Bruton’s Tyrosine Kinases Inhibitors and MS

Over the past several years, Bruton’s tyrosine kinase inhibitors, better known as BTKi’s, have emerged as a potential new class of therapy in multiple sclerosis (MS). Unlike current FDA approved MS treatments, BTKi’s work through a different mechanism of action. 

BTKi’s work by reducing the activation of  B lymphocytes, a type of white blood cell involved in MS inflammation and damage. They also inhibit other immune system cells found in the central nervous system (brain and spinal cord) and known to be contributors to MS damage, including macrophages and microglia. Microglia are believed to be a driver of MS progression. By inhibiting the activity of these cells, BTKi’s reduce inflammation and may also slow disability progression. 

BTKi's in Clinical Trials

At present, there have been multiple clinical trials of BTKi’s in MS. The BTKi’s have been or are currently being studied in relapsing MS, primary progressive MS and also non-relapsing secondary progressive MS. BTKi’s that have been studied in the past and at present include: evobrutinib, tolebrutinib, fenebrutinib, remibrutinib, and orelabrutinib. So, where are we with all the BTKi studies at present?  

Evobrutinib was the first BTKi to show early promise in reducing relapses in relapsing MS. However, in two large, Phase III trials, evobrutinib did not demonstrate a reduction in relapses  compared to the FDA-approved DMT, teriflunomide.  

Tolebrutinib has been studied in relapsing MS, non-relapsing secondary progressive MS  and primary progressive MS. In Phase III clinical trials  of non-relapsing secondary progressive MS, tolebrutinib met the endpoint of a delay in confirmed disability progression, however, it  did not demonstrate a reduction in relapses in the secondary progressive trial or in the relapsing MS trial. In addition, it did not  meet the primary endpoint of delay in disability progression in the  Phase III primary progressive MS clinical trial. In December 2025, the FDA informed the manufacturer that its application for nrSPMS could not be approved in its current form, though the company continues to work with regulators toward a potential path forward. 

More recently, fenebrutinib has shown encouraging clinical trial results. It was studied  in relapsing MS and primary progressive MS. In the Phase III relapsing MS trial fenebrutinib was compared to the FDA approved DMT, teriflunomide and was found to significantly reduce relapses compared to teriflunomide. In the Phase III primary progressive MS trial, fenebrutinib was found to be at least as effective as FDA approved ocrelizumab in slowing disability progression. 

Remibrutinib is currently recruiting for secondary progressive MS studies. It has also completed phase III studies in relapsing MS compared with teriflunomide, and those results are currently being analyzed. 

Lastly, orelabrutinib has completed a phase II study in MS, and further studies are anticipated in the future. 

Side Effects and Future of BTKi's

Side effects of the BTKi’s are generally similar and include elevation in liver enzymes, increased risk of infections and cold/flu-like symptoms. There is also a risk of liver toxicity. Monitoring of liver function through blood tests will be necessary to ensure safety.  

Despite mixed results so far, BTKi’s remain a promising area of MS research. Although they share a common mechanism, differences among individual drugs may affect both effectiveness and side-effect profiles. Ongoing studies are expected to provide more clarity about the role of BTKi’s in treating both relapsing and progressive forms of MS and more should be learned in 2026 and beyond.