Fenebrutinib Hits Key Phase 3 Marks in Relapsing and Primary Progressive MS

Genentech recently announced that its investigational Bruton’s tyrosine kinase (BTK) inhibitor fenebrutinib met primary end points in 2 pivotal phase 3 studies of relapsing (RMS) and primary progressive multiple sclerosis (PPMS). These included the FENhance 2 (NCT04586010) study, which compared the therapy with teriflunomide (Aubagio; Sanofi) in RMS and FENtrepid (NCT04544449), which compared it with ocrelizumab (Ocrevus; Genentech) in PPMS.¹

"The results of our Phase 3 trials indicate that investigational fenebrutinib substantially reduced relapses in RMS and delayed progression to disability in PPMS," Levi Garraway, MD, PhD, chief medical officer and head of Global Product Development at Genentech, told NeurologyLive^® in a recent interview. "Based on these results, potent and selective BTK inhibition with fenebrutinib may potentially emerge as an important new treatment option for people with both forms of MS, where considerable unmet need remains despite the progress of recent years. These results underscore the abiding commitment of Roche and Genentech to research and develop best-in-class medicines to people with this challenging disease.”

FENhance 2 and its previous trial FENhance 1 (NCT04586023) are similarly designed phase 3 multicenter, randomized, double-blind, double-dummy, parallel-group studies that investigate the efficacy and safety of fenebrutinib against teriflunomide in a total of 1497 adult patients with RMS. Findings from the FENhance 2 study showed that treatment with fenebrutinib led to significant reductions in annualized relapse rate (ARR), the primary outcome, compared with teriflunomide over at least 96 weeks. The company noted that liver safety was consistent with prior studies of fenebrutinib and that the results of FENhance 1 are expected by the first half of 2026.

In the FENhance 2 trial, investigators randomized participants 1:1 to receive either oral fenebrutinib twice daily plus a teriflunomide-matched placebo or oral teriflunomide once daily plus a fenebrutinib-matched placebo for a minimum of 96 weeks. The primary end point of the study is ARR, with key secondary end points including the time to onset of composite 24-week confirmed disability progression (CDP), 12-week CDP, and 24-week CDP. After the double-blind treatment period, participants have the option to enter an open-label extension (OLE) phase, in which all would receive fenebrutinib.

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The FENtrepid trial is a phase 3 multicenter, randomized, double-blind, double-dummy, parallel-group study to assess the efficacy and safety of fenebrutinib compared with ocrelizumab in 985 adult patients with PPMS. Results of the study revealed that fenebrutinib was noninferior compared with ocrelizumab, as measured by a delay in the onset of composite CDP, the primary outcome, over a treatment period of at least 120 weeks. Notably, the company reported that a numerical benefit for fenebrutinib compared with ocrelizumab was observed early as 24 weeks and lasted throughout the observation period.

In FENtrepid, participants were randomized 1:1 to receive either daily oral fenebrutinib once daily plus an intravenous (IV) ocrelizumab–matched placebo or IV ocrelizumab plus an oral fenebrutinib–matched placebo for a minimum of 120 weeks. The primary end point of the study is the time to onset of 12-week composite CDP. Similar to the FENhance 2 trial, the key secondary end points include the time to onset of 24-week composite CDP, 12-week CDP and 24-week CDP. Upon completion of the double-blind phase, participants could enroll in an OLE phase where they would all receive treatment with fenebrutinib.

Data presented earlier this year at the 2025 Consortium of Multiple Sclerosis Centers (CMSC) Annual Meeting, from the OLE of the previously completed phase 2 FENopta study (NCT05119569) showed that patients with RMS treated with fenebrutinib had low relapse rates with no active brain lesions or disability progression after 2 years of treatment. The data included 99 patients who entered the OLE, 93 of whom remained following 96 weeks of treatment.² In the OLE, investigators recorded a low ARR of 0.06, coupled with no change in disability progression, measured through Expanded Disability Status Scale scores. In addition, treatment with fenebrutinib led to suppression of disease activity in the brain.

In a prior NeurologyLive Peer Exchange series, experts discussed BTK inhibitors, which block the actions of B cells and may affect other cell types that can facilitate inflammation, recent key clinical data on BTK inhibitors in MS, and how to incorporate these novel agents into treatment plans once they become available. During the panel discussion, Amit Bar-Or, MD, FRCPC, Melissa and Paul Anderson President’s Distinguished Professor of Neurology at the University of Pennsylvania Perelman School of Medicine, summarized fenebrutinib phase 2 results for the treatment of MS.

REFERENCES
1. Genentech’s Fenebrutinib Shows Unprecedented Positive Phase III Results as the Potential First and Only BTK Inhibitor in Both Relapsing and Primary Progressive Multiple Sclerosis. News release. Genentech. November 9, 2025. Accessed November 11, 2025. https://www.gene.com/media/press-releases/15089/2025-11-09/genentechs-fenebrutinib-shows-unpreceden
2. Genentech’s Fenebrutinib Maintains Near-Complete Suppression of Disease Activity and Disability Progression for up to Two Years in People With Relapsing Multiple Sclerosis. News release. Genentech. May 29, 2025. Accessed May 30, 2025. https://www.gene.com/media/press-releases/15064/2025-05-29/genentechs-fenebrutinib-maintains-near-c