ACTRIMS 2026: Fenebrutinib matches Ocrevus in PPMS trial
BTK inhibitor reduces disability progression risk
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- Fenebrutinib matched Ocrevus in reducing disability progression in PPMS.
- This oral treatment significantly slowed disability progression in a Phase 3 trial.
- Genentech plans to seek approval for fenebrutinib following further trial results.
The investigational BTK inhibitor fenebrutinib was as effective as the approved therapy Ocrevus (ocrelizumab) at reducing the risk of disability progression in people with primary progressive multiple sclerosis (PPMS), meeting the main goal of a Phase 3 trial.
According to fenebrutinib’s developer, Genentech, the therapy is the first in more than 10 years to slow disability progression in this multiple sclerosis (MS) population. It has shown benefit in other trials for people with relapsing forms of the disease.
The company sees the oral treatment as a potential first-in-class therapy across MS types.
“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 for Genentech, said in a company press release “We look forward to advancing our regulatory submission following the upcoming readout of our second pivotal [relapsing MS] study,” expected in the first half of this year.
The PPMS data came from the Phase 3 FENtrepid clinical trial (NCT04544449) and were shared by trial investigator Amit Bar-Or, MD, a professor at the University of Pennsylvania, in an oral presentation titled, “Efficacy and Safety of Fenebrutinib vs Ocrelizumab in Primary Progressive Multiple Sclerosis: Primary Results of the Phase III FENtrepid Study,” at the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) Forum 2026, held Feb. 5-7 in San Diego and virtually.
Few therapies for PPMS
While more than 20 therapies are approved for MS, most are specifically indicated for relapsing forms of the disease. Currently, only Ocrevus and its under-the-skin formulation Ocrevus Zunovo (ocrelizumab and hyaluronidase-ocsq) are approved for PPMS.
Fenebrutinib is designed to block BTK, an enzyme involved in the activation of immune cells that contribute to MS-related inflammation and nervous system damage. Not only does it target circulating immune cells that drive MS relapses and new MRI activity, but it can also get into the brain and spinal cord to target cells involved in progressive disease.
Its developers hope that fenebrutinib will have benefits “across the MS disease continuum,” Bar-Or said.
FENtrepid involved 985 adults with PPMS who were randomly assigned to receive oral fenebrutinib (twice daily) or into-the-vein Ocrevus (once every six months) for at least 120 weeks, or a little under 2.5 years. The study’s main goal was to show that fenebrutinib is at least as effective as Ocrevus in delaying the onset of confirmed disability progression.
“This, I think for many of us, was a pretty brave, bold trial to embark on with a head-to-head to the only approved therapy in primary progressive MS,” Bar-Or noted. Genentech previously reported positive results from the trial, which the researcher expanded on in the presentation.
Evaluating progression
Disability progression was evaluated with a composite 12-week confirmed disability progression (cCDP12) measure that incorporated the Expanded Disability Status Scale (EDSS), which measures functional disability; the timed 25-foot walk test (T25FW), which assesses walking function; and the nine-hole peg test (9HPT), which measures hand and finger dexterity.
Progression was defined as worsening on the EDSS or at least a 20% worsening on the T25FW or 9HPT that was sustained for at least three months. If a patient showed a sustained progression on any of those measures, they were considered to have met the primary endpoint of cCDP12.
The trial met its main goal of showing that fenebrutinib was as good as Ocrevus at delaying cCDP12. While the study was not designed to show significant differences between the drugs, the data demonstrated that fenebrutinib numerically reduced the risk of cCDP12 by 12% compared with Ocrevus. The difference was evident as early as six months and persisted throughout the treatment duration.
The strongest effect of fenebrutinib was observed in the 9HPT, with the experimental treatment lowering the risk of worsening dexterity by 26% compared with Ocrevus. It reduced the risk of worsening EDSS by 16% and T25FW by 7%.
In later analyses, fenebrutinib was found to lower the risk of a combined endpoint involving only EDSS and 9HPT by 22%.
Had this been the primary endpoint of the study, Bar-Or said, “fenebrutinib would have demonstrated superiority over [Ocrevus],” meaning it would have statistically outperformed the approved therapy in slowing disability progression.
These benefits of fenebrutinib were observed across patient subgroups, regardless of age, sex, time since symptom onset, prior treatment use, and disability level. Fenebrutinib had a greater relative effect over Ocrevus in the subset of people without inflammatory lesions on MRI scans — a type of damage more closely associated with relapsing disease.
That finding “reinforces the notion that this drug is having its effect in this trial more based on individuals with nonrelapsing progressive disease,” Bar-Or said.
The side effect profiles of fenebrutinib and Ocrevus were similar, although temporary and reversible elevations in liver enzymes were more common with fenebrutinib. More deaths occurred in the fenebrutinib group, but they were all considered unrelated to treatment.
An open-label extension part of the trial, in which all participants are receiving fenebrutinib, is ongoing.
“Hopefully, the subsequent trial data will provide us with further insight in terms of how fenebrutinib impacts both relapsing and nonrelapsing progressive disease,” Bar-Or said.
The Multiple Sclerosis News Today team is providing virtual coverage of the ACTRIMS Forum 2026 from Feb. 5-7. Go here to see the latest stories from the conference.
