Genentech, part of the Roche Group, reported positive Phase III data from the FENtrepid trial in which its investigational Bruton’s tyrosine kinase (BTK) inhibitor fenebrutinib met its primary endpoint in individuals with primary progressive multiple sclerosis (PPMS), a form of MS with few effective treatment options.
The FENtrepid results, presented at the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) Forum 2026, showed that fenebrutinib was non‑inferior to Ocrevus (ocrelizumab), the only FDA‑approved therapy for PPMS, in slowing disability progression over at least 120 weeks.
The primary endpoint of the trial measured the time to onset of 12-week composite confirmed disability progression (cCDP12). Fenebrutinib demonstrated a 12% reduction in the risk of cCDP12 compared with Ocrevus, with separation of treatment curves beginning as early as Week 24.
Importantly, fenebrutinib demonstrated a particularly robust effect on upper‑limb function, reducing the risk of worsening on the nine‑hole peg test (9HPT) by 26% compared with Ocrevus, a meaningful indicator of daily functioning, giving it a potential advantage over Ocrevus.
In a post hoc analysis, Roche combined scores from the 9HPT and the Expanded Disability Status Scale (EDSS) as a composite endpoint to assess functional disability. Fenebrutinib outperformed Ocrevus on this metric with a 22% reduction in risk. The composite measure used in the primary analysis also included a timed 25‑foot walk test.
PPMS affects roughly 15% of people living with MS and is characterized by steadily worsening disability without clear relapses. Fenebrutinib is an oral, CNS‑penetrant BTK inhibitor designed to target both inflammatory and neurodegenerative pathways implicated in MS. By blocking BTK, a key enzyme in B‑cell and microglial activation, the therapy aims to address both relapsing and progressive aspects of the disease.
With Ocrevus remaining the only approved treatment in the space, fenebrutinib’s positive Phase III results mark the first significant advance in over a decade for PPMS therapy.
The therapy’s performance in PPMS follows recent positive data from the FENhance 2 Phase III study in relapsing multiple sclerosis (RMS), which met its primary endpoint by significantly reducing relapse rates compared with teriflunomide.
If supported by the pending FENhance 1 readout, expected in the first half of 2026, Roche plans to compile all Phase III fenebrutinib data for regulatory submission in both RMS and PPMS later this year.
The safety profile of fenebrutinib in FENtrepid was generally comparable to Ocrevus, with similar rates of common adverse events such as infections and nausea. Transient and reversible liver enzyme elevations were reported more frequently in the fenebrutinib arm, but no cases meeting criteria for severe liver injury were observed.
BTK inhibitors have been associated with liver enzyme elevations and, in rare cases, severe drug-induced liver injury.
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Fenebrutinib had previously been placed on partial FDA hold in 2023 after two cases of elevated liver enzymes in a relapsing MS trial, but only one met Hy’s Law criteria, an indicator of possible severe liver injury. Roche has reported no further cases after implementing liver monitoring.
Analysts note fenebrutinib could become the first BTK inhibitor approved for MS, particularly given the unmet need in PPMS, but caution that liver safety monitoring will likely be required, potentially giving Novartis’ remibrutinib a competitive edge if it maintains a cleaner safety profile. Roche CEO Teresa Graham emphasized it is too early to compare the two molecules directly.
In reporting by Fierce Pharma, on a January earnings call, Graham also cautioned against drawing comparisons to Sanofi’s tolebrutinib, which the FDA rejected for MS due to severe drug-induced liver injury seen in prior trials.
Roche plans to report a second Phase III trial in relapsing MS in the first half of 2026, after which it will pursue regulatory approval in both RMS and PPMS.
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