The investigational Bruton’s tyrosine kinase (BTK) inhibitor fenebrutinib demonstrates its noninferiority to ocrelizumab in reducing the risk of disability progression in patients with primary progressive multiple sclerosis (PPMS) in the phase III FENtrepid study.
Specifically, fenebrutinib use resulted in a 12-percent decrease in disability progression risk relative to ocrelizumab as early as 24 weeks.
“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,” lead study author Professor Amit Bar-Or, Director of the Center for Neuroinflammation and Neurotherapeutics, Perelman School of Medicine, University of Pennsylvania, US, said in a press statement.
“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.” [https://www.roche.com/media/releases/med-cor-2026-02-07]
Overall, 985 patients with PPMS (mean age 48.9 years, median baseline Expanded Disability Status Scale [EDSS] score 5.0) were included in the analysis. Of these, half were female (49.5 percent) and the majority (84 percent) had no prior exposure to disease-modifying therapies. The mean durations since MS symptom and diagnosis was 9.0 and 4.7 years, respectively. [EAN 2026, abstract EPO-0779]
Disability status
Compared with ocrelizumab, fenebrutinib reduced the risk of disability progression by 12 percent, as measured by the time to onset of 12-week composite confirmed disability progression (cCDP12; hazard ratio [HR], 0.88, 95 percent confidence interval [CI], 0.75‒1.03), with curves separating as early as week 24. [https://www.roche.com/media/releases/med-cor-2026-02-07]
“A consistent treatment effect on cCDP12 was observed across patient subgroups and for the entire treatment duration,” according to Bar-Or and colleagues.
The primary endpoint, cCDP12, included the confirmed disability progression based on the EDSS for functional disability, as well as the timed 25-foot walk for walking speed and the nine-hole peg test (9HPT) for upper limb function.
Fenebrutinib showed its strongest effect on reductions in the risk of worsening on the 9HPT (HR, 0.74, 95 percent CI, 0.56‒0.98) relative to ocrelizumab. In a post hoc analysis, fenebrutinib also exhibited its superiority to ocrelizumab on two of the three components of cCDP12 (ie, EDSS and 9HPT), with a risk reduction of 22 percent (HR, 0.78, 95 percent CI, 0.64‒0.95).
Safety
The incidence of adverse events (AEs) was similar between the fenebrutinib and ocrelizumab groups: infections (67.0 percent vs 70.9 percent), nausea (12.0 percent vs 7.1 percent), and haemorrhage (10.2 percent vs 8.1 percent).
Serious AEs were also comparable between treatment groups (19.1 percent vs 18.9 percent), as was withdrawal from treatment (4.3 percent vs 3.0 percent). Deaths occurred in 1.4-percent of patients on fenebrutinib and 0.2 percent of those treated with ocrelizumab, but these were deemed unrelated to the study treatment by the investigators.
In a separate presentation, Bar-Or stated that “a multidisciplinary team approach involving a range of healthcare professionals is the optimal way of managing MS. However, many people with MS still do not have access to multidisciplinary care.” [Ann Indian Acad Neurol 2009;12:296-306; Mult Scler 2016;22,34-46; Health Expert 2024;27:e14042; Front Neurol 2023;14:1101521]
“Both pharmacological and non-pharmacological interventions should be considered as part of holistic treatment for people with MS,” he added. [www.eanvirtualcongress.org/programme/session/91735]
FENtrepid
The phase III, multicentre, randomized, double-blind FENtrepid study investigated the noninferiority of fenebrutinib vs ocrelizumab in adult patients with PPMS (2017 McDonald criteria; EDSS score 3.0‒6.5). Participants were randomly allocated in a 1:1 ratio to receive oral fenebrutinib 200 mg twice daily or intravenous ocrelizumab 600 mg every 24 weeks
The investigational BTK inhibitor fenebrutinib boasts of an optimized pharmacokinetics profile and high potency. “While most current BTK inhibitors are covalent and irreversible, meaning they form a permanent chemical bond with the enzyme, fenebrutinib binds and then eventually releases the enzyme. These design features may help limit off-target effects,” according to the investigators. [https://www.roche.com/media/releases/med-cor-2026-02-07]