Tolebrutinib Delays Disability Progression in nrSPMS in Phase 3 Trial

Treatment with tolebrutinib results in delay in time-to-onset of disability progression in non-relapsing secondary progressive multiple sclerosis (nrSPMS), according to a press release¹ and phase 3 trial² presented at the 40th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS), held in Copenhagen, Denmark, from September 18 to 20, 2024.

Previous research has highlighted the benefits of brain-penetrant Bruton tyrosine kinase (BTK) inhibitor tolebrutinib in reducing disability in MS.²

Researchers conducted a phase 3 double-blinded randomized placebo-controlled trial (HERCULES; ClinicalTrials.gov Identifier: NCT04411641) to determine the safety and efficacy of tolebrutinib in nrSPMS.^1,2

Primary study endpoint was time to onset of 6-month disability progression, measured using the Expanded Disability Status Scale (EDSS). Secondary endpoints included other measures of disability, magnetic resonance imaging (MRI) outcomes, and safety.^1,2

Eligible participants had nrSPMS and were aged from 18 to 60, with an EDSS score between 3.0 to 6.5, evidence of disability progression in the prior 12 months, and lack of clinical relapses during the prior 24 months before study assessment. Participants were randomly assigned 2:1 to receive 60 mg of once-daily oral tolebrutinib or placebo for approximately 48 months, and were stratified by age and country.^1,2

Between 2020 and 2023, 1131 patients (mean age, 48.9; women, 62%) were included in the study. At baseline, mean time since symptom onset was 17.3 years and most recent relapse was 7.5 years. Mean EDSS score was 5.53. The majority of patients received at least 1 disease-modifying therapy. A total of 145 participants (12.8%) had gadolinium-enhancing T1 lesions; mean T2 volume was 18.9 cm³.²

The researchers found that tolebrutinib vs placebo delayed time-to-onset of confirmed disability progression by 31% (hazard ratio [HR], 0.69; 95% CI, 0.55-0.88; P =.0026).In addition, the number of participants who had an improvement in disability was 10% with tolebrutinib vs 5% with placebo (HR, 1.88; 95% CI, 1.10-3.21; nominal P =.021).¹

Although adverse events occurred in 10% or fewer patients receiving tolebrutinib, these events were slightly higher in the tolebrutinib vs placebo group; for example, liver enzyme elevations were 4.1% in the tolebrutinib vs 1.6% in the placebo group. In addition, 0.5% of the tolebrutinib group had peak alanine transaminase (ALT) increases that occurred within the first 90 days of treatment; however, they resolved without treatment.The mortality rate across both groups was 0.3%.¹

Houman Ashrafian, MD, PhD, head of research and development at Sanofi noted, “With no treatment options currently available for the broad population of patients with [nrSPMS], tolebrutinib has demonstrated its ability to delay disability by targeting underlying drivers of the disease.”¹

Multiple study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of the authors’ disclosures.