What’s the Outlook for BTK Inhibitors in Progressive Multiple Sclerosis?

The potential use of Bruton’s tyrosine kinase (BTK) inhibitors for the treatment of multiple sclerosis (MS) is under intense scrutiny. After early clinical trials, hopes ran high that this class of oral drugs could offer a promising new type of therapy. But mixed efficacy results in phase 3 trials and associated liver toxicity have led to increased questioning of this strategy.

The promise of BTK inhibitors

The prospect of a novel treatment is especially important for nonrelapsing progressive MS, which currently has no approved FDA therapies.

BTK inhibitors are currently used to treat B-cell cancers, as they tamp down activation of malignant B cells. BTK receptors also play an important role in the central nervous system (CNS) in activating myeloid cells, including macrophages and microglia cells, which are believed to drive the inflammatory processes of progressive MS, leading to accrual of disability. In contrast, inflammatory processes that cause more discrete events of disability in early progressive and relapsing forms of MS are believed to take place peripherally.

Unlike most other MS therapies, many BTK inhibitors can cross the blood-brain barrier, allowing them to potentially reduce neuroinflammation both centrally and peripherally, indicating that some BTK inhibitors may be useful for addressing progressive and relapsing MS processes simultaneously.

“BTK inhibitors offer a completely new paradigm for MS, so there are many unknowns,” says Robert Fox, MD, staff neurologist at the Mellen Center for Multiple Sclerosis at Cleveland Clinic and a leader in investigations of BTK inhibitors for MS. “Clinical trials have yielded some very intriguing results, but their potential role in MS therapy must still be regarded as unclear.”

Research update on BTK inhibitors for MS

Several BTK inhibitors are under investigation for MS therapy.

Tolebrutinib recently underwent two phase 3, placebo-controlled clinical trials in progressive MS: HERCULES for treatment of nonrelapsing secondary progressive MS (N Engl J Med. 2025;392[19]:1883-1892) and PERSEUS for primary progressive MS.

HERCULES found a very encouraging 31% delay in onset of six-month disability progression compared with placebo over median follow-up of 2.5 years. Disappointingly, PERSEUS did not meet its similar primary endpoint but did show positive signs for secondary endpoints, including significantly fewer new or enlarged T2 lesions on MRI versus placebo and a trend toward reduction of risk for progression on the Expanded Disability Status Scale.

Safety concerns associated with tolebrutinib were evident in both trials. Most serious were significantly elevated alanine aminotransferase levels in some patients, leading the FDA to deny approval of the drug in December 2025, while also citing insufficient evidence of benefit. However, the European Medicines Agency recently recommended clearance of tolebrutinib for patients with secondary progressive MS who have not relapsed in the previous two years.

“The possibility of liver toxicity associated with BTK inhibitors must be addressed with close monitoring, especially during the first three months of use, when risk is highest,” advises Dr. Fox, who was the principal investigator of both HERCULES and PERSEUS. “I think the European decision reflects the major unmet need for an effective treatment for nonrelapsing progressive disease, with the rationale that benefits may outweigh risks if appropriate safety measures are taken.”

Fenebrutinib is the first oral therapy to demonstrate efficacy in primary progressive MS. The FENtrepid trial, presented at the ACTRIMS Forum in February 2026, found it to be noninferior to IV ocrelizumab, an anti-CD20 monoclonal antibody that is the only approved treatment for the condition. Other trials (FENhance I and FENhance 2) have had positive outcomes comparing fenebrutinib with standard MS therapy in patients who have relapsing MS, which is a benefit not seen with tolebrutinib.

Similar to tolebrutinib, safety concerns with liver toxicity were evident, along with an imbalance in on-study deaths: In FENtrepid, seven deaths occurred in the fenebrutinib group versus one death in the ocrelizumab group.

Remibrutinib is being compared with teriflunomide (a standard oral disease-modifying therapy for relapsing MS) in the parallel REMODEL-1 (NCT05147220) and -2 (NCT05156281) clinical trials for patients with relapsing MS. Remibrutinib is also being evaluated in patients switching from a standard MS therapy, ocrelizumab.

Orelabrutinib is being compared with placebo in phase 3 clinical trials in patients with primary progressive MS (NCT07067463) and secondary progressive MS (NCT07299019). Both trials are at an early stage, with completion expected mid-2030.

Evobrutinib was evaluated for treatment of relapsing MS in several studies, but development was terminated for lack of evident benefit.

BIIB091 and civorebrutinib are additional BTK inhibitors being tested in MS; both are in phase 2 trials.

Unraveling a complex picture

“Why clinical trial results have been so mixed in terms of efficacy is the million-dollar question about which there is considerable speculation,” Dr. Fox says. “Unlike other drug classes, in which drugs are pretty similar, individual BTK inhibitors seem to behave quite differently from one another.”

Some theories of varying efficacy results include differences in brain penetration, in how BTK inhibitors bond to cells (covalently vs. noncovalently) and in which other kinases are modulated beyond BTK. In addition, drugs would be expected to behave differently in the various forms of MS.

“We have good models for developing and testing drugs that target active inflammatory events of relapsing disease,” Dr. Fox explains. “But we still don’t understand well what is driving the gradual accrual of disability that is characteristic of progressive disease. This makes developing therapies especially challenging.”

“The fact that some BTK inhibitors cross the blood-brain barrier and are expected to act on activated CNS-resident microglia — a prime suspect in driving abnormal immune responses in progressive disease — continues to spur hope that they will one day become much-needed effective therapies, especially for progressive MS,” Dr. Fox continues. “Time will tell if one or more BTK inhibitors will be approved and adopted, as ongoing research from clinical trials and long-term experience informs our understanding of their efficacy and safety.”