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  • Review Article
  • Published:

Bruton tyrosine kinase inhibitors for multiple sclerosis

Nature Reviews Neurology volume 19, pages 289–304 (2023)Cite this article

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Abstract

Current therapies for multiple sclerosis (MS) reduce both relapses and relapse-associated worsening of disability, which is assumed to be mainly associated with transient infiltration of peripheral immune cells into the central nervous system (CNS). However, approved therapies are less effective at slowing disability accumulation in patients with MS, in part owing to their lack of relevant effects on CNS-compartmentalized inflammation, which has been proposed to drive disability. Bruton tyrosine kinase (BTK) is an intracellular signalling molecule involved in the regulation of maturation, survival, migration and activation of B cells and microglia. As CNS-compartmentalized B cells and microglia are considered central to the immunopathogenesis of progressive MS, treatment with CNS-penetrant BTK inhibitors might curtail disease progression by targeting immune cells on both sides of the blood–brain barrier. Five BTK inhibitors that differ in selectivity, strength of inhibition, binding mechanisms and ability to modulate immune cells within the CNS are currently under investigation in clinical trials as a treatment for MS. This Review describes the role of BTK in various immune cells implicated in MS, provides an overview of preclinical data on BTK inhibitors and discusses the (largely preliminary) data from clinical trials.

Key points

  • Bruton tyrosine kinase (BTK) is an important intracellular signalling molecule involved in regulating the maturation, proliferation, survival and activation of B cells and myeloid cells.

  • BTK inhibitors might concurrently target adaptive and innate immune mechanisms in the periphery and central nervous system (CNS).

  • This ability makes BTK inhibitors a promising therapeutic approach for relapsing and progressive forms of multiple sclerosis (MS).

  • Preclinical studies show that BTK inhibition can suppress key pathological features of MS, including B cell activation, CNS lymphocyte infiltration, leptomeningeal inflammation, pro-inflammatory microglial activation and demyelination.

  • The efficacy and safety of five BTK inhibitors are currently being evaluated in clinical trials in patients with relapsing and progressive MS.

  • The BTK inhibitors under investigation in clinical trials differ in their selectivity, mode of binding, target occupancy, inhibitory potency and CNS penetrance.

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Fig. 1: Bruton tyrosine kinase signalling pathways in B cells, macrophages and microglia.
Fig. 2: Putative mechanism of action of Bruton tyrosine kinase inhibitors in multiple sclerosis.

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Acknowledgements

The research of authors is supported by the German Research Council (DFG) grants SFB-CRC TR128 A09 and SFB-CRC TR128 Z02 and funding from Deutsche Myasthenie Gesellschaft, all to H.W. Editorial and graphics assistance was provided by Elevate Scientific Solutions, a division of Envision Pharma Group, and funded by Sanofi. Writing assistance (assistance with drafting of the manuscript text and tables as directed by the authors, data checking and incorporation of comments from reviewers) was provided by R. J. Hogan and C. Underwood of Elevate Scientific Solutions.

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Authors and Affiliations

  1. Department of Neurology with Institute of Translational Neurology, University Hospital Münster, Münster, Germany

    Julia Krämer & Heinz Wiendl

  2. Center for Neuroinflammation and Neurotherapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA

    Amit Bar-Or

  3. Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA

    Amit Bar-Or

  4. Sanofi, Cambridge, MA, USA

    Timothy J. Turner

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J.K. and H.W. researched data for the article and J.K. wrote the first draft. All authors contributed substantially to discussions of the manuscript content, critically reviewed the drafts and approved the final version for submission.

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Correspondence to Heinz Wiendl.

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J.K. declares that she has received honoraria for lecturing from Biogen, Merck, Mylan, Novartis, Roche, Sanofi and Teva and has received financial research support from Amicus Therapeutics and Sanofi. A.B.-O. declares that he has received grant support to the University of Pennsylvania from Biogen Idec, EMD Serono, Novartis and Roche Genentech. He has participated as a speaker in meetings sponsored by and received consulting fees from Accure, Atara Biotherapeutics, Biogen, Bristol-Myers Squibb, GlaxoSmithKline, Gossamer, Janssen, Medimmune, EMD Serono, Novartis, Roche Genentech and Sanofi. T.J.T. is an employee of and may have ownership interests in Sanofi. H.W. declares that he has acted as a member of the Scientific Advisory Boards of Abbvie, Alexion, Argenx, Bristol Myers Squibb, Janssen, Merck and Novartis. He also declares that he has received speaker’s honoraria and travel support from Alexion, Biogen, Bristol-Myers Squibb, F. Hoffmann-La Roche, Genzyme, Merck, Neurodiem, Novartis, Roche, Teva and WebMD Global and acts as a paid consultant for Abbvie, Actelion, Argenx, Biogen, Bristol-Myers Squibb, EMD Serono, Fondazione Cariplo, Gossamer Bio, Idorsia, Immunic, Immunovant, Janssen, Lundbeck, Merck, NexGen, Novartis, PSI Contract Research Organization, Roche, Sanofi, UCB and Worldwide Clinical Trials. His research is funded by Alexion, Amicus Therapeutics, Argenx, Biogen, CSL Behring, F. Hoffmann-La Roche, Genzyme, Merck, Novartis, Roche and UCB.

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Krämer, J., Bar-Or, A., Turner, T.J. et al. Bruton tyrosine kinase inhibitors for multiple sclerosis. Nat Rev Neurol 19, 289–304 (2023). https://doi.org/10.1038/s41582-023-00800-7

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