How does BTK inhibitor works


I thought interesting, BTK as the new kid on the block should inhibit B cell activity and it should inhibit memory B cell activity. I saw the title and thought interesting and then saw the contents and its mouse EAE and at this point I sort of switched off. Because mice have different B cells and importantly it is a hard core T cell mediated disease in mice. Indeed it was shown by the company making the molecule that anti-CD20 did not inhibit the EAE model and the BTK inhibitor did and implied it was due to a microglia effect.

However this is forgotten and now it is working by B cells. Why do I say ugh when I see this in the beasties, because it shows it isn’t that great. Put fingolimod in this scenario and there would be nothing 0/12 with disease and the score is zero. Here we have essentialy all animals getting disease and the severity drops from 4 to 2.5. Look at the tissue and in the control you see lots of cells (top right) and nothing in BTK treated (Bottom right) problem this does not fit with the data on the left because the score is 2.5 and not 0 and so you would expect to see something. This is the problem when you can cherry pick your data

Then they show that BTK inhibitor blocks B cell function in mice and give preliminary data in humans. We know this is how these inhibitors work. They show that the BTK does not inhibit the number of B cells so it is going to be hard to support the memory cell hypothesis with this one, so maybe I will shut up on this one.

Inhibition of Bruton’s tyrosine kinase interferes with pathogenic B-cell development in inflammatory CNS demyelinating disease.Torke S, Pretzsch R, Häusler D, Haselmayer P, Grenningloh R, Boschert U, Brück W, Weber MS.Acta Neuropathol. 2020 Aug 6. doi: 10.1007/s00401-020-02204-z. Online ahead of print.

Anti-CD20-mediated B-cell depletion effectively reduces acute multiple sclerosis (MS) flares. Recent data shows that antibody-mediated extinction of B cells as a lasting immune suppression, harbors the risk of developing humoral deficiencies over time. Accordingly, more selective, durable and reversible B-cell-directed MS therapies are needed. We here tested inhibition of Bruton’s tyrosine kinase (BTK), an enzyme centrally involved in B-cell receptor signaling, as the most promising approach in this direction. Using mouse models of MS, we determined that evobrutinib, the first BTK inhibiting molecule being developed, dose-dependently inhibited antigen-triggered activation and maturation of B cells as well as their release of pro-inflammatory cytokines. Most importantly, evobrutinib treatment functionally impaired the capacity of B cells to act as antigen-presenting cells for the development of encephalitogenic T cells, resulting in a significantly reduced disease severity in mice. In contrast to anti-CD20, BTK inhibition silenced this key property of B cells in MS without impairing their frequency or functional integrity. In conjunction with a recent phase II trial reporting that evobrutinib is safe and effective in MS, our mechanistic data highlight therapeutic BTK inhibition as a landmark towards selectively interfering with MS-driving B-cell properties.

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  • I just wish there was a cure! I know I’m being daft and having RRMS I would love a cure, I could go back and be a ward sister in the NHS, which I was before MS appeared

    • Take alemtuzumab. Its may not work for everyone but does work for the majority. I know the risks can be scary but if you do your bloods regular they can be managed. Earlier you take it the more spectacular the results. Ok if the effect only last 10 years or even 7 years. By then pharma would come with more robust treatments to make ms patient life as normal as possible. Granted at a fortune that nhs will have to pay. But give up hope for a cure. Pharma has a complete strangle hold on all medical research. But you can live normally as long as you take treatment periodically, whats the difference between cure and treatment? Really alemtuzumab is the best of all evils and less risky then HSCT. I only preach what I am willing to do. 2 years my last infusion of alemtuzumab. Sometimes I forget I have ms for periods of weeks.

        • You can get alemtuzumab if you have highly active ms. Which means you still have relapses when you are on another dmt, such as tecfidera. You can request you neurologist to put you forward for the first fusion. That’s my understanding perhaps barts can clarify. It use to be first line therapy. Prof G raves about alemtuzumab and his a professor so must do what it says on the tin.

          • Ok thank u, it has been highly active and I was put on Tysabri after diagnosis in Dec 2017. Am still on Tysabri I’ll have a talk with my neurologist x

  • I have to say, a lot of the figures in this paper are not at all convincing. They appear to measure everything they can think of and find a few tiny differences that are supposedly statistically significant, but just look at Fig 3, which they claim shows “Evobrutinib reduces expression of activation markers on B and T cells.” Really? All those groups of dots are basically identical to the naked eye! Certainly nothing leaps off the page as dose-dependent (which they try to assert is because they’ve already saturated the BTK with the 3 mg/kg dose).

    In addition, the treatment regimen here is really a prophylactic regimen: the drug is administered 7 days before the MOG immunization. In humans, the drug would be given to people who already have MS — so why not test mice *after* inducing EAE? I can only assume they don’t want to know how bad *those* results would look.

    • “They don’t want to know how bad *those* results would look”…..:-). If you dont get that they probably do next to nothing in mice, you keep trying to shoehorn the results into someething you think is going to happen…End result…pants

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