Phase III HERCULES Trial Shows Tolebrutinib Significantly Slows Disability Progression in Non-Relapsing Secondary Progressive MS

Credit: ralwel | stock.adobe.com

Findings from the Phase III HERCULES trial (NCT04411641) published by The New England Journal of Medicine (NEJM) show tolebrutinib (Sanofi) significantly delayed disability progression in patients with non-relapsing secondary progressive multiple sclerosis (nrSPMS).^1,2 Investigators said these results demonstrate the potential of tolebrutinib as a first-in-class, brain-penetrant Bruton’s tyrosine kinase (BTK) inhibitor in treating nrSPMS, which currently lacks any FDA-approved treatments.

“Tolebrutinib represents a new class of therapy for the treatment of multiple sclerosis. In this large Phase III study, tolebrutinib was found to slow the progression of disability in a subset of multiple sclerosis for which we have no approved therapies—non-relapsing secondary progressive disease,” HERCULES global steering committee chair Robert Fox, MD, vice chair of Research at Cleveland Clinic’s Neurological Institute, Cleveland, Ohio, said in a press release. “The results of this study signal a new chapter in multiple sclerosis because we finally found a potential way to treat non-relapsing secondary progressive forms.”³

Tolebrutinib was developed to target smoldering neuroinflammation, which is among the primary drivers of disability progression in patients with MS, according to Sanofi. In December 2024, the FDA granted Breakthrough Therapy Designation to tolebrutinib for nrSPMS based on positive findings from the HERCULES trial.⁴

“Tolebrutinib is an oral, brain-penetrant, and bioactive BTK inhibitor intended to target disease-associated microglia and B cells within the [central nervous system (CNS)] in addition to their counterparts in the periphery,” the study authors wrote in NEJM. “With the sole exception of ocrelizumab, which is indicated for primary progressive disease, currently approved disease-modifying therapies are limited to relapsing forms of multiple sclerosis, including active secondary progressive disease. No treatment has shown efficacy in slowing disability accrual in persons with secondary progressive multiple sclerosis without relapses.”¹

Trial Design

The double-blind, randomized, HERCULES trial evaluated tolebrutinib’s efficacy and safety in patients with nrSPMS compared with placebo. Enrollment criteria included an SPMS diagnosis with an expanded disability status scale (EDSS) score between 3.0 and 6.5, no clinical relapses across the prior 24-month period, and documented evidence of disability progression over the preceding 12 months. A total of 1131 participants were randomly assigned in a 2:1 ratio to receive a daily dose of oral tolebrutinib (n = 754) or matching placebo (n = 377) for approximately 48 months, with a median follow-up of 133 weeks.

The trial’s primary endpoint was six-month confirmed disability progression (CDP), defined as an increase of ≥1.0 point from baseline EDSS score if the score is ≤5.0, or increase of ≥0.5 point if the baseline EDSS score was >5.0. The trial’s secondary endpoints included safety and tolerability; time to onset of three-month CDP as per EDSS score; amount of new or enlarging T2 hyperintense lesions detected by MRI; time to onset of confirmed disability improvement; and three-month change in nine-hole peg test and T25-FW test.

Results show that 22.6% of participants administered tolebrutinib had confirmed disability progression (CDP) sustained for at least six months compared to 30.7% in the placebo cohort (hazard ratio [HR], 0.69; 95% confidence interval [CI], 0.55 to 0.88; P=0.003). Compared to placebo, tolebrutinib was found to delay time to onset of six-month CDP by 31% (HR 0.69; 95% CI 0.55-0.88; p=0.003).

“By targeting disability progression mechanisms behind the blood-brain barrier, tolebrutinib has the potential to be a practice-changing therapeutic option for people living with multiple sclerosis,” said Erik Wallström, MD, PhD, Sanofi global head of Neurology Development, in a press release.³

In terms of safety, serious adverse events were reported in 15.0% of patients administered tolebrutinib compared to 10.4% of patients administered placebo. Four percent of patients administered tolebrutinib showed increases in alanine aminotransferase levels of greater than three times the normal range upper limit compared to 1.6% in the placebo cohort.

“Tolebrutinib effectively penetrates the CNS, reaching cerebrospinal fluid concentrations that exceed the 90% inhibitory concentration,” the study authors wrote. “This feature has not been observed for other tested BTK inhibitors, including evobrutinib, which was not associated with a lower risk of disability worsening than teriflunomide in two phase 3, randomized trials involving participants with relapsing multiple sclerosis. Additional analyses will evaluate the effect of tolebrutinib on pathophysiological substrates of chronic CNS neuroinflammation, including disease-associated microglial activity around chronic active lesions.”¹

References

1. Fox R., et al. Tolebrutinib in Nonrelapsing Secondary Progressive Multiple Sclerosis. N Engl J Med 2025. DOI: 10.1056/NEJMoa2415988.

2. Nonrelapsing Secondary Progressive Multiple Sclerosis (NRSPMS) Study of Bruton's Tyrosine Kinase (BTK) Inhibitor Tolebrutinib (SAR442168) (HERCULES). ClinicalTrials.gov. Updated February 3, 2025. Accessed April 10, 2025. https://clinicaltrials.gov/study/NCT04411641

3. Press Release: Tolebrutinib phase 3 data published in NEJM demonstrate benefit on disability progression in multiple sclerosis. Sanofi. April 8, 2025. Accessed April 10, 2025. https://www.sanofi.com/en/media-room/press-releases/2025/2025-04-08-17-11-11-3057931

4. Tolebrutinib designated Breakthrough Therapy by the FDA for non-relapsing secondary progressive multiple sclerosis. Sanofi. December 13, 2024. Accessed April 10, 2025. https://www.sanofi.com/en/media-room/press-releases/2024/2024-12-13-06-00-00-2996609