Progressive MS – Medicom Eduction

In the randomised phase 3 FENtrepid trial, fenebrutinib was non-inferior to ocrelizumab at reducing the risk of disability progression in patients with primary progressive MS (PPMS). The oral Bruton tyrosine kinase inhibitor (BTKi) fenebrutinib significantly slowed disability progression [1].

Fenebrutinib is an oral, highly selective, non-covalent, reversible BTKi that penetrates the central nervous system. In the phase 2 trial FENopta (NCT05119569), it rapidly reduced acute inflammatory activity in relapsing MS [2]. The FENtrepid trial (NCT04544449) evaluated the efficacy and safety of fenebrutinib in adult patients with PPMS. Prof. Amit Bar-Or (University of Pennsylvania, PA, USA) noted that a “bold” decision was taken to compare fenebrutinib head-to-head with ocrelizumab, which remains the only approved therapy for PPMS.

FENtrepid was designed as a phase 3, multicentre, randomised, double-blind, double-dummy, parallel-group study. The composite primary endpoint was 12-week confirmed disability progression (cCDP-12), defined as an increase in the Expanded Disability Status Scale (EDSS), Timed 25-Foot Walk Test (T25-FW), and/or 9-Hole Peg Test (9-HPT).

A total of 985 patients with PPMS were randomised 1:1 to receive either oral fenebrutinib 200 mg twice daily plus placebo infusions, or intravenous ocrelizumab 600 mg plus oral placebo every 24 weeks. The mean age at baseline was 48.9 years (SD 10.3).

The median baseline EDSS score was 5.0; the mean duration since MS symptom onset and diagnosis was 9.0 and 4.7 years, respectively. The trial achieved its primary goal of demonstrating non-inferiority of fenebrutinib versus ocrelizumab at delaying cCDP-12. cCDP-12 occurred in 58.8% of patients in the fenebrutinib group versus 66.1% in the ocrelizumab group, representing a relative risk reduction of 12%. As this trial was not powered to detect superiority, this difference was not statistically significant. The strongest treatment effect of fenebrutinib was observed on the 9-HPT component. Treatment effects were consistent across subgroups. The rate of serious adverse events was similar between groups: 19.1% with fenebrutinib versus 18.9% with ocrelizumab. In the fenebrutinib arm, a higher incidence of liver enzyme elevations was observed, as well as a higher number of fatalities (7 versus 1); none of the fatalities was considered related to the study drug.

Prof. Bar-Or added that fenebrutinib reduced the risk of a combined endpoint comprising EDSS and 9-HPT only by 22%. “Had this been the primary endpoint, fenebrutinib would have demonstrated superiority over ocrelizumab.” He also observed that fenebrutinib showed greater relative benefits in patients with non-relapsing progressive disease.

Bar-Or A, et al. Efficacy and safety of fenebrutinib vs ocrelizumab in primary progressive multiple sclerosis: Primary results of the phase III FENtrepid study. LB1.5, ACTRIMS Congress 2026, 4–7 February, San Diego, California, USA.
Bar-Or A, et al. Lancet Neurol. 2025;24(8):656-666.

In the phase 3 PERSEUS trial, tolebrutinib did not meet the primary endpoint of time to onset of composite confirmed disability progression (cCDP) after 6 months. No significant differences compared with placebo were observed in any of the secondary disability endpoints. Safety findings were consistent with those from previous phase 3 trials of tolebrutinib.

Tolebrutinib is an oral, brain-penetrant, and bioactive Bruton tyrosine kinase inhibitor (BTKi). Dr Robert Fox (Cleveland Clinic, OH, USA) presented the main results from the PERSEUS trial (NCT04458051), evaluating the efficacy and safety of tolebrutinib in primary progressive MS (PPMS) [1]. The 767 participants were aged 18–55 years, had an Expanded Disability Status Scale (EDSS) score of 2.0–6.5, positive cerebrospinal fluid findings, and could not or would not use ocrelizumab. Participants were randomised 2:1 to once-daily oral tolebrutinib 60 mg (n=515) or placebo (n=252). The composite primary endpoint was sustained increase over ≥6 months in EDSS (by ≥1 point for a baseline score of ≤5.5, or by ≥0.5 points with a score of >5.5), Timed 25-Foot Walk (T25-FW) by ≥20%, and/or 9-Hole Peg Test (9-HPT) by ≥20%.

The mean age was 45.3 years, and the mean time since PPMS diagnosis was 4.2 years. At baseline, the mean EDSS was 4.9, 59% of participants were treatment-naïve, and 89% had no gadolinium-enhancing (Gd+) lesions on MRI. In total, 588 patients completed the trial: 398 (77.3%) in the tolebrutinib group and 190 (75.4%) in the placebo group.

Tolebrutinib did not differ from the placebo on the primary endpoint, with a cumulative incidence of cCDP of 66% versus 61%, respectively (HR 1.01; 95% CI 0.81–1.26; P=0.94). Over half of the composite events were driven by the T25-FW component (59% and 55%, respectively). For the secondary endpoint of time to 6-month confirmed disability progression (CDP), Dr Fox noted a non-significant trend favouring tolebrutinib. Tolebrutinib was associated with fewer new or enlarging T2-lesions, with an adjusted rate ratio of 0.54 versus placebo (95% CI 0.35–0.83; P=0.005), and with less brain volume loss after 4 years (P=0.01). The general adverse event profile, including the risk of drug-induced liver injury, was consistent with previous tolebrutinib studies.

“Disability accumulation observed in this PERSEUS PPMS population appears to be less impacted by tolebrutinib than seen in other trials of this BTK inhibitor,” Dr Fox concluded. He highlighted the key differences between PERSEUS and the phase 3 ORATORIO trial of ocrelizumab in PPMS [2]. Fewer participants in PERSEUS had Gd+ T1 lesions at baseline, and a higher proportion had been previously treated.

Reich DS, et al. Efficacy and safety of tolebrutinib versus placebo in primary progressive multiple sclerosis: Results from the phase 3 PERSEUS trial. LB1.4, ACTRIMS Congress 2026, 4–7 February, San Diego, California, USA.
Montalban X, et al. N Engl J Med. 2017;376(3):209-20.

Fenebrutinib is non-inferior to ocrelizumab in PPMS

Tolebrutinib is not effective in PPMS in the PERSEUS trial