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BTK Inhibitors in Multiple Sclerosis: Comparison, Evidence and Future Perspectives

Bruton's tyrosine kinase (BTK) inhibitors represent one of the most promising emerging therapeutic strategies in multiple sclerosis (MS). Unlike conventional disease-modifying therapies that mainly target peripheral lymphocytes, BTK inhibitors aim to modulate immune activation both in the periphery and within the central nervous system (CNS), potentially addressing mechanisms involved in disease progression.

1. What are BTK inhibitors and why are they relevant in MS?

Bruton's tyrosine kinase is a key intracellular signaling molecule involved in the activation of B cells and several cells of the innate immune system, including macrophages and microglia. In multiple sclerosis, these pathways contribute to chronic inflammation, tissue damage and neurodegeneration.

Most established MS therapies primarily suppress peripheral immune activity. However, with disease progression, inflammation becomes increasingly compartmentalized within the CNS. BTK inhibitors are designed to modulate immune signaling rather than completely deplete immune cells, and some compounds are capable of penetrating the blood–brain barrier.

2. Advantages and limitations of BTK inhibitors

Potential advantages

  • Oral administration (tablet therapy)
  • Functional modulation of immune cells rather than complete B-cell depletion
  • Potential effect on microglial activation within the CNS
  • Therapeutic relevance for progressive forms of MS
  • Possibly lower degree of long-term immunosuppression compared with monoclonal antibodies

Limitations and concerns

  • Class still under development; long-term efficacy remains under evaluation
  • Hepatic safety monitoring is required for several compounds
  • Not yet a replacement for high-efficacy therapies in highly active relapsing MS
  • Optimal sequencing with existing therapies is still being defined

3. Comparison: BTK inhibitors vs anti-CD20 vs anti-CD19 vs CAR-T therapy

Feature Anti-CD20 Anti-CD19 BTK inhibitors CAR-T
Main target CD20+ B cells Broader B-cell lineage BTK signaling pathways CD19+ B cells (via T cells)
Mechanism B-cell depletion Deeper B-cell depletion Immune modulation Immune system re-engineering
Impact on CNS inflammation Limited Limited Key therapeutic goal Indirect
Effect on relapses/MRI activity Very high High (expected) Moderate to high Potentially very high
Clinical status in MS Established standard Investigational Phase III / emerging Experimental

4. When might BTK inhibitors be considered?

  • Progressive MS with limited inflammatory activity on MRI
  • Ongoing disability progression despite good relapse control
  • Need to explore therapies beyond classical B-cell depletion
  • Participation in clinical trials

5. Key clinical trial results of major BTK inhibitors

Evobrutinib

Phase II studies demonstrated a reduction in MRI activity, but phase III trials did not show superiority over teriflunomide in reducing relapse rates. Liver enzyme elevations were observed, requiring close monitoring.

Tolebrutinib

Demonstrated dose-dependent MRI effects in relapsing MS and showed a reduction in confirmed disability progression in non-relapsing secondary progressive MS. Hepatic safety remains a critical consideration.

Fenebrutinib

A non-covalent BTK inhibitor with favorable MRI outcomes in phase II trials. Considered potentially more selective, with ongoing evaluation in late-phase studies.

Orelabrutinib

Early studies reported robust MRI lesion reduction in relapsing MS. Long-term clinical outcomes are still being investigated.

References

  1. Montalban X, Arnold DL, Weber MS, et al. Placebo-controlled trial of an oral BTK inhibitor in multiple sclerosis. New England Journal of Medicine. 2019;380:2406–2417. DOI: 10.1056/NEJMoa1901981
  2. Montalban X, Fox RJ, et al. Efficacy and safety of evobrutinib versus teriflunomide in relapsing multiple sclerosis (evolutionRMS 1 and 2). The Lancet Neurology. 2024. DOI: 10.1016/S1474-4422(24)00328-4
  3. Reich DS, Arnold DL, Vermersch P, et al. Tolebrutinib, a brain-penetrant BTK inhibitor, in relapsing multiple sclerosis: a phase 2b randomized trial. The Lancet Neurology. 2021;20(9):729–738. DOI: 10.1016/S1474-4422(21)00237-4
  4. Fox RJ, Miller DH, Phillips JT, et al. Tolebrutinib in nonrelapsing secondary progressive multiple sclerosis. New England Journal of Medicine. 2024. DOI: 10.1056/NEJMoa2415988
  5. Bar-Or A, Cree BAC, Fox RJ, et al. Fenebrutinib in relapsing multiple sclerosis: a randomized, double-blind, phase 2 study. The Lancet Neurology. 2025. DOI: 10.1016/S1474-4422(25)00174-7
  6. Weber MS, Hemmer B. Bruton’s tyrosine kinase inhibitors in multiple sclerosis: targeting peripheral and CNS-compartmentalized inflammation. Nature Reviews Neurology. 2023;19:417–431. DOI: 10.1038/s41582-023-00807-1
  7. Airas L, et al. Bruton tyrosine kinase inhibitors in multiple sclerosis: mechanisms of action and clinical evidence. Multiple Sclerosis Journal. 2024. DOI: 10.1177/17562864241233041
  8. Hauser SL, Bar-Or A, Comi G, et al. Ocrelizumab versus interferon beta-1a in relapsing multiple sclerosis. New England Journal of Medicine. 2017;376:221–234. DOI: 10.1056/NEJMoa1601277
  9. Montalban X, Hauser SL, Kappos L, et al. Ocrelizumab versus placebo in primary progressive multiple sclerosis. New England Journal of Medicine. 2017;376:209–220. DOI: 10.1056/NEJMoa1606468
  10. Hauser SL, Kappos L, Montalban X, et al. Ofatumumab versus teriflunomide in multiple sclerosis (ASCLEPIOS I and II). New England Journal of Medicine. 2020;383:546–557. DOI: 10.1056/NEJMoa1917246
  11. Mackensen A, Müller F, Mougiakakos D, et al. Anti-CD19 CAR T cell therapy for refractory autoimmune disease. New England Journal of Medicine. 2022;387:1186–1195. DOI: 10.1056/NEJMoa2207254
  12. Schett G, McInnes IB, Neurath MF. Reprogramming the immune system with CAR T cells in autoimmune disease. New England Journal of Medicine. 2023;388:185–187. DOI: 10.1056/NEJMc2300238
Medical disclaimer: This information is for educational purposes only and does not replace professional medical consultation. Treatment decisions in multiple sclerosis must be individualized.
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