Citation: Krämer J, et al. Bruton tyrosine kinase inhibitors for multiple sclerosis. Nat Rev Neurol. 2023 May;19(5):289-304. doi: 10.1038/s41582-023-00800-7. PMID: 37055617; PMCID: PMC10100639.

This review provides an overview of Burton tyrosine kinase (BTK) discovery, role of BTK signaling in immune system and evidence of BTK involvement in multiple sclerosis (MS), current BTK inhibitors (BTKi) in MS trials, and a summary of safety and efficacy data from two completed phase 2 trials, evobrutinib tolebrutinib.

• BTK is an intracellular signaling molecule in B cells and most other hematopoietic cell lineages including monocytes, macrophages, microglia, mast cells and neutrophils) except for natural killer cells and fully differentiated plasma cells.
• BTK is crucial for B cell maturation and development, from pre-B cell to immature B cells, and has role in signaling in B cells, macrophages, and microglia
• BTK signaling pathways also communicate will Toll-receptor pathways, and signaling network connecting to innate immunity including mast cells and basophils.

EVIDENCE OF ROLE OF BTK IN MS

• Memory B cells isolated from RRMS or SPMS patients had a higher ratio of phosphorylated BTK to unmodified BTK protein
• The levels of BTK-positive cells were higher at the rim of lesions in SPMS brain autopsy
• Higher staining of BTK protein in the microglia and increased concentration of BTK CD68 cells in the lesions were seen in SPMS brain tissues
• BTK mRNA levels were higher in PPMS and SPMS lesions
• Higher BTK mRNA enrichment and BTK activation signature was seen in patient-derived microglia

ADVANTAGES OF BTK INHIBITORS OVER CD20 MONOCLONAL ANTIBODIES

• BTKi are CNS-penetrant versus anti-CD20 mabs such as ocrelizumab, rituximab, ofatumumab which have poor CNS penetration. CNS-compartmentalized B cells which are now considered main drivers of MS pathophysiology, are not affected by anti-CD20 therapies.
• Oral dosing versus infusions or injections
• Unlike anti-CD20 therapies that deplete B cells, BTKi alters B cells function, preserving viability and survival.
• Evobrutinib BTKi has been shown to promotes apoptosis of activated macrophages. Fenebrutinib BTKi was shown to reduce microglial activation in mice.
• New evidence suggests that BTKi may have potential benefit on tissue protection and repair:

In a mouse model of cortical demyelination induced by administration of recombinant antibodies derived from patients with MS and human complement components, pretreatment with the tolebrutinib-like compound PRN2675 inhibited myelin degradation and the migration of microglia to sites of demyelination and also prevented the loss of myelin and oligodendrocytes.

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BTK INHIBITORS IN PHASE 2 OR 3 MS TRIALS

• 5 BTKi currently in phase 2 or phase 3 MS trials are

Evobrutinib (M2951), Merck KGaA (10.1021/acs.jmedchem.9b00794)

Tolebrutinib (SAR442168), Sanofi

Fenebrutinib (GDC–0853 and RG7845), Genentech

Remibrutinib (LOU064), Novartis

Orelabrutinib (SAR442168), InnoCare Pharma and Biogen

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• All except fenebrutinib bind irreversibly to BTK (cysteine 481 residue in the ATP-binding site of BTK), ie, covalent irreversible binding. Fenebrutinib binds non-covalently and weakly (ie, reversible binding) to a specific pocket in the SH3 domain. Theoretically, covalent binding may allow higher potency, lower dose and/or frequency, but may also increase safety challenge due to potential immunogenicity of drug-receptor conjugate.
• All 5 BTKi have differences in MW, kinase sensitivity, IC50, and PK parameters including AUC, peak serum concentration, time to reach maximum concentration, and half-life. Thus, safety profiles are expected to vary in phase 3 trials and real-world setting.
• Preliminary data also shows differences in CNS penetrance: Tolebrutinib shows increased CNS penetrance, higher potency and faster reaction rates of BTK inhibition compared with both evobrutinib and fenebrutinib
• Toxicity profile depends on off-target effects (ie, kinase selectivity) and unwanted on-target effects (BTK inhibition in non-target cells). The five second-generation BTKi in MS trials have better kinase receptor selectivity than first generation (eg, ibrutinib) introduced in oncology. Of note, tolebrutinib has lower selectivity for BTK than either fenebrutinib or orelabrutinib.

PUBLISHED TRIALS ON BTK INHIBITORS IN MS

• Phase 2 trial for evobrutinib in RRMS or SPMS (Montalban, 2019)
• Phase 2b trial for tolebrutinib in RRMS and relapsing SPMS (Reich, 2021)