Key Clinical Summary

• The phase 3 FENtrepid trial enrolled 985 adults with primary progressive multiple sclerosis (PPMS) to compare fenebrutinib with ocrelizumab.
• Fenebrutinib is an oral, highly selective Bruton tyrosine kinase inhibitor (BTKi) designed to penetrate the central nervous system and target progressive MS biology.
• The study’s primary endpoint assessed confirmed disability progression using Expanded Disability Status Scale (EDSS), Timed 25-Foot Walk Test, and 9-Hole Peg Test measures.

Primary progressive MS remains an area of significant unmet clinical need, with ocrelizumab currently the only approved therapy for PPMS. The phase 3 FENtrepid trial evaluated whether fenebrutinib, an investigational oral BTKi, can improve disability outcomes compared with active comparator ocrelizumab in adults with PPMS.

Fenebrutinib previously demonstrated rapid reductions in acute inflammatory disease activity in relapsing MS during the phase 2 FENopta study. However, its impact on progressive forms of MS has not yet been established.

FENtrepid Trial Design and Patient Population

FENtrepid is a multicenter, randomized, double-blind, double-dummy, parallel-group phase 3 clinical trial comparing oral fenebrutinib with intravenous ocrelizumab in patients with PPMS aged 18 to 65 years. Eligible participants met the 2017 revised McDonald diagnostic criteria for PPMS and had baseline EDSS scores ranging from 3.0 to 6.5.

Participants were randomized in a 1:1 ratio to receive either oral fenebrutinib 200 mg twice daily or intravenous ocrelizumab 600 mg every 24 weeks. The primary endpoint was time to onset of composite confirmed disability progression. Disability progression was defined as a 12-week confirmed increase in 1 or more functional systems measured by EDSS, Timed 25-Foot Walk Test, or 9-Hole Peg Test assessments.

The trial enrolled 985 patients with PPMS. Investigators reported that 84% of participants had not recently received prior disease-modifying therapies. Mean baseline age was 48.9 years, with a standard deviation of 10.3 years. The median baseline EDSS score was 5.0, indicating moderate disability at study entry.

Mean duration since MS symptom onset was 9.0 years, while the mean duration since diagnosis was 4.7 years. According to investigators, primary efficacy and safety results will be presented in future analyses.

Researchers described FENtrepid as the first clinical trial evaluating a new PPMS therapy against ocrelizumab as an active comparator rather than placebo.

Potential Impact on Progressive Multiple Sclerosis Treatment

The FENtrepid trial addresses a major therapeutic gap in PPMS management, where treatment options remain limited. Ocrelizumab is currently the only approved therapy for PPMS, and disability progression continues to be a substantial burden for patients, clinicians, and health systems.

Fenebrutinib’s mechanism may offer a distinct approach to targeting both relapsing and progressive MS disease biology. As a reversible, noncovalent BTKi capable of penetrating the central nervous system, the therapy is designed to modulate immune pathways implicated in neuroinflammation and disease progression.

For payers and managed care stakeholders, the study could have implications for future treatment sequencing and comparative effectiveness considerations in progressive MS. The use of an active comparator also may provide clinically relevant evidence regarding disability outcomes relative to the current standard of care.

Investigators Highlight Need for Additional PPMS Therapies

Investigators stated that “FENtrepid will provide the first evidence on the effect of fenebrutinib treatment on disability progression in PPMS, relative to an active comparator of ocrelizumab.”

The study authors also noted that BTKis “have the potential to impact both relapsing and progressive multiple sclerosis disease biologies,” highlighting ongoing interest in BTK-targeted therapies for progressive neurologic disease.

Fenebrutinib previously demonstrated central nervous system penetration and reduced acute inflammatory disease activity in relapsing MS during the phase 2 FENopta study, according to the study background.

The FENtrepid trial represents an important late-stage investigation into whether BTK inhibition can alter disability progression in PPMS. Pending efficacy and safety results may help clarify the role of fenebrutinib compared with ocrelizumab in addressing persistent unmet needs in PPMS care.

Reference

Bar-Or A, Oh J, Giovannoni G, et al. Efficacy and safety of fenebrutinib vs ocrelizumab in primary progressive multiple sclerosis: primary results of the phase III FENtrepid study. Presented at: Consortium of Multiple Sclerosis Centers Annual Meeting; May 27-29, 2026; Charlotte, NC.