about treatments aimed at targeting these cells in advanced MS. 

In comparison, B-cells and plasma cells are a different story. These cells are part of the adaptive immune system and are likely producing pathogenic, or damaging, antibodies. B cells and plasma cells set-up shop in the brain and spinal cords of MSers and churn out these heat-seeking missiles that are likely to be responsible for smouldering MS; i.e. the cortical lesions and the slowly expanding lesions or (SELs), which cause disease worsening even in those MSers who are NEDA (no relapses or no new or enhancing MRI lesions). The problem we have is that our current DMTs don’t appear to target these cells with the possible exception of cladribine that is a small molecule and gets into the brain and spinal cords of MSers.  Konrad Rejdak and colleagues in Poland have shown that about 50% of cladribine treated MSers lose their oligoclonal IgG bands (OCBs) from their CSF and that the patients who lose their OCBs tend to be stable compared to those who don’t lose their OCBs. We need to replicate these findings and supports our hypothesis to target CNS-resident plasma cells in MS.

Please note spinal fluid OCBs and immunoglobulin free light chains are at the bottom of our treat-2-target pyramid. This is our new goalposts.

This is why we are starting two studies in parallel, and want to start more studies with additional agents, to see if we can get rid of OCBs in MSers.

Our first study will look at oral cladribine’s effect on B-cell and plasma cell activity within the brain and spinal cords of MSers. Does cladribine reduce OCBs and immunoglobulin production? This study is called the “Oral Cladribine B-cell study” or CLAD B.

The following are the inclusions criteria for CLAD B:

  1. Patients with RRMS who are being treated with oral cladribine at Barts Health NHS Trust
  2. Patients must be willing and able to undergo lumbar punctures
  3. Patients who are OCB positive in their CSF (from previous diagnostic lumbar puncture) 

In our second study, we are testing a myeloma drug called Ixazomib in MS. Ixazomib is a second-generation proteasome inhibitor that works against malignant plasma cells. This study is called “Safety of targeting plasma cells in Multiple Sclerosis: A phase 1b randomised, double-blind, placebo-controlled trial” or SIZOMUS.

The following are the SIZOMUS inclusion criteria:

Each participant must meet all of the following inclusion criteria to be enrolled in the SIZOMUS study:

  1. Male and female patients 18 to 65 years old at screening.
  2. Must have a diagnosis of MS, and:
    1. Patients with RRMS must be on DMT
    2. Patients with progressive MS must not be on DMT
  3. Participants with RRMS must be on stable DMT (i.e. must not have had a relapse within 1 month prior to the screening visit)
  4. OCB positive CSF either from a previous CSF analysis or from the screening CSF analysis
  5. Patients must be willing and able to undergo lumbar punctures
  6. Agree to use of effective contraception

For those interested in proteasome inhibitors there is an emerging evidence base of them working in autoimmune diseases in general, in particular with the 1st-generation drug called Bortezomib

Do you think we are crazy? We have been working on getting these trials off the ground for over 3 years and the ideas, and hypotheses, underpinning these trials goes back more than 15 years. I originally wanted to do a thalidomide trial, targeting plasma cells, way back in 1997. However, I was advised against it by Professor W. Ian McDonald who thought it would be too risky. 

If you live in London, or the home counties, and are interested in participating in these trials, and you think you are eligible, let your HCP know and they can contact us.

Baker et al. Plasma cell and B cell-targeted treatments for use in advanced multiple sclerosis. Mult Scler Relat Disord. 2019 Jun 26;35:19-25

There is increasing evidence that agents that target peripheral B cells and in some instances plasma cells can exhibit marked effects on relapsing multiple sclerosis. In addition, B cells, including plasma cells, within the central nervous system compartment are likely to play an important role in disease progression in both relapsing and progressive MS. However, current B cell-targeting antibodies may not inhibit these, because of poor penetration into the central nervous system and often oligoclonal bands of immunoglobulin persist within the cerebrospinal fluid despite immunotherapy. Through targeting B cells and plasma cells in the CNS, it may be possible to obtain additional benefit above simple peripheral depletion of B cells. As such there are a number of inhibitors of B cell function and B cell depleting agents that have been developed for myeloma and B cell leukaemia and lymphoma, which could potentially be used off-label or as an experimental treatment for advanced (progressive) MS.

CoI: multiple

About the author

Gavin

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

39 comments

  • regarding lumbar punctures for CSF testing…is everyone who is diagnosed with MS supposed to have have one done, or evoked potential tests as well?
    thanks

      • “unlike grumpy people that we can name”

        What do you expect..? total confusion of this disease..
        Just read about 2 people turned away in u.s. for hsct…one had ms 20 years the other 30 years…both left the country…one went edss 6 to 1…the other edss 6 to 3….

        Same thread has …two rrms who had hsct and relapsed after 1-2 yrs….????…

  • sure I sent this before, but can’t see it…
    Is the lumbar puncture for CFS oligoclonal bands a standard MS test in UK? Are evoked potentials?
    thanks

      • I’ve had neither and been offered neither and was diagnosed in November last year.
        CSF can determine treatment options,…in what ways?

        ps…..ignore that dr dre codswallop—-nobody makes them read the blog!

        • In what way?.
          If you have high neurofilament it is an indictator of active inflammatory activityeven when you can’t spot it on MRI. Meaning you need a DMT.

          Not all neuros use this, but we offer it as a service that can be requested.

        • Dre. It’s like sparring.,..he/she cries like a baby if we push his/her buttons.
          If you dish it out you have to take it.

  • Re: “Do you think we are crazy?”

    Nah, brah… woefully running in circles like headless serpents, perhaps, but crazy sounds too exciting and adventurous for a bunch of journeymen ‘scientists’, who’ve probably done more to slow down progress than accelerate it.

    Only the most easy to please, not to mention intellectually incapacitated, of your readership will be buzzed about any of this insipid silly stuff.

    Stop with the toxifying crap old drugs, Don Giovannoni, and give these poor sufferers something groundbreaking, homeboy. Ain’t you sorta embarrassed by how little you’ve delivered in the decade of this waning blog of yours?

      • I was wondering what your view is on persistent OCBs in people who have undergone HSCT(or Alemtuzumab for that matter), and remained progression and otherwise disease free at 5+ years?

        • If you have persistent OCB then there is activity. It shows HSCT and altuzmab don’t deal with issues in the CNs

          • Interesting that their disease seems to stop otherwise, especially considering it occurs in other conditions not MS.

            I guess the longer term data will be revealing.

          • Have ask you time and again alemtuzumab been a protein its likely dont get into the brain

            How you explain alemtuzumab efficacy and disease free after 8 years?

          • ” It shows HSCT and altuzmab don’t deal with issues in the CNS”

            Yeah..and that’s the best we have.

            Only thing that does “sometimes” does is full myeloblative hsct.

          • From Joachim Burman’s PhD thesis out of Uppsala …”intrathecal antibody production can be demonstrated in a vast majority of MS patients. It has been claimed that
            oligoclonal IgG bands persist in the CSF of almost all patients, but in another study with a high intensity regimen 75% retained oligoclonal bands.143 In Swedish patients, only 69 % retained oligoclonal bands after a
            low-intermediate conditioning. This discrepancy may be due to that Swedish
            patients were on average treated earlier, most of them still in the relapsing remitting phase. The biological significance of these antibodies is not clear and for all we know they could be an epiphenomenon. It is well known that
            oligoclonal bands are present to variable degrees in other inflammatory CNS
            disease, not least in infection with B burgdorferi, when antibody
            production can persist for years after the infection has been cleared.

            The latter illustrates that is not necessary to lose the oligoclonal bands to
            allow us to speak of cure”…

            https://www.diva-portal.org/smash/get/diva2:714003/FULLTEXT01.pdf

          • “The biological significance of these antibodies is not clear and for all we know they could be an epiphenomenon. It is well known that
            oligoclonal bands are present to variable degrees in other inflammatory CNS
            disease, not least in infection with B burgdorferi, when antibody
            production can persist for years after the infection has been cleared.”

            EXACTLY

        • ” on persistent OCBs in people who have undergone HSCT(or Alemtuzumab for that matter), and remained progression and otherwise disease free at 5+ years?”

          Ever heard of “smoldering” ms..?

  • Congratulations on your trials! Like in poker, the Bart’s team seems “all in” and this will likely be a career defining moment for all involved.

    What are your endpoints in both progressive and RRMS patients respectively?

    Are you able to comment on your results thus far and as the trials go on with cladribine? It may influence one’s choice of medication, with the help of their neurologist. Many of us do not have not enough time to wait for completion and replication of your trials?

  • Agents that are currently approved for patients with MS have no or very limited bioavailability in the brain and spinal cord. In contrast, cyclophosphamide (CYC), an alkylating agent, penetrates the blood—brain barrier and CNS parenchyma well. Cyclophosphamide is used in HSCT and is the reason why OCB and NFL levels return to normal after the procedure. Personally I would like to have yearly lumbar puncture testing to see if my levels stay within normal range and if not immediately act upon it to prevent reoccurring ms and accumulating damage in my CNS to stay stable and wait for better treatment options in the near future. I would love to have a chat with Bart’s to see if we can expand these trials to Dutch ms research centers.

    • “Personally I would like to have yearly lumbar puncture testing to see if my levels stay within normal range and if not immediately act upon it to prevent reoccurring ms and accumulating damage..’

      Ok…but what would you do..go for cyclophosphamide again and redo hsct…

  • CSF examination
    The number of oligoclonal bands did not change in any
    patient. For the cladribine group, relative oligoclonal
    concentrations at baseline and at 6 months and 12 months
    averaged 29-9 (4-2), 26.5 (3-4), and 25-0 (3-3) a significant
    decline (Fg = 5-17, P < 0 -02). Corresponding values for the
    placebo group were 26-2 (3-8), 29-9 (3-8), and 29-9 (4-7), a
    modest but non-significant increase (Fg =181,p=0-18).
    Among the matched pairs, the placebo patients tended to
    have higher values than their counterparts on cladribine:
    The mean paired difference (placebo minus matched
    cladribine) in relative oligoclonal immunoglobulin
    concentrations at 6 months relative to baseline is 4-3 (2-0)
    (95% CI 0-1-8-5); at 12 months it was 7-3 (3-3) (95% CI
    0-5-14-1).

    Cladribine in treatment of chronic progressive multiple sclerosis

    https://www.sciencedirect.com/science/article/pii/S0140673694910464

    • If they have had HSCT aren’t people cured? Isn’t this what is being spun…and way I will let NDG answer but if there are oligoclonal bands there is immune activity.

      • Oligoclonal bands… what role does T cell help play? How do these helpers change after HSCT? Is the role of oligoclonal bands different after HSCT? The immunology of HSCT is SO INTERESTING! I moved to Sweden from NZ partly because the treatment options are so poor there. I am really starting to believe that newly diagnosed patients should be encouraged to undergo HSCT as soon as they get their heads around it(I mean it isn’t a walk in the park) but the fear of the unknown with other treatments and steady subsequent decline in function and slowly burning impending fear of doom is real. Especially in in the classic early-diagnosed 25-35 y/o otherwise healthy.

        P.S other autoimmune diseases also respond.

      • The closest thing to a cure right now is indeed HSCT. However it’s not a given hsct treated ms patients, like me, won’t go on and develop progressive disease, because of previous accumulated CNS damage. I opt for these patients to enter neuro protective trials as well.

        • Yes of course, HSCT is targetting the immune aspect of the disease primarily. But as with all treatment of EVERYTHING a silver bullet is an idealistic dream most of the time

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