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Bruton's tyrosine kinase (BTK) inhibitors can no longer be viewed only as a distant experimental prospect. In 2026, one drug in the class — tolebrutinib — received European Union authorization for a defined group of patients with secondary progressive MS, while fenebrutinib and remibrutinib reported positive phase III results.
At the same time, outcomes differ substantially between individual drugs. It is therefore more accurate not to speak of a single “BTK class effect”, but to evaluate each molecule separately, together with the MS phenotype, trial endpoint and safety profile.
BTK is an intracellular signaling enzyme involved in activation of B lymphocytes and several innate immune cell populations. Some BTK inhibitors can cross the blood–brain barrier and influence immune cells within the central nervous system.
BTK participates in B-cell receptor signaling. BTK inhibition reduces pathological B-cell activation but, unlike anti-CD20 therapy, does not necessarily cause profound B-cell depletion.
BTK is also expressed in myeloid cells, including microglia. The class is therefore being studied as a possible way to influence chronic inflammation within the CNS.
Interest in BTK inhibition increased as understanding grew of progressive MS biology and disability accumulation without obvious relapses.
| Drug | Main evidence | MS phenotype | Status |
|---|---|---|---|
| Tolebrutinib Cenrifki | HERCULES: lower risk of confirmed disability progression in nrSPMS | SPMS without relapses | Approved in the EU |
| Fenebrutinib | FENhance 1/2: superiority to teriflunomide for relapse rate; FENtrepid: non-inferior to ocrelizumab for the primary PPMS endpoint | RMS and PPMS | Under regulatory review |
| Remibrutinib | REMODEL-1/2: positive phase III topline results for relapse rate and MRI activity | RMS | Investigational |
| Evobrutinib | Phase III trials did not show superiority to teriflunomide | RMS | Program did not confirm expected efficacy |
| Orelabrutinib | Marked MRI effect in earlier studies | RMS | Earlier stage of development |
The most important tolebrutinib trial was HERCULES in patients with secondary progressive MS without relapses. Tolebrutinib was compared with placebo, with disability accumulation as the principal focus.
The risk of 6-month confirmed disability progression was lower with tolebrutinib.
This proportion of participants reached the primary disability-progression endpoint.
This proportion of participants reached the same endpoint in the control group.
In June 2026, the European Commission approved Cenrifki (tolebrutinib) for adults with secondary progressive MS who had not experienced relapses during the previous two years.
For a person with nonrelapsing SPMS, the main problem is not frequent attacks but gradual accumulation of neurological disability. HERCULES is therefore important as an attempt to influence progression itself, rather than only classical inflammatory activity.
More about recognizing transition to progression: secondary progressive multiple sclerosis.
In the two GEMINI trials, tolebrutinib did not show superiority to teriflunomide for annualized relapse rate. This is an important example of why BTK inhibitors should not simply be viewed as “new powerful tablets against relapses”.
A pooled GEMINI analysis suggested a signal for 6-month confirmed disability worsening, but because of the statistical testing hierarchy this should not be interpreted as a separately proven formal advantage.
The PERSEUS study in primary progressive MS did not meet its primary endpoint. This again shows that even for the same drug, results depend on the clinical phenotype of MS.
Fenebrutinib differs from most other molecules in the class because it is a reversible, noncovalent BTK inhibitor. In 2026, results from three key phase III trials were presented.
Compared with teriflunomide, annualized relapse rate was reduced by 51.1% in FENhance 1 and by 58.5% in FENhance 2.
New active MRI lesions were also substantially reduced. Favorable trends were observed for progression measures, but the main conclusions from these studies relate primarily to control of relapsing inflammatory activity.
Fenebrutinib was compared not with placebo, but with ocrelizumab. The study met its primary objective of non-inferiority for 12-week composite confirmed disability progression.
The hazard ratio was 0.88 versus ocrelizumab; the risk was numerically 12% lower, but the study was designed primarily to demonstrate non-inferiority.
Fenebrutinib is not yet a routinely approved MS therapy. Its program has been submitted for regulatory review, and its eventual place in treatment will depend not only on efficacy but also on the final safety assessment.
On 1 September 2026, results from the two phase III REMODEL-1 and REMODEL-2 trials in relapsing MS were announced.
In both studies, remibrutinib significantly reduced annualized relapse rate compared with teriflunomide.
Superiority was reported for key secondary MRI measures of inflammatory disease activity.
The pooled analysis showed a favorable signal for confirmed disability progression, including a nominally significant result for 6-month CDP.
The preliminary company announcement did not identify the drug-induced liver-injury signal seen in some other BTK programs. Until the full dataset is available, however, this should not be considered a definitive comparative safety advantage.
Evobrutinib was one of the first BTK inhibitors to show a marked MRI effect in phase II. However, in the evolutionRMS 1 and 2 trials, it did not outperform teriflunomide on the primary clinical endpoint.
Liver safety was an additional limitation. This experience substantially changed how BTK inhibition is viewed as a class: CNS penetration and BTK suppression alone are not enough; selectivity, pharmacokinetics and the safety of each specific molecule also matter.
Ocrelizumab, ofatumumab and other treatments in this strategy strongly reduce peripheral B-cell activity and have well-established high efficacy against relapses and new MRI activity.
Their advantages include a large evidence base and a clearly defined place in modern MS treatment strategy.
They do not necessarily cause profound B-cell depletion and may potentially influence microglia and compartmentalized inflammation within the CNS.
The class is still heterogeneous: efficacy and risks differ substantially between individual molecules.
When new clinical or MRI activity appears, the first task is to establish whether the current treatment is truly providing insufficient control. More: when to switch treatment in multiple sclerosis.
Drug-induced liver injury is recognized as an important risk with tolebrutinib, so strict laboratory monitoring is required. Transaminase elevations have also been observed in some other BTK programs.
The degree of immune-system effect depends on the molecule and its selectivity. BTK inhibitors should not automatically be assumed to be less immunosuppressive or safer than monoclonal antibodies.
For new drugs, not only the first 1–2 years of trials matter, but also longer follow-up, rare adverse events and experience outside clinical trials.
This is the first approval of a BTK inhibitor in MS and an important confirmation that progression without relapses can be a separate therapeutic target.
Both drugs have reported positive phase III data against teriflunomide, but their final place among highly effective therapies will become clearer after regulatory review and further safety data.
FENtrepid demonstrated non-inferiority for the primary endpoint compared with ocrelizumab. This may be important for people with primary progressive MS, where disease-modifying treatment options remain limited.
The decision should consider MS activity, rate of progression, MRI, biomarkers, previous treatment and the individual risk profile. Modern biomarkers can complement this assessment but do not replace clinical judgment.
During consultation, MS phenotype and activity, MRI changes, signs of progression, previous therapy and individual risks can be reviewed together, followed by discussion of reasonable options for the next treatment strategy.
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