Tolebrutinib is not effective in PPMS in the PERSEUS trial

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.