Genentech’s Fenebrutinib Is the First Investigational Medicine in Over a Decade That Reduces Disability Progression in Primary Progressive Multiple Sclerosis (PPMS)
- Late-breaking Phase III FENtrepid results presented at ACTRIMS show investigational fenebrutinib met its primary endpoint of non-inferiority compared to the current standard of care, Ocrevus, in reducing disability progression in PPMS
Genentech, a member of the Roche Group announced today new late-breaking data from the Phase III FENtrepid study showing the investigational Bruton’s tyrosine kinase (BTK) inhibitor fenebrutinib met its primary endpoint of non-inferiority compared to Ocrevus® (ocrelizumab) in reducing disability progression in patients with primary progressive multiple sclerosis (PPMS).
Fenebrutinib showed a 12% reduction in the risk of disability progression compared to Ocrevus, the only approved medicine for PPMS, as measured by the time to onset of 12-week composite confirmed disability progression (cCDP12) (hazard ratio [HR] 0.88; 95% confidence interval [CI]: 0.75, 1.03) with curves separating as early as 24 weeks. A consistent treatment effect on cCDP12 was observed across patient subgroups and for the entire treatment duration.
The cCDP12 primary endpoint included the confirmed disability progression (CDP) based on the Expanded Disability Status Scale (EDSS) for functional disability, the timed 25-foot walk (T25FW) for walking speed and the nine-hole peg test (9HPT) for upper limb function. The strongest treatment effect was observed on the risk of worsening on the 9HPT by 26% (HR 0.74; 95% CI: 0.56, 0.98) compared to Ocrevus.
“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,” said Professor Amit Bar-Or, Director of the Center for Neuroinflammation and Neurotherapeutics, Perelman School of Medicine, University of Pennsylvania. “With only one 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.”
“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,” said Levi Garraway, M.D., Ph.D., chief medical officer and head of Global Product Development. “We look forward to advancing our regulatory submission following the upcoming readout of our second pivotal RMS study, FENhance 1.”
Additionally, a post-hoc analysis showed that fenebrutinib was superior to Ocrevus on a composite endpoint including two of the three components of cCDP12 (EDSS and 9HPT), with a 22% reduction in risk (HR 0.78; 95% CI: 0.64, 0.95).
Adverse events (AEs) commonly (≥10%) observed in the fenebrutinib group were comparable to Ocrevus: infections (67.0% vs 70.9%), nausea (12.0% vs 7.1%) and hemorrhage (10.2% vs 8.1%). Transient and reversible liver enzyme elevations were observed more often in the fenebrutinib group (13.3% vs 2.9%), and all cases resolved after study drug discontinuation. No Hy’s law cases (an indicator for potential severe liver injury) were observed. Serious AEs were reported in 19.1% of patients receiving fenebrutinib (vs 18.9% on Ocrevus) and led to 4.3% withdrawing from treatment (vs 3.0% on Ocrevus).
In the FENtrepid study there were 1.4% fatal cases in the fenebrutinib arm vs 0.2% in the Ocrevus arm, all of which were assessed as unrelated to the study treatment by the investigators and no pattern was observed in timing or cause. Epidemiological studies have shown that fatality rates are higher in people living with MS compared to the general population.1-4
Results were shared today as a late-breaking oral presentation at the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) Forum 2026 in San Diego, California. These data follow Genentech’s announcement in November 2025 that the FENtrepid study and the first of two Phase III relapsing multiple sclerosis (RMS) studies (FENhance 2) met their primary endpoints. Once the second RMS study (FENhance 1) has read out, which is expected in the first half of 2026, data from all Phase III fenebrutinib trials will be submitted to regulatory authorities.
About the FENtrepid study
FENtrepid is a Phase III multicenter, randomized, double-blind, double-dummy, parallel-group study to evaluate the efficacy and safety of fenebrutinib compared with Ocrevus in 985 adult patients with PPMS. Eligible participants were randomized 1:1 to receive treatment with either daily oral fenebrutinib (and placebo matched to intravenous [IV] Ocrevus) or IV Ocrevus (and placebo matched to oral fenebrutinib) for at least 120 weeks.
The primary endpoint is the time to onset of 12-week composite confirmed disability progression (cCDP12). The cCDP incorporates three measures of disability – total functional disability measured by the Expanded Disability Status Scale (EDSS), walking speed measured by the timed 25-foot walk (T25FW), and upper limb function measured by the nine-hole peg test (9HPT). This comprehensive composite endpoint offers greater sensitivity than the EDSS alone, capturing additional aspects of disability and often earlier. Key secondary endpoints include the time to onset of 24-week composite confirmed disability progression (cCDP24), 12-week confirmed disability progression (CDP12) and 24-week confirmed disability progression (CDP24).
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