AAN 2022 Impacting on the Real MS

A

ProfG has argued that Slowly Expanding Lesions are the indicators for progressive MS and that we need to target these to inhibit the “realMS”. At the centre of these lesions we have microglia and these could be inhibited by Brutons tyrsoine kinases which inhibit B cell and macrophage function

Douglas Arnold et al. Effects of Evobrutinib, a Bruton’s Tyrosine Kinase Inhibitor, on Slowly Expanding Lesions: An Emerging Imaging Marker of Chronic Tissue Loss in Multiple Sclerosis

Objective:To evaluate the effect of evobrutinib treatment versus comparator on SEL volume from baseline to Week 48 in a phase II trial.

Background:Slowly expanding lesions (SELs) are chronically active, demyelinated multiple sclerosis (MS) lesions, likely driven by sustained microglia/macrophage activity, resulting in irreversible neural tissue damage and axonal loss. Evobrutinib, a highly selective Bruton’s tyrosine kinase inhibitor (BTKi), targets B cells, macrophages, and microglia. In a phase II trial (NCT02975349) in patients with relapsing MS, evobrutinib 75mg twice-daily (BID) reduced T1 gadolinium-enhancing lesions (Week 24) vs placebo.

Design/Methods: SELs were identified, via MRI, as radially expanding areas of pre-existing T2 lesions of ≥10 contiguous voxels (size ~30mm3). Analysis of SEL volume, stratified by baseline T2 lesion volume tertiles, was based on Week 48/end-of-treatment values (completers + discontinuers); treatment effect was analyzed via stratified Hodges-Lehman estimate of distribution shift and stratified Wilcoxon rank sum test. Evobrutinib dose groups (25mg once-daily [QD], n=50; 75mg QD, n=51; 75mg BID, n=53) were compared with placebo/evobrutinib 25mg QD (n=53). Pooled groups (evobrutinib high doses [HD; 75mg QD and BID] vs low dose [LD; placebo and evobrutinib 25mg QD]) were used for subgroup analyses.

Results:Relative to the comparator,SEL volume decreased with increasing evobrutinib dose (25mg QD, -136.5mm3 [p=0.505]; 75mg QD, -246.0mm3 [p=0.192]; 75mg BID, -474.5mm3 [p=0.047]). SEL volume was significantly reduced for evobrutinib HD vs LD within the following subgroups: baseline EDSS ≥3.5 (-652.0mm3 [p=0.020]), relapsing-remitting MS (-317.0 mm3 [p=0.025]) and longer disease duration (≥8.5 years; -729.3mm3 [p=0.040]). Analysis of SEL volume as a percentage of baseline T2 lesion volume provided similar results.

Conclusions:Evobrutinib reduces SEL volume in a dose-dependent manner in relapsing MS and is especially apparent in more advanced disease. This is the first evidence that a BTKi impacts brain lesions associated with chronic inflammation and tissue loss, probably via microglia.

So targeting microglial may be a good thing. Evobrutinib is not the only drug being developed against this target

Ross Gruber et al. Evaluating the Effect of BTK Inhibitor Tolebrutinib in Human Tri-culture

Objective:Characterize pharmacological properties of the CNS-penetrant Bruton’s tyrosine kinase (BTK) inhibitor tolebrutinib in human neural cells by using a human tri-culture system.

Conclusions: We extend our previous findings on the role of BTK in microglia to show that BTK-dependent inflammatory signalling in human microglia and tri-cultures can be modulated using tolebrutinib in vitro.

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MouseDoctor

22 comments

  • MD – if lesions are caused by the peripheral response to whats going on in the CNS then how can SEL represent the real MS? without a peripheral response, there would not be lesions to slowly expand but there would still be something going on in the CNS

    • You got me….I didn’t bring up the “realMS” concept and not sure I buy into the idea, becuase the concept was generated on a false logic, thinking there s a two process disease….but the reason I mentioned it is because other people have when they want to focus on what is driving progressive MS as opposed to relapsing MS (A little joke)….I currently view it as a continum that one drives the other.

      • MD,

        Would it not be possible to develop half a dozen theoretical models of what MS is and then test them? EG:

        1. Virus (EBV) gets in the CNS, peripheral immune system responds, lesions formed, microglia / macrophages activation in response to damage caused by the lesion or continued presence of virus.

        2. As above but peripheral immune response leaves B cells / plasma cells in the CNS which secrete antibodies leading to continuing CNS immune response.

        The plan to test each theory would include:

        1. Anti-viral
        2. Anti microglia/ macrophage drug
        3. Anti B cell / anti plasma cell drug (which gets in CNS)

        Some of these trial are underway but don’t appear to be part of a coordinated research response more a “let’s try this and see what happens”

        • The problem is who pays of it and who does it.
          1. Give ProfG the drug and the cash and he will bite your arm off to do it
          2. There is anti-CSF-1 for microglia with drug made by an MS Company but without dealing with other immune elements I wonder
          3. Sizomus, cladribine

  • MD1,

    Many thanks for this. I’m sure they’ll be some bumps in the road with the BTK inhibitors, but targeting what’s causing unrelenting tissue loss (not just relapses) had to be the way forward.

    • it takes time forstuff to filter through and secondly it has to be presented in a way that people can see a link forexample years ago we and others showed that blocking sodium channels saved nerves….then it was shown that these block microglia, but becuase neuros dont do the right experiments in the studies this was never linked to SELS, so wewereway aheadof ourtime and perhaps too early forpeople to grasp the significances

  • Mouse,

    Are we anywhere nearer to understanding what causes the lesion? One theory is that it is caused by the infiltration of immune cells into the CNS. However, others have proposed that damage (a lesion) precedes the infiltration of immune cells which are just a response. Also, are all lesions SELs? I’m also not clear how EBV fits in given that it seems to have a critical role to play in either triggering or driving the disease. Sorry, one more question. If microglia are causing the damage in SELs how will the Sizomus trial help – I think the drug being trialled targets plasma cells (B cell lineage not microglia)?

    • I would argue that the view that infiltration is just a response is incorrect because if it was just a response then natalizumab that stops these cells arriving would not be beneficial…..and when people with PMLdie their brains should be a battle zone of whats causing MS.

      There are theories but until you stop MS by targeting the theory ……it remains a theory. Like T cells cause MS…where is the proof?

      “Also, are all lesions SELs?”
      Good question..hard to say histology lacks the “in time” element to see change and MRI lacks the resolution to know what it is really looking. SELS are another MRI concept not property tied to histological outcomes….they are like chronic active histological rims with a demyelinated core and a macrophage or microglia rich edge. They could be chronic active lesions, mixed active/inactive lesions, smouldering lesions

      “Detection of SELs uses calculated deformation fields to detect foci of gradual and concentric expansion within existing T2-lesions on serial MRI scans… MRI data do not support the proposition that SELs are a specific marker of PMS as traditionally defined clinically but rather indicate that they are a marker of progressive biology, which is increasingly appreciated to occur from the onset of MS throughout the disease course”.(Arnold et al 2021)

      I’m also not clear how EBV fits in given that it seems to have a critical role to play in either triggering or driving the disease.

      It depends on you view ofwhere EBV fits in you view it could have been there at the core of when the SEL formed or could have triggered the response that led to the core of the SEL

      Sorry, one more question. If microglia are causing the damage in SELs how will the Sizomus trial help – I think the drug being trialled targets plasma cells (B cell lineage not microglia)?

      I doubt it is just microglia in a SEL it could be macrophages too, ut you can ask what drives the hot microglia andone answer is the action of B cells and this may be antibodies…block those…inhibit SELS and MS

  • Please explain to me one thing: what is the relationship between SELs and grey matter atrophy? Does targeting the former impact the latter? Do we know if alemtuzumab target SELs at all?

    • It is bound to some how because white matter lesions impact on grey matter volumes….To answer your question. Stop axonal damage inwhite matter (SELS) limit neuronal damage in grey matter (cortical atrophy) remeber they are connected ina pathway.

      Slowly Expanding Lesions Predict 9-Year Multiple Sclerosis Disease Progression
      Preziosa et al. 2022, DOI: https://doi.org/10.1212/NXI.0000000000001139

      Explain ONE thing…so next do we know….it will stop them forming I suspect because how do we explain long term treatment benefit?….Does it target them directly…possibly to limited extent as not sure how much CD52 onmicroglial but the antibody is not going to enter the brain much

  • Hello readers,
    Now I understand that most pathology does not rely on one anomaly alone. It’s a combination of ‘inconveniences’ that causes the anomaly.
    This must be understood before effective treatment can be designed.
    Most anti-MS drugs address the consequences of MS, no one cures. Mostly the drugs retard progress, but this takes place clinically in almost all cases of MS.
    Of course the factors that contributes to pathology (hypo vit.D, HLA, et c) deferentially contribute to disease phenotype but in the end the cause of evil is localized viral-latency, facilitated by personal + environmental factors.
    Adequate treatment involves not the eradication of community spreading virus (not feasible), but the hindering of pathogenic-disease maintaining virus proteins. This by blocking the production of these proteins (siRNA or antisense) or by altering the biochemical functions (small molecules).

  • Hi MD,
    How does this effect compared to CD20? I remember you said SEL’s will eventually stop expanding on its own?
    Thanks!

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