The take on BTK inhibitors: AAN 2021 has the answers

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The scientific sessions at AAN 2021 were pretty devoid of exciting new developments (not surprising given COVID19), but did present updates on the use of BTK (Bruton’s Tyrosine Kinase) inhibitors in multiple sclerosis (MS).

For those of you who hearing this term for the first time today, BTK inhibitors target both B cells in the periphery and resident microglia in the brain (see slide below). They are currently the only serious contender for Ocrelizumab, and may soon usurp it as we heard in the programme at AAN. BTK inhibitors are CNS penetrant, are of high efficacy in reducing MRI enhancing lesions and the appearance of new MS lesions, and have a favourable side effect profile.

Slide: Function of Bruton’s Tyrosine Kinase (BTK) inhibitors presented by Ross C Gruber, AAN 2021

The BTK inhibitors that were presented in the programme were Evobrutinib, Tolebrutinib and Fenebrutinib. The BTK inhibitor that I am most familiar with coming into contact with haem-oncology patients is Ibrutinib used in the treatment of B-cell cancers – commonly CLL (although even in these circles it’s considered somewhat old-fashioned). The current BTK inhibitors in trial are the newer generation and I would accept that many of the rarer but serious side effects described, such as atrial fibrillation and bleeding may are sample specific and related to the cancer population. But for the same reason, we have yet to work out the safety profile BTK inhibitors in MS patients.

My thoughts on potential side effects of BTK inhibitors to consider in MS are as follows:

  1. Reversible versus irreversible BTK inhibitors: conformational changes in BTK determine function, inhibitors that form reversible covalent bonds with BTK and temporarily inactivate have fewer off-target side effects. Similarly, a targeted effect is more important as there are multiple structurally related kinases and may again lead to unwanted off-target side effects.
  2. The main functional effect as far as B cells and microglia are concerned is the homing of these cells to factors in the tissue microenvironment. The problem related to the MS tissue microenvironment persists regardless of BTK inhibition and when the drug is stopped it will restart again.
  3. There may be differential effects on naive B cells versus memory B cells. In the presentation by Marvin Van Luijn in an in vitro model of naive and memory B-cell differentiation Evobrutinib addition was associated with differences in IgG secretion. Increased IgG was noted in the naive B cell cultures as class switching was inhibited, but not plasmablasts leading to a rise in IgG, whereas in the memory B cell cultures there was reduction in plasmablast formation leading to a reduction in IgG (see below).
Slide: Evobrutinib suppresses naive B cell class switching, but interferes with the transformation of memory B cells to IgG+ ASC (antibody secreting cell) formation; presented by Marvin Van Luijn

Disclaimer: Please note that the opinions expressed here are those of the author NDG and do not reflect the positions of the Barts and The London School of Medicine and Dentistry nor Barts Health NHS Trust or Queen Mary University of London.

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Neuro Doc Gnanapavan

15 comments

Leave a Reply to Fabio Cancel reply

  • Thank you for this update.
    2. Should we expect rebound?
    Was any proof of microglia inhibition shown? I have read elsewhere it inhibits microglia but I could not come across a biological proof.

    • It depends whether it’s targeting the naive pool (probably not) or memory pool (yes). The two may cancel out, but I’m some individuals there will be an effect.

  • Is there any evidence so far that BTK inhibitors maybe slowing disability progression independent of relapses?

    Are they having and impact on EDSS scores or is it to early to tell?

    • Too early the outcome measures in the Phase II studies are MRI based, the Phase III studies will be more informative.

  • I’m assuming this will be at the highest drug tier in terms of efficiency if it works? What can we expect for side effects?

  • How do you think BTK inhibitors (i.e. Tolebrutinib or Imbruvica) will fare in AQP4(-) MOG patients/trials versus IL-6 monoclonal antibodies (e.g. satralizumab)?

    • The data suggest about 25% of absorbed cladribine gets into the CNS. Circumstantial evidence suggests some pwMS lose their oligo-clonal bands as a result. We’re looking into this further in our CLADRIPLAS project, which is going to report in 2023. Don’t think there is any comparative data with BTK inhibitors.

      • Thanks boss. Speaking as an ignoramus who’s been excluded from the Sizomus trial for its own safety – which I do understand really matters – and conscious of progression progressing without allopathic intervention, I am looking yearningly at cladribine.

        The data showing its efficacy in treating SPMS is pretty plain – but pwMS inhabit a pathology which is to a weird degree the fanciful invention of US health insurers (PP/RR/SP/excuse me?) rather than doctors or pharmacists. All seems a bit bassackwards.

        Anyway, thank you good doctors for fighting good fights – very much appreciated. Very best wishes for 22

        • Thanks, and a Happy 2022 to you too. Our cladribine protocol is in the public domain, you ‘only’ need to identify a doctor to evaluate and then administer it to you.

          • Thanks really very much. Haven’t seen my prof for some years but will get a registrar’s attention after 2 years soonish and that sounds like a very interesting conversation to have.

            Shalom-22

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