BTK Inhibitor Fenebrutinib Demonstrates Long-Term Suppression of MS Activity in Open-Label Extension

Newly presented results from the open-label extension (OLE) of the phase 2 FENopta study (NCT05119569) showed that patients with relapsing multiple sclerosis (RMS) on fenebrutinib (Genentech) had low relapse rates with no active brain lesions or disability progression after 2 years of treatment. Phase 3 studies assessing the investigational Bruton tyrosine kinase (BTK) inhibitor in relapsing and primary progressive MS are expected to start reading out at year end.¹

The data, unveiled at the 2025 Consortium of Multiple Sclerosis Centers (CMSC) Annual Meeting, held May 28-31, in Phoenix, Arizona, included 99 patients who entered the OLE, 93 of whom remained after 96 weeks of treatment. Throughout the OLE, investigators recorded a low annualized relapse rate (ARR) of 0.06, coupled with no change in disability progression, measured through Expanded Disability Status Scale (EDSS) scores. In addition, treatment with the oral, reversible, and non-covalent BTK inhibitor led to suppression of disease activity in the brain.

"These data show that patients treated with fenebrutinib experienced an annualized relapse rate equal to one relapse every 17 years and no observed disability progression up to two years," Levi Garraway, MD, PhD, chief medical officer and head of Global Product Development at Genentech, said in a statement. "Fenebrutinib is potent, highly selective and the only reversible BTK inhibitor currently in Phase III trials for multiple sclerosis, and we look forward to seeing the first of those results later this year."

Fenebrutinib remains the only reversible dual inhibitor of both B-cell and microglia activation currently in development for MS. In addition to FENopta, the medication is being tested in the phase 3 FENhance 1 (NCT04586023) and 2 (NCT045586010) trials of RMS, as well as the FENtrepid trial (NCT04544449) of primary progressive MS.

In the latest 96-week data, there were no reports of new T1 gadolinium-enhancing lesions, markers of active inflammation, and a safety profile that was consistent with previous reports. Among those who switched from placebo to fenebrutinib in the OLE, the annualized rate of new or enlarging T2 lesions decreased from 6.72 at the end of the 12-week double-blind period to 0.34 by 96 weeks.

Among fenebrutinib-treated patients, the most common adverse events (AEs) were COVID-19 (10%), urinary tract infection (10%), pharyngitis (6%), and respiratory tract infection (5%). Serious AEs occurred in 2% of patients, including 1 case of asymptomatic ALT elevation at OLE week 4 (after 16 weeks of treatment), which resolved after discontinuation.

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In the double-blind portion of FENopta, data announced in mid-2023 showed that fenebrutinib met its primary and secondary end points, demonstrating a significant reduction in MRI markers of MS activity in the brain relative to placebo. At the conclusion of the 12-week study, treatment with the BTK inhibitor led to an attenuation in total number of new gadolinium-enhancing T1 brain lesions, the primary end point, compared with placebo (P = .0022). In addition, fenebrutinib-treated patients had significant reductions in new or enlarging T2 lesions, with more patients remaining free of new gadolinium-enhancing T1 or T2 brain lesions relative to placebo.²

The clinical community eagerly awaits the results from FENtrepid, a study of fenebrutinib in primary progressive MS, later this year. This double-blind, double-dummy, parallel-group trial includes 946 patients aged 18 to 65 years who are randomly assigned 1:1 to either fenebrutinib or placebo or intravenous ocrelizumab (Ocrevus; Genentech), the first and only approved therapy for progressive MS, for 120 weeks. An OLE may follow FENtrepid, depending on the observed benefits.

In November 2023, the FDA placed a clinical hold on the development program for fenebrutinib, citing cases of drug-induced liver injury that was documented in the blinded FENhance studies. The decision was based on 2 patients who developed hepatic transaminase elevations in conjunction with elevated bilirubin; however, both patients were asymptomatic and had elevations return to normal levels following the discontinuation of fenebrutinib. As a result of the hold, new enrollment for FENhance 1 in the U.S. was paused, while enrollment in countries continued on.³

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REFERENCES
1. 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
2. Genentech’s BTK inhibitor fenebrutinib significantly reduced brain lesions in people with relapsing forms of multiple sclerosis. News release. May 17, 2023. Accessed May 30, 2025. https://www.businesswire.com/news/home/20230516005196/en/Genentech%E2%80%99s-BTK-Inhibitor-Fenebrutinib-Significantly-Reduced-Brain-Lesions-in-People-With-Relapsing-Forms-of-Multiple-Sclerosis
3. Fenebrutinib multiple sclerosis clinical trial program update. News release. Genentech/Roche. November 30, 2023. Accessed May 30, 2025. https://www.gene.com/media/statements/ps_113023