By Judy George, Deputy Managing Editor, MedPage Today
October 27, 2026
The landscape of multiple sclerosis (MS) treatment is on the precipice of a significant transformation. As the medical community converges at MSToronto2026—the joint meeting of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) and the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS)—new data surrounding the investigational Bruton’s tyrosine kinase (BTK) inhibitor, fenebrutinib, has emerged as a focal point of clinical optimism.
For decades, the primary challenge in managing MS has been the "silent" progression of the disease—the gradual, relentless accumulation of disability that often occurs beneath the surface of clinical relapses. New phase III clinical trial data suggest that fenebrutinib may finally provide a targeted mechanism to curb the chronic active lesions that drive this biological decline.
The Core Science: Targeting Chronic Active Lesions
The excitement surrounding fenebrutinib stems from its ability to address two critical MRI biomarkers: slowly expanding lesions (SELs) and paramagnetic rim lesions (PRLs). According to Jiwon Oh, MD, PhD, of the University of Toronto, these imaging markers are the "smoking guns" of chronic active inflammation.
"The field is quite interested in both SELs and PRLs because both are imaging biomarkers of chronic active lesions, which we know are a dominant driver of progressive disease biology," Dr. Oh explained during a late-breaking presentation at the conference.
Unlike acute inflammatory lesions, which often resolve, chronic active lesions persist and expand, contributing to the neurodegeneration that defines progressive MS. Dr. Oh noted that progressive MS biology is not a late-stage phenomenon but rather a process that occurs from the onset of the disease in almost every patient, regardless of their initial clinical presentation. By potentially halting the expansion of these lesions, fenebrutinib aims to address the most significant unmet need in neurology: the mitigation of long-term disability progression.
Chronology of the Fenebrutinib Development Program
The path to the current FDA priority review status for fenebrutinib has been marked by a rigorous, multi-year clinical development program.
- Early Development: Initial interest in fenebrutinib was piqued by its unique profile as a non-covalent, reversible, and highly selective BTK inhibitor. Unlike some earlier candidates in the class, its reversible nature was theorized to offer a better safety and efficacy balance.
- Phase II Success: The momentum began with the FENopta study, which demonstrated the drug’s ability to reduce brain lesions in patients with relapsing MS, providing the necessary proof-of-concept to proceed to large-scale trials.
- Phase III Expansion: The program scaled significantly with the initiation of the FENhance 1 and 2 trials (relapsing MS) and the FENtrepid trial (primary progressive MS). These studies were designed not only to assess standard metrics like annualized relapse rates (ARR) but to specifically interrogate the drug’s impact on markers of progressive biology.
- Regulatory Milestone: In September 2026, the FDA formally accepted the New Drug Application (NDA) for fenebrutinib for the treatment of both relapsing and primary progressive MS, granting it priority review. This makes fenebrutinib the first BTK inhibitor to reach this stage for both indications simultaneously.
Supporting Data: Comparative Efficacy and Imaging Metrics
The data presented at MSToronto2026 provided a granular look at how fenebrutinib performs against current standard-of-care treatments, including teriflunomide (Aubagio) and ocrelizumab (Ocrevus).
Relapsing MS (FENhance 1 and 2)
In the pooled analysis of the FENhance trials, fenebrutinib demonstrated a 30.5% relative reduction in SEL volume compared to teriflunomide over 96 weeks (P<0.0001). Furthermore, participants treated with fenebrutinib showed a 62% lower odds of a net increase in PRLs compared to the control group.
Clinical outcomes were equally compelling. Maria Pia Sormani, PhD, of the University of Genoa, reported that fenebrutinib reduced the annualized relapse rate by 55% compared to teriflunomide. Additionally, the drug showed a 22.8% reduction in annual total brain volume loss and a 16% reduction in 12-week composite confirmed disability progression, both reaching statistical significance.
Primary Progressive MS (FENtrepid)
In the primary progressive MS population, the focus shifted to a comparison against the potent monoclonal antibody ocrelizumab. Fenebrutinib achieved a 27.5% relative reduction in SEL volume over 120 weeks (P=0.0006). Regarding disability progression, the trial concluded that fenebrutinib was non-inferior to ocrelizumab, marking a significant achievement for an oral medication attempting to match the efficacy of an infused biologic.
Safety and Tolerability Profiles
As with any potent immunomodulator, safety remains a critical consideration. The clinical trials observed transient and reversible liver enzyme elevations across the study arms.
In the FENhance trials, two isolated cases met the criteria for Hy’s law—a clinical indicator of potential drug-induced liver injury. Both cases were asymptomatic and resolved entirely once the study drug was discontinued. In the FENtrepid trial, liver enzyme elevations were more frequent in the fenebrutinib arm (13.3%) compared to the ocrelizumab arm (2.9%), though investigators emphasized that all instances were manageable and resolved upon cessation of the medication. The research teams continue to monitor these trends to provide clear prescribing guidance should the drug receive final approval.
Implications for Future Practice
The potential approval of fenebrutinib represents a shift toward "proactive" disease management. For decades, MS therapy focused almost exclusively on preventing acute relapses. While highly effective at managing visible symptoms, these therapies often left the underlying, smoldering progression of the disease untouched.
If the FDA grants approval, neurologists will gain a powerful tool that combines the convenience of an oral, daily medication with a mechanism of action that targets the very biology of disease progression.
"Therapeutically, the greatest unmet need in the field are treatments that target mechanisms underlying progressive disease biology," Dr. Oh reiterated. "When PRLs have been evaluated, they seem to be present in most people early in the disease course." By intervening early with a BTK inhibitor that crosses the blood-brain barrier and impacts chronic lesion activity, clinicians may be able to significantly delay the point at which patients experience life-altering disability.
Looking Ahead
The medical community is now awaiting the final FDA decision, expected in the coming months. If approved, the introduction of fenebrutinib will likely trigger a re-evaluation of current MS treatment algorithms. Clinicians will have to weigh the comparative benefits of BTK inhibitors against existing B-cell depleting therapies, considering factors like dosing convenience, safety profiles, and the specific patient profile regarding disease progression.
As researchers analyze the remaining subsets of MRI data—particularly the 3-Tesla imaging samples—the industry remains optimistic. Fenebrutinib is not merely another drug in a crowded market; it is a candidate that speaks directly to the most challenging aspect of MS. For the millions living with the condition, the data presented at MSToronto2026 offers more than just a statistical victory—it offers the prospect of a future where MS progression is no longer an inevitability.
