Tolebrutinib Preserves Notable MS Quality-of-Life Features in Nonrelapsing Secondary Progressive Multiple Sclerosis

A post-hoc analysis of the phase 3 HERCULES trial (NCT04411641) revealed that tolebrutinib (Sanofi), an investigational Bruton tyrosine kinase (BTK) inhibitor under review, led to sustained health-related quality of life (HRQoL) outcomes among patients with nonrelapsing secondary progressive multiple sclerosis (nrSPMS).¹

Presented at the 2025 European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) Congress, held September 24-26, 2025, in Barcelona, Spain, the analysis assessed tolebrutinib’s impact on HRQoL using the Multiple Sclerosis Quality of Life-54 (MSQoL-54) questionnaire. Patients underwent assessments at baseline and every 6 months until the end of study (EOS) visit, which ranged between 18 to 43 months post baseline depending on enrolment date.

Led by Patrick Vermersch, MD, PhD, vice president of research and head of one of the departments of neurology at the University of Lille, the study looked at specific domains of the MSQoL-54, from which Physical and Mental Health Composite (HC) scores were derived. Coming into the study, the mean composite score in the intent-to-treat population (n = 1131) was 46.4 (SD, 15.5) for the Physical HC and 59.3 (SD, 18.9) for the Mental HC. Of note, role limitation-physical, physical function, and change in health were the 3 most impacted subscales at study entry, with scores of 26.3, 29.3, and 31.5, respectively.

After 12 months of treatment, no between-group differences were statistically significant for any score, further supporting tolebrutinib’s impact on HRQoL. At the 24-month time point, mean difference in Physical HC scores (least square mean difference [LSMD], 3.10; 95% CI, 1.27-4.94; P = .0009) and Mental HC scores (LSMD, 4.14; 95% CI, 1.88-6.39; P = .0003) favored tolebrutinib. When averaged across all visits, mean differences favored tolebrutinib for the Physical HC score (LSMD, 1.78; 95% CI, 0.13-3.42; P = .0344) and the social function, overall QoL, and change in health domain scores.

Additional data at 24 months showed favorable outcomes for tolebrutinib on 6 of the other MSQoL-54 subdomains, including physical function, role limitation-psychical, role limitation-emotional, emotional well-being, social function, and overall QoL. At the conclusion of the study, no significant differences were observed for Physical and Mental HC scores, and most of the subscale scores.

Tolebrutinib, an oral, brain-penetrant therapy designed to target smoldering neuroinflammation, is currently under review by both the FDA and the EMA as a treatment for nrSPMS. The agent originally had a PDUFA date of September 28, 2025, but the FDA recently pushed back the timetable for review until late December, citing that additional information to the application constituted a major amendment.² If approved, it would become the only marketed BTK available for the treatment of MS, as well as the first marketed BTK specific to patients with nrSPMS.

READ MORE: ECTRIMS Studies Showcase Treatment Benefits of Ofatumumab for NMOSD

The new drug application, accepted in March, was based on data from HERCULES, as well as 2 other phase 3 studies (GEMINI 1 [NCT04410978] and GEMINI 2 [NCT04410991]) in relapsing MS. HERCULES comprised 1131 patients with nrSPMS who were randomly assigned to tolebrutinib or placebo for 48 months. Overall, treatment with the investigational agent resulted in delayed time to onset of 6-month confirmed disability progression (CDP), the primary end point, by 31% compared with placebo (HR, 0.69; 95% CI, 0.55-0.88; P = .0026).³

Additional data from HERCULES revealed a 2-fold increase in the number of patients with confirmed disability improvement on tolebrutinib relative to placebo (HR, 1.88; 95% CI, 1.10-3.21; P = .021). A post-hoc analysis also showed that paramagnetic rim lesion (PRL) count has an impact on the therapy’s efficacy. In HERCULES, therapy reduced the risk of 6-month CDW by 54% in patients with at least 4 baseline PRLs. In GEMINI, similar reductions were seen—46% with 1 to 3 PRLs and 49% with at least 4 PRLs—though these data are unrelated to the current FDA submission for tolebrutinib.⁴

Tolebrutinib remains in development for patients with primary progressive MS, with the phase 3 PERSEUS trial (NCT04458051) expected to have data read out later this year. PERSEUS, a double-blind, placebo-controlled study, enrolled around 767 participants with primary progressive MS, aged 18 to 55 years, with Expanded Disability Status Scale scores of 2.0 to 6.5. The study’s primary end point is delay in CDP over 6 months, with secondary end points that include MRI lesion activity, cognitive performance, physical function, QoL, and safety/tolerability.

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REFERENCES
1. Vermersch P, Oreja-Guevara C, Traboulsee A, et al. Effects of Tolebrutinib on MSQoL-54 in the HERCULES Phase 3 trial in nrSPMS. Presented at: ECTRIMS Forum 2025; September 24-26; Barcelona, Spain. Abstract P810.
2. Press Release: Update on the US regulatory review of tolebrutinib in non-relapsing, secondary progressive multiple sclerosis. News release. September 22, 2025. Accessed September 23, 2025. https://www.globenewswire.com/news-release/2025/09/22/3153624/0/en/Press-Release-Update-on-the-US-regulatory-review-of-tolebrutinib-in-non-relapsing-secondary-progressive-multiple-sclerosis.html
3. Fox RJ, Bar-Or A, Traboulsee A, et al. Efficacy and Safety of Tolebrutinib Versus Placebo in Non-Relapsing Secondary Progressive Multiple Sclerosis: Results from the Phase 3 HERCULES Trial. Presented at: 2024 ECTRIMS; September 18-20; Copenhagen, Denmark. Abstract 4027.
4. Oh J, Fox RJ, Arnold DL, et al. LB1.1. Paramagnetic Rim Lesions as a Prognostic and Predictive Biomarker in the Tolebrutinib Phase 3 Trials for Disability Outcomes. Presented at: 2025 ACTRIMS Forum; February 27-March 1; West Palm Beach, FL. ABSTRACT LB1.1