Important new data are expected this year on the efficacy and safety of Bruton’s tyrosine kinase (BTK) inhibitors, a new class of disease-modifying therapies in development for multiple sclerosis.

These agents block the BTK enzyme expressed by B cells and myeloid cells in the periphery and the CNS. They are oral small molecules that cross the blood-brain barrier, reducing the activation of B cells, macrophages/microglia, dendritic cells and mast cells. Pre-clinical studies showed that BTK inhibitors blocked B cell maturation, lowered the release of pro-inflammatory cytokines, and reduced leptomeningeal inflammation (Bhargava et al. Brain 2021;144:1396-1408). Individual second-generation BTK inhibitors in development for MS differ with respect to their binding (covalent [e.g. tolebrutinib] vs. non-covalent [e.g. fenebrutinib]), selectivity (fenebrutinib > evobrutinib), off-target binding (tolebrutinib > remibrutinib), time to dissociation (slowest with fenebrutinib), pharmacokinetics/pharmacodynamics and drug concentration in the CNS (Airas et al. Ther Adv Neurol Disord 2024;17:17562864241233041).

The following is a list of trials that are expected to present or publish data in 2026.

Tolebrutinib: The phase III GEMINI 1 and 2 trials in RMS failed to show that tolebrutinib was superior to teriflunomide with respect to annualized relapse rate (ARR) (Oh et al. N Engl J Med 2025;392:1893-1904). The results recalled those from the evolutionRMS1/2 trials of evobrutinib, which was no better than teriflunomide in reducing ARR (Montalban et al. Lancet Neurol 2024;23:1119-1132). Evobrutinib was first in class, but its unfavourable benefit-risk profile ended its development.

The results from the HERCULES trial in non-relapsing SPMS were more promising (Fox et al. N Engl J Med 2025;392:1883-1892). The rate of 6-month confirmed disability progression (CDP) was lower with tolebrutinib compared to placebo (22.6% vs. 30.7%) at a median 133 weeks. There was one death due to liver complications in the tolebrutinib group. In December, it was announced that tolebrutinib failed to delay 6-month CDP versus placebo in PPMS patients in the phase III PERSEUS study. Dr. Robert Fox, Cleveland Clinic, is scheduled to present the PERSEUS data at this year’s ACTRIMS Forum in February.

Also anticipated: further discussions with the FDA about the fate of tolebrutinib. Sanofi submitted a new drug application for tolebrutinib for non-relapsing SPMS but was rejected by the FDA in December. The drug is approved for nrSPMS in the United Arab Emirates and is in review with the European Union.

Fenebrutinib: The phase II FENopta study demonstrated efficacy versus placebo with respect to new Gd+ lesions; 96% of patients were relapse-free during the 48-week extension (Bar-Or et al. Lancet Neurol 2025;24:656-666). Positive results have been announced for the FENhance 2 trial comparing fenebrutinib with teriflunomide in RMS. Expect the full results to be presented/published this year. Data from FENhance 1, a second phase III trial in RMS, are expected later in the year and may be available at ECTRIMS.

Of particular interest is the FENtrepid study, which has reported that fenebrutinib was non-inferior to ocrelizumab in slowing disability progression in PPMS. Fenebrutinib was reportedly numerically superior after week 24. The primary endpoint was time to onset of composite 12-week CDP. Ten Canadian sites were involved. Dr. Amit Bar-Or, University of Pennsylvania, is scheduled to present efficacy and safety data at this year’s ACTRIMS Forum in February.

Remibrutinib: No studies have been published in MS. The REMODEL I and II trials comparing remibrutinib with teriflunomide in RMS were announced (Wiendl et al. Mult Scler Relat Disord 2023;80: abstract 1129), and the trials are scheduled to be completed in April. The REMASTER trial in SPMS is still recruiting.

Orelabrutinib: Favourable results from a phase II dose-ranging study were announced at ACTRIMS Forum 2025, which showed a reduction in new Gd+ lesions with orelabrutinib versus placebo at weeks 12 and 24 (Xu et al. ACTRIMS Forum 2025; abstract P094). Further details may be presented this year. A phase III trial in PPMS is reportedly recruiting. The FDA has also recommended a second phase III trial in SPMS.

BIIB091: This compound is being investigated in the phase II FUSION study as monotherapy or in combination with diroximel fumarate in RMS. Recruitment is ongoing.