The FDA accepted fenebrutinib's new drug application under priority review for relapsing and primary progressive MS, based on 3 phase 3 trials comparing the BTK inhibitor with teriflunomide and ocrelizumab.
The FDA has accepted a new drug application (NDA) under priority review for fenebrutinib (Genentech), an investigational oral, noncovalent Bruton tyrosine kinase (BTK) inhibitor, for the treatment of both relapsing multiple sclerosis (RMS) and primary progressive MS (PPMS). The submission is supported by 3 phase 3 studies, FENhance 1 and 2 (NCT04586010; NCT04586023) in RMS and FENtrepid (NCT04544449) in PPMS, and marks the first time a BTK inhibitor has received FDA filing acceptance in both indications.1
“People living with multiple sclerosis need treatments that go beyond controlling relapses to help preserve function and independence as the disease progresses,” Levi Garraway, MD, PhD, chief medical officer and head of Global Product Development at Genentech, said in a statement.1 If approved, fenebrutinib would be the first oral therapy for PPMS, where ocrelizumab (Ocrevus; Genentech) has been the only approved disease-modifying therapy since 2017, based on results of the phase 3 ORATORIO trial.2
FENhance 1 and 2 were identically designed phase 3 trials comparing fenebrutinib with teriflunomide (Aubagio; Sanofi) in adults with RMS. Over 96 weeks, fenebrutinib reduced the annualized relapse rate (ARR) by 51.1% in FENhance 1 (P <.001) and by 58.5% in FENhance 2 (P <.00001) relative to teriflunomide, alongside reductions in active and chronic brain lesions.1 Disability end points, including 12-week composite confirmed disability progression (cCDP12), were described by the company as showing consistent trends favoring fenebrutinib; formal statistical results for these measures were not included in the announcement.
In FENtrepid, a double-blind, double-dummy trial, fenebrutinib was compared directly with intravenous ocrelizumab in adults with PPMS.3 The study met its primary end point of noninferiority on time to onset of cCDP12 (HR, 0.88; 95% CI, 0.75-1.03), corresponding to a numerical 12% risk reduction, with curves separating as early as week 24. The company reported a consistent treatment effect across subgroups, including patients without evidence of active inflammation.1
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Serious adverse event rates were 9% with fenebrutinib vs 9% with teriflunomide in FENhance 1, 11% vs 6% in FENhance 2, and 19% vs 19% with ocrelizumab in FENtrepid. Liver enzyme elevations were comparable with teriflunomide but occurred more often with fenebrutinib than with ocrelizumab. Genentech also acknowledged an imbalance in deaths across the 3 pivotal studies, stating that the fatalities occurred at different time points and had varied causes; the number and causes of deaths were not specified.1 The company reports a safety database of more than 2700 participants.
Unlike most BTK inhibitors in development, which bind the enzyme covalently and irreversibly, fenebrutinib binds reversibly. The agent is CNS-penetrant and is designed to inhibit both B cells, which drive the acute inflammation underlying relapses, and microglia, which are thought to contribute to the chronic inflammation associated with disability progression.1 Hepatic safety has been a recurring question for the program: in 2023, the
Several caveats temper interpretation of the data. The upper bound of the FENtrepid confidence interval crosses 1, meaning the trial established noninferiority to ocrelizumab rather than superiority. In RMS, the relapse benefit was measured against teriflunomide, a lower-efficacy comparator, leaving fenebrutinib’s performance relative to anti-CD20 therapies in relapsing disease untested in phase 3, and its effect on disability in RMS has not been confirmed. Full peer-reviewed publications, detailed hepatic data, and characterization of the fatality imbalance could be central to the FDA’s benefit-risk assessment.
That assessment comes amid a mixed regulatory record for the class. In December 2025, the FDA issued a complete response letter for Sanofi’s tolebrutinib in nonrelapsing secondary progressive MS, a decision the company described as a reversal from earlier agency feedback.4 How regulators weigh fenebrutinib’s efficacy against its liver and mortality signals will likely shape expectations for BTK inhibition across the MS spectrum.
