- Preliminary Phase 3 trial results announced in November 2025 showed fenebrutinib was not inferior to ocrelizumab (an existing treatment) in delaying confirmed disability progression in primary progressive MS.
- More detailed results released in February 2026 show the strongest effect in preserving arm function, and a safety profile generally comparable to that of ocrelizumab.
- These results will form part of submissions to regulators, to potentially provide a new oral treatment option for people with primary progressive MS.
What is fenebrutinib?
Fenebrutinib is an experimental oral drug being studied for its ability to treat both relapsing MS and primary progressive MS. It is in a class of medications known as Bruton’s tyrosine kinase (BTK) inhibitors. BTK is an enzyme (a biological molecule that speeds up reactions within cells) that is important for many immune “B cells” as well as immune cells in the brain and spinal cord, known as microglia.
This means that BTK inhibitors can target the immune cells that are thought to be involved in disease progression inside and outside the brain. Additionally, because BTK inhibitors only target B cells that contain BTK, rather than all B cells, they offer a potentially safer and more targeted treatment than those currently available.
Other BTK inhibitors that have been tested in MS, evobrutinib and tolebrutinib, bind to BTK in a permanent way, while fenebrutinib binds to BTK reversibly.
Fenebrutinib and primary progressive MS – the FENtrepid trial
There is currently only one medication, ocrelizumab, approved in Australia for primary progressive MS (PPMS), however, it is not listed on the Pharmaceutical Benefits Scheme (PBS). BTK inhibitors, which can penetrate the brain and spinal cord, therefore represent a promising treatment for progressive forms of MS.
A Phase III clinical trial of fenebrutinib in PPMS, FENtrepid, compared outcomes of participants on fenebrutinib with those on ocrelizumab.
FENtrepid was designed as a “non-inferiority trial”, where the goal is not to prove that a new treatment is better (as in a traditional design), but rather that it is “not significantly worse” than an established treatment.
The preliminary results, released in November 2025, showed that fenebrutinib was non-inferior to ocrelizumab as measured by the delay in the onset of composite confirmed disability progression over a period of at least 120 weeks of treatment.
The 12-week composite confirmed disability progression measure (cCDP12) 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). Any increase in disability is retested 12 weeks later to confirm. It is considered more sensitive than EDSS and captures a wider range of disability.
New results from FENtrepid released
More detailed analysis of the FENtrepid trial was released at the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) Forum 2026, on 7 February in San Diego, California.
Compared with ocrelizumab, fenebrutinib was associated with a 12% reduction in the risk of disability progression. Although the trial was not designed to be able determine this definitively, fenebrutinib appears to be a little better at limiting progression of disability in PPMS than ocrelizumab. This difference from ocrelizumab was found as early as 24 weeks into the trial and was observed throughout (at least 120 weeks; up to 240 weeks for some)
Results for the various components of disability progression were also analysed. The strongest treatment effect was seen for arm function, with fenebrutinib reducing the risk of worsening arm function (9HPT) by 26% compared with ocrelizumab. If EDSS and 9HPT were both included in the analysis, there was a 22% reduction in the risk of disability progression for these measures compared to ocrelizumab.
Safety profile of fenebrutinib in PPMS
In general, the safety profile of fenebrutinib was similar to that of ocrelizumab. There were common side effects in at least 10% of participants, including infections (67.0% vs 70.9%), nausea (12.0% vs 7.1%), and haemorrhage (10.2% vs 8.1%; percentages represent fenebrutinib vs ocrelizumab)
BTK inhibitors are known to raise liver enzymes in some individuals. In FENtrepid, increased liver enzymes were observed more frequently in participants receiving fenebrutinib than ocrelizumab (13.3% vs 2.9%). However, these were temporary, and all cases resolved when the study treatment was stopped.
There were no cases of severe liver injury in this study, a safety issue that has been seen occasionally in trials of other BTK inhibitors.
Serious side effects occurred at similar rates in people taking fenebrutinib and ocrelizumab (19.1% and 18.9%, respectively). These side effects led some participants to stop treatment (4.3% with fenebrutinib and 3.0% with ocrelizumab).
A small number of fatal events occurred in the study – 1.4% in the fenebrutinib arm and 0.2% in the ocrelizumab arm. These events were assessed as unrelated to study treatment, and no consistent pattern in timing or cause was identified.
What does this mean for people with MS?
FENtrepid is the first positive Phase 3 clinical trial for PPMS in over a decade. The results suggest that fenebrutinib may represent a highly effective oral treatment for PPMS, directly targeting the biology of progressive disease in the brain.
There have been three Phase 3 trials of fenebrutinib conducted in MS. Two have been completed and reported positive outcomes (FENtrepid and FENhance 2). The trial sponsor plans to submit applications to regulators for the use of fenebrutinib in MS once the final trial is complete (FENhance 1 in relapsing MS). This is expected in the first half of 2026.
Given that ocrelizumab is currently the only approved therapy for PPMS in Australia and is not PBS‑listed, the prospect of a second treatment option represents a significant milestone towards improving access to treatments for people living with PPMS.
