BTK inhibitors in multiple sclerosis: Where do remibrutinib and fenebrutinib fit after MS Toronto 2026?

Phase 3 data presented at MSToronto2026 strengthen the case for oral, central nervous system-penetrant Bruton’s tyrosine kinase inhibition in multiple sclerosis. However, differences between individual agents, limited head-to-head data with high-efficacy therapies, and unanswered questions around long-term disability and safety will determine where they ultimately fit in clinical practice.

New phase 3 data for two investigational Bruton’s tyrosine kinase (BTK) inhibitors were among the most closely watched presentations at MSToronto2026, the 10th Joint Meeting of the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) and the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS), held in Toronto, Canada, on October 21–23, 2026.

Results from the phase 3 REMODEL-1 (NCT05147220) and REMODEL-2 (NCT05156281) trials showed that remibrutinib reduced relapse activity compared with teriflunomide in people with relapsing multiple sclerosis (RMS).^1,2 The results were presented as a late-breaking abstract and published simultaneously in The Lancet.

Fenebrutinib was represented by several phase 3 analyses. Pooled FENhance 1 (NCT04586010) and FENhance 2 (NCT04586023) data provided further evidence of efficacy in RMS, while a late-breaking analysis from FENhance and FENtrepid (NCT04544449) examined magnetic resonance imaging (MRI) markers associated with chronic active inflammation.^3–5

Together, the findings move BTK inhibition closer to the clinical treatment landscape, while raising an important question: if these agents are approved, where might they sit alongside established high-efficacy therapies, particularly anti-CD20 monoclonal antibodies?

Why target Bruton’s tyrosine kinase?

BTK is an intracellular signaling enzyme expressed in B cells and several myeloid-cell populations, including microglia. Unlike B-cell-depleting anti-CD20 therapies, BTK inhibitors modulate signaling within these cells rather than removing circulating B cells.⁶

The potential relevance to multiple sclerosis (MS) extends beyond peripheral inflammation. Some BTK inhibitors are sufficiently central nervous system (CNS) penetrant to potentially influence microglial and other immune activity behind the blood–brain barrier. This has generated interest in whether the class could affect both the acute inflammatory activity associated with relapses and compartmentalized inflammation thought to contribute to progressive disability.⁶

Importantly, BTK inhibitors are not interchangeable. Agents differ in binding mechanism, selectivity, CNS penetration, pharmacokinetics, and safety profiles, and these differences may translate into clinically meaningful variation in efficacy and tolerability.⁶

Remibrutinib: superiority to teriflunomide in relapsing multiple sclerosis

Remibrutinib is an oral, covalent, highly selective, CNS-penetrant BTK inhibitor. REMODEL-1 and REMODEL-2 were identical randomized, double-blind, double-dummy, event-driven phase 3 trials conducted at 407 centers in 46 countries.^1,2

Adults aged 18–55 years with RMS, an Expanded Disability Status Scale (EDSS) score of 0–5.5, and evidence of recent disease activity were randomized 1:1 to remibrutinib 100 mg twice daily or teriflunomide 14 mg once daily. In total, 2,007 participants were randomized: 1,000 in REMODEL-1 and 1,007 in REMODEL-2.¹

The primary endpoint was annualized relapse rate (ARR), and remibrutinib was superior to teriflunomide in both studies.¹

In REMODEL-1, ARR was 0.073 with remibrutinib compared with 0.112 with teriflunomide, corresponding to a 35.2% relative reduction (rate ratio [RR] 0.648; 95% confidence interval [CI] 0.453–0.927; p=0.018). In REMODEL-2, ARR was 0.080 and 0.116, respectively, representing a 31.2% relative reduction (RR 0.688; 95% CI 0.487–0.972; p=0.034).¹

MRI activity was also reduced. New or enlarging T2 lesion activity was 65% and 70% lower with remibrutinib than with teriflunomide in REMODEL-1 and REMODEL-2, respectively, while gadolinium-enhancing T1 lesion activity was reduced by approximately two-thirds.⁷

A preplanned pooled analysis also suggested a reduction in confirmed disability progression. The risk of 6-month confirmed disability progression was reduced by 29.2%, with nominal statistical significance, while the reduction in 3-month confirmed disability progression showed a positive trend.⁷ These findings are encouraging but should be interpreted in the context of the prespecified statistical hierarchy and will require longer follow-up.

Commenting on the findings in a Novartis press release, Prof. Heinz Wiendl (Medical Center, University of Freiburg, Freiburg, Germany) noted that “treatment goals in MS continue to evolve beyond relapse control alone.”⁷ This is an important distinction: the clinical value of emerging BTK inhibitors will ultimately depend not only on suppressing relapses and MRI activity, but also on whether they can meaningfully alter longer-term disability progression.

Safety may prove particularly relevant to the positioning of remibrutinib. Adverse events leading to treatment discontinuation occurred in 3.1% of remibrutinib-treated participants compared with 5.8% receiving teriflunomide. The most common adverse events included upper respiratory tract infection, nasopharyngitis, diarrhea, and alopecia, and the investigators reported no liver safety concerns.¹

Fenebrutinib: broad disease control in relapsing multiple sclerosis

Fenebrutinib differs pharmacologically from remibrutinib: it is a reversible, noncovalent, highly selective, CNS-penetrant BTK inhibitor.⁶

Its potential ability to influence immune activity in both the periphery and CNS is central to the rationale for its development. In a Roche press release discussing the phase 3 FENhance findings, Dr Jiwon Oh (St Michael’s Hospital, University of Toronto, Toronto, ON, Canada) described fenebrutinib as targeting “dual drivers of MS within the central nervous system and periphery.”¹³

This mechanistic concept is particularly relevant to the BTK inhibitor class, although it should not be interpreted as evidence that CNS penetration has yet translated into superior long-term disability outcomes compared with existing high-efficacy therapies.

At MSToronto2026, a pooled analysis of 1,497 participants from the phase 3 FENhance 1 and 2 trials provided further detail on its efficacy in RMS.³ Participants received fenebrutinib 200 mg twice daily or teriflunomide 14 mg once daily for a minimum of 96 weeks.

Pooled ARR was 0.06 with fenebrutinib compared with 0.13 with teriflunomide, corresponding to an approximately 55% reduction (p<0.001).³

The effect was also evident across MRI and biomarker outcomes. The rate of gadolinium-enhancing T1 lesions was 0.08 per scan with fenebrutinib compared with 0.32 with teriflunomide, while annualized new or enlarging T2 lesion rates were 1.16 and 5.64, respectively (both p<0.001).³

Annual total brain volume loss was reduced by 22.8% relative to teriflunomide (p<0.001). The risk of 12-week composite confirmed disability progression was also reduced (hazard ratio [HR] 0.84; 95% CI 0.71–0.99; p=0.04), although the corresponding 24-week analysis did not reach statistical significance (HR 0.84; 95% CI 0.68–1.02; p=0.08).³

Serum neurofilament light chain levels, a marker of neuroaxonal injury, also decreased to a greater extent with fenebrutinib.³

A separate analysis reported that approximately 75% of fenebrutinib-treated participants achieved no evidence of disease activity (NEDA-3) at approximately 2 years, adding to the evidence for broad suppression of relapsing disease activity.⁴

Fenebrutinib and chronic active lesions

Perhaps the most distinctive fenebrutinib findings presented at MSToronto2026 related to slowly expanding lesions (SELs) and paramagnetic rim lesions (PRLs), MRI features associated with chronic active MS pathology.⁵

The late-breaking O137 analysis included pooled FENhance data in RMS and FENtrepid data in primary progressive multiple sclerosis (PPMS). In FENhance, 750 participants received fenebrutinib and 747 received teriflunomide; in FENtrepid, 493 received fenebrutinib and 492 received ocrelizumab.⁵

Compared with teriflunomide in RMS, fenebrutinib was associated with approximately 18% fewer SELs and 30% lower total SEL volume. In PPMS, fenebrutinib was associated with approximately 21% fewer SELs and 27% lower SEL volume compared with ocrelizumab.⁵

Fenebrutinib also reduced the odds of PRL accumulation in RMS compared with teriflunomide (odds ratio 0.38; 95% CI 0.22–0.68; p=0.001). However, the corresponding comparison with ocrelizumab in PPMS was not statistically significant (odds ratio 0.64; 95% CI 0.22–1.83; p=0.405).⁵

There are important limitations. PRLs were evaluable in only 29% of participants in FENhance and 45% in FENtrepid. Furthermore, SELs and PRLs are imaging biomarkers: whether reducing these measures translates into a clinically meaningful reduction in long-term disability remains to be established.

Nevertheless, the investigators described the findings as the first prospective phase 3 demonstration of a treatment effect on chronic active lesion measures in MS.⁵ The observation that SEL accumulation was reduced relative to ocrelizumab in PPMS is particularly interesting because it provides a direct comparison with an established anti-CD20 therapy, although it does not demonstrate superior clinical efficacy.

Where could BTK inhibitors fit alongside anti-CD20 therapy?

This remains the key clinical question.

In RMS, both remibrutinib and fenebrutinib were compared with teriflunomide rather than a high-efficacy anti-CD20 therapy. Their phase 3 programs therefore cannot tell us whether either BTK inhibitor provides equivalent or superior relapse control to agents such as ofatumumab, ocrelizumab, or ublituximab.

Anti-CD20 therapies have demonstrated substantial effects on inflammatory disease activity. In the ASCLEPIOS I and II trials, ofatumumab reduced ARR compared with teriflunomide and reduced the risk of confirmed disability worsening.⁸ Ublituximab similarly produced substantially lower relapse rates than teriflunomide in the ULTIMATE I and II trials.⁹

It is tempting to compare these results with REMODEL and FENhance because the trials shared teriflunomide as an active comparator. However, such cross-trial comparisons are inherently unreliable. Differences in patient populations, baseline disease activity, geography, trial timing, follow-up, and — importantly — the relapse rate observed in the teriflunomide groups can substantially influence relative treatment effects.

The PPMS setting provides a more informative direct comparison. In FENtrepid, fenebrutinib was tested against ocrelizumab and met its primary endpoint of noninferiority for time to 12-week composite confirmed disability progression (HR 0.88; 95% CI 0.75–1.03).¹⁰ It did not demonstrate superiority.

This means that, at present, the strongest case for differentiation from anti-CD20 therapy may not be superior relapse control. Instead, potential advantages could include oral administration, avoidance of chronic B-cell depletion, and effects on CNS-compartmentalized inflammatory biology. Whether those theoretical and imaging advantages translate into better long-term clinical outcomes remains unanswered.

Safety may differentiate individual BTK inhibitors

Safety cannot be considered a single class characteristic.

The experience with tolebrutinib illustrates this clearly. In December 2025, the US Food and Drug Administration issued a complete response letter after concluding that a favorable benefit–risk profile could not be established because of the risk of severe drug-induced liver injury.¹¹ In Europe, however, tolebrutinib subsequently received authorization in June 2026 for adults with secondary progressive MS without relapses in the previous 2 years, with liver monitoring incorporated into risk-management requirements.¹²

For remibrutinib, no liver safety concerns were identified in the published REMODEL trials.¹ For fenebrutinib, liver enzyme elevations in the RMS studies were reported to be comparable with teriflunomide, while elevations occurred more frequently with fenebrutinib than with ocrelizumab in FENtrepid.¹⁰

These differences reinforce the need to assess each BTK inhibitor according to its individual pharmacologic and safety profile rather than assuming a uniform class effect.

Longer follow-up will also be required to understand less frequent adverse events, infection risk, effects on immunoglobulins and immune function, reproductive safety, and the consequences of long-term treatment.

What do the MS Toronto data tell us?

MSToronto2026 provided some of the strongest evidence yet that BTK inhibition is likely to become an important part of the future MS treatment discussion.

Both remibrutinib and fenebrutinib remain investigational for MS. The US Food and Drug Administration accepted fenebrutinib for priority review for both RMS and PPMS in September 2026, while Novartis has announced plans to seek regulatory approval for remibrutinib based on the REMODEL program.^7,10