Fenebrutinib Shows Promise to Reduce Disability Progression in Primary Progressive Multiple Sclerosis

Roche’s fenebrutinib is the first investigational medicine in over a decade that reduces disability progression in primary progressive multiple sclerosis (PPMS). In the phase 3 FENtrepid (NCT04544449) study, the oral Bruton tyrosine kinase (BTK) inhibitor met its primary end point of noninferiority compared with ocrelizumab, which remains the only approved therapy for PPMS.¹

“Fenebrutinib showed a consistent clinical benefit as early as week 24, notably in upper limb function, which is essential for preserving independence and daily functioning,” Amit Bar-Or, MD, FRCPC, director of the Center for Neuroinflammation and Neurotherapeutics in the Perelman School of Medicine at the University of Pennsylvania, said in a news release.¹ “With only 1 disease-modifying therapy available for people with PPMS, fenebrutinib has the potential to be a high-efficacy, oral treatment option that acts directly in the brain, targeting progressive biology, and may slow disability.”

About the FENtrepid Trial

The FENtrepid trial was a multicenter, randomized, double-blind study involving 985 adult patients who received either daily oral fenebrutinib or intravenous ocrelizumab for at least 120 weeks. Progress was measured through a composite end point that incorporated the expanded disability status scale, walking speed, and the 9-hole peg test for upper limb function. This comprehensive approach offers greater sensitivity than traditional measures, capturing earlier aspects of disability.^1,2

Data revealed that fenebrutinib reduced the risk of disability progression by 12% compared with ocrelizumab as early as 24 weeks. A post-hoc analysis further suggested a 22% reduction in risk when focusing on functional disability and upper limb function, the latter of which saw a 26% reduction in worsening, which is a factor for maintaining patient independence.¹

The clinical significance for pharmacists lies in fenebrutinib's unique pharmacological profile as a noncovalent, reversible, and central nervous system-penetrant BTK inhibitor. Unlike most current BTK inhibitors that form permanent chemical bonds with the enzyme, fenebrutinib is designed to bind and eventually release it, which may help limit off-target effects. Its ability to cross the blood-brain barrier allows it to target both B cells and microglia, addressing the chronic damage in the brain thought to drive long-term disability progression.^1,2

Previous and Future Data About Fenebrutinib

Fenebrutinib also demonstrated efficacy in relapsing multiple sclerosis (RMS). The phase 4 FENhance 2 (NCT04586023) study showed that the drug significantly reduced the annualized relapse rate compared with teriflunomide over 96 weeks. These findings are bolstered by results from the phase 2 FENopta (NCT05119569) open-label extension, where patients experienced an annualized relapse rate equivalent to just 1 relapse every 17 years and showed near-complete suppression of active brain inflammation as measured by MRI.^2,3

From a safety perspective, pharmacists should note that liver safety was consistent with previous trials. Although transient and reversible liver enzyme elevations were more frequent in the fenebrutinib group than the ocrelizumab group at 13.3% compared with 2.9%, all cases resolved after discontinuing the drug, and no cases of severe liver injury were observed. Common adverse events included infections, nausea, and respiratory tract infections, with serious adverse events occurring at similar rates to the active comparator.^1-3

As the MS community awaits the readout of the second pivotal RMS study, FENhance 1 (NCT04586010), expected in the first half of 2026, Roche plans to submit the complete data package from all phase 3 trials to regulatory authorities. If approved, fenebrutinib would represent the first high-efficacy oral treatment option for both RMS and PPMS, potentially shifting the standard of care for millions living with the disease.^1,2

“Fenebrutinib represents the first potential scientific breakthrough for the PPMS community in over a decade, demonstrating a meaningful clinical benefit in reducing disability progression in a study versus the only approved treatment in PPMS,” Levi Garraway, MD, PhD, chief medical officer and head of global product development at Roche, said in the news release.¹ “We look forward to advancing our regulatory submission following the upcoming readout of our second pivotal RMS study, FENhance 1.”

READ MORE: Neurology Resource Center

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REFERENCES

1. Roche’s fenebrutinib is the first investigational medicine in over a decade that reduces disability progression in primary progressive multiple sclerosis (PPMS). News release. Roche. February 6, 2026. Accessed February 9, 2026. https://www.roche.com/media/releases/med-cor-2026-02-07

2. 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 February 9, 2026. https://www.gene.com/media/press-releases/15089/2025-11-09/genentechs-fenebrutinib-shows-unpreceden

3. Gallagher A. Fenebrutinib maintains low levels of multiple sclerosis activity for 96 weeks. Drug Topics. May 31, 2025. Accessed February 9, 2026. https://www.drugtopics.com/view/fenebrutinib-maintains-low-levels-of-multiple-sclerosis-activity-for-96-weeks