BTK inhibitors for relapsing & Progressive MS

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The next major class of agents coming your way if the trials are positive and the liver issues are acceptable (I believe this is a drug-class effect) . Read this review about the drugs in development.

I was going to do a review of these but this has surfaced

Geladaris A, Torke S, Weber MS. Bruton’s Tyrosine Kinase Inhibitors in Multiple Sclerosis: Pioneering the Path Towards Treatment of Progression? CNS Drugs. 2022 Sep 30. doi: 10.1007/s40263-022-00951-z.

n multiple sclerosis (MS) persisting disability can derive from acute relapses or, alternatively, from slow and steady deterioration, termed chronic progression. Emerging data suggest that the latter process occurs largely independent from relapse activity or development of new central nervous system (CNS) inflammatory lesions. Pathophysiologically, acute relapses develop as a consequence of de novo CNS infiltration of immune cells, while MS progression appears to be driven by a CNS-trapped inflammatory circuit between CNS-established hematopoietic cells as well as CNS-resident cells, such as microglia, astrocytes, and oligodendrocytes. Within the last decades, powerful therapies have been developed to control relapse activity in MS. All of these agents were primarily designed to systemically target the peripheral immune system and/or to prevent CNS infiltration of immune cells. Based on the above described dichotomy of MS pathophysiology, it is understandable that these agents only exert minor effects on progression and that novel targets within the CNS have to be utilized to control MS progression independent of relapse activity. In this regard, one promising strategy may be the inhibition of the enzyme Bruton’s tyrosine kinase (BTK), which is centrally involved in the activation of B cells as well as myeloid cells, such as macrophages and microglia. In this review, we discuss where and to what extent BTK is involved in the immunological and molecular cascades driving MS progression. We furthermore summarize all mechanistic, preclinical, and clinical data on the various BTK inhibitors (evobrutinib, tolebrutinib, fenebrutinib, remibrutinib, orelabrutinib, BIIB091) that are currently in development for treatment of MS, with a particular focus on the potential ability of either drug to control MS progression.

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MouseDoctor

6 comments

  • Thank you. Is there any way to see the full paper for free? So many are behind paywall or via subscription only, of course.

  • If BTKi’s are not suitable for long-term use, and it doesnt deplete cells, what’s the benefit for pwMS already on CD20 therapies? Sure it gets in CNS then as soon as u get off the drug damage starts again?

    • They are used in cancer and are taken until side effects occur or there is disease breakthrough so there will be a history that we can learn about MS. I know they say that B cells don’t deplete but one has to ask is whether the repertoire is maintained, I would have to look for the answer. That may be the difference between cancer and MS The advantages over cd20 is brain penetration and macrophage inhibition.

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