Neurologists and MS specialists managing patients with nonrelapsing secondary progressive multiple sclerosis should note that the HERCULES trial reported a lower risk of confirmed disability progression sustained for at least 6 months with tolebrutinib versus placebo, using the trial dose of 60 mg once daily ^[1]. The trial results support that tolebrutinib produced a numerical and hazard-ratio–based benefit on the trial primary end point in this specific population ^[1]. Key open questions for clinicians include how tolebrutinib’s benefit–risk profile will compare with other investigational and approved agents in progressive MS and which patients with nonrelapsing SPMS are most likely to derive net clinical benefit?

Q1 What did the HERCULES trial show?

The HERCULES trial showed that tolebrutinib lowered the risk of confirmed disability progression sustained for at least 6 months versus placebo in participants with nonrelapsing secondary progressive multiple sclerosis, with a hazard ratio of 0.69 (95% CI, 0.55 to 0.88) and event rates of 22.6% in the tolebrutinib group versus 30.7% in the placebo group. The randomized comparison used a time-to-event analysis for the primary end point.

Q2 Who was enrolled in HERCULES?

HERCULES enrolled participants with nonrelapsing secondary progressive multiple sclerosis. A total of 1,131 participants were randomized in a 2:1 ratio, with 754 assigned to tolebrutinib and 377 to placebo. The median follow-up reported in the trial was 133 weeks. Detailed baseline demographics and inclusion/exclusion criteria were reported in the primary trial publication.

Q3 What were the side effects reported in the trial?

In HERCULES, serious adverse events occurred in 15.0% of participants in the tolebrutinib group and in 10.4% of those in the placebo group. Elevations in alanine aminotransferase (ALT) to more than 3 times the upper limit of normal were reported in 4.0% of participants receiving tolebrutinib versus 1.6% receiving placebo. Additional safety details are reported in the trial publication.

Q4 What does the HERCULES result mean for practice now?

The HERCULES results indicate a lower risk of disability progression sustained for at least 6 months with tolebrutinib versus placebo in nonrelapsing SPMS within the trial context, using tolebrutinib 60 mg once daily. Clinicians should await regulatory decisions, label information, and prescribing guidance before routine use and should consult the full trial report and future prescribing information for patient selection and monitoring details.

Clinicians should consult current prescribing information for complete dosing guidance.