FDA Accepts Roche’s Fenebrutinib NDA Under Priority Review for Relapsing and Primary Progressive MS

The U.S. Food and Drug Administration has accepted Roche’s New Drug Application for fenebrutinib, an investigational oral, non-covalent Bruton’s tyrosine kinase (BTK) inhibitor for RMS and PPMS. The application is supported by the Phase III FENhance 1, FENhance 2 and FENtrepid studies.

If approved, fenebrutinib would become the first BTK inhibitor indicated for MS and the first high-efficacy oral therapy intended to treat both relapsing and primary progressive forms of the disease.

Strong Relapse Reduction in RMS

FENhance 1 and FENhance 2 compared fenebrutinib with teriflunomide in patients with RMS over 96 weeks.

Fenebrutinib reduced the annualized relapse rate by 51.1% in FENhance 1 (p<0.001) and 58.5% in FENhance 2 (p<0.00001) versus teriflunomide. The trials also showed reductions in active and chronic brain lesions.

Measures of disability progression, including 12-week composite confirmed disability progression (cCDP12), consistently favored fenebrutinib, although the reported findings were described as positive trends rather than definitive superiority for this endpoint.

FENtrepid Evaluated Disability Progression in PPMS

The Phase III FENtrepid trial compared fenebrutinib with ocrelizumab (Ocrevus), the only FDA-approved treatment for PPMS.

Fenebrutinib met the trial’s primary non-inferiority endpoint for time to cCDP12. The treatment produced a 12% numerical reduction in the risk of disability progression versus ocrelizumab, corresponding to a hazard ratio of 0.88 (95% CI, 0.75–1.03).

The disability-progression curves separated from approximately 24 weeks onward, with the treatment effect remaining consistent across patient subgroups, including patients without active inflammation.

CNS Penetration Extends BTK Inhibition Beyond Relapses

Fenebrutinib is an oral, reversible and non-covalent BTK inhibitor that crosses the blood-brain barrier. Its pharmacology allows BTK inhibition in peripheral immune cells and within the central nervous system.

By inhibiting B-cell activity, fenebrutinib can suppress inflammatory processes associated with MS relapses. Its CNS penetration also allows it to target microglia, which are implicated in chronic inflammation and tissue damage associated with progressive disability.

This dual biological activity is central to fenebrutinib’s development across both relapsing and progressive MS.

Safety Profile Across Three Phase III Studies

Serious adverse events occurred in 9% of fenebrutinib and 9% of teriflunomide-treated patients in FENhance 1, and 11% and 6%, respectively, in FENhance 2. In FENtrepid, serious adverse events occurred in 19% of patients in both the fenebrutinib and ocrelizumab groups.

Liver enzyme elevations were comparable between treatment groups in the RMS studies but occurred more frequently with fenebrutinib than ocrelizumab in FENtrepid. Roche also reported an imbalance in fatalities across the pivotal studies, although the deaths occurred at different timepoints and had varied causes.

The overall safety database includes more than 2,700 participants across Phase III and earlier studies.

FDA Priority Review Sets Next Milestone

The FDA’s priority review moves fenebrutinib toward a regulatory decision covering both RMS and PPMS. Roche is seeking to establish an oral BTK inhibitor as a treatment option spanning relapsing and progressive MS, with the potential to address both inflammatory disease activity and disability progression.

For a disease affecting more than 3 million people worldwide, the regulatory review will determine whether the clinical evidence supports expanding treatment options beyond existing disease-modifying therapies.

Reference

Roche’s fenebrutinib is the first BTK inhibitor to receive U.S. FDA filing acceptance in both relapsing and primary progressive multiple sclerosis, Roche, 30 September 2026