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

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