Trial results for the HERCULES study (NCT04411641) investigating tolebrutinib for non-relapsing secondary progressive multiple sclerosis (NRSPMS) were posted on ClinicalTrials.gov on 2025-06-18. The study showed that tolebrutinib significantly reduced the risk of 6-month confirmed disability progression (CDP) with a hazard ratio of 0.693 (p-value 0.0026) compared to placebo, and also reduced the mean number of new T2-hyperintense lesions.

Background

Tolebrutinib is a Bruton's Tyrosine Kinase (BTK) inhibitor. This trial investigated its potential as a treatment for non-relapsing secondary progressive multiple sclerosis (NRSPMS), a form of multiple sclerosis characterized by progressive neurological decline without distinct relapses.

Trial design

The HERCULES study (NCT04411641) was a Phase 3, randomized, placebo-controlled trial that enrolled 1131 participants. The study investigated tolebrutinib 60 mg compared to placebo in individuals diagnosed with non-relapsing secondary progressive multiple sclerosis. The primary objective was to determine the efficacy of tolebrutinib in delaying disability progression, specifically measured by the time to onset of 6-month confirmed disability progression (CDP) as assessed by the Expanded Disability Status Scale (EDSS).

Key results

The trial results indicated that tolebrutinib demonstrated efficacy in several key measures of disease progression. For the primary outcome of time to onset of 6-month confirmed disability progression (CDP) as assessed by EDSS, the median time was 11.97 months for the placebo group and 12.04 months for the tolebrutinib 60 mg group. A Cox regression analysis showed a Hazard Ratio (HR) of 0.693 (95% Confidence Interval: 0.546 to 0.88) for tolebrutinib versus placebo, with a p-value of 0.0026, indicating a statistically significant reduction in the risk of 6-month CDP.

Similarly, for the time to onset of 3-month confirmed disability progression, the median time was 11.96 months for placebo and 12.04 months for tolebrutinib 60 mg. The Cox regression analysis yielded an HR of 0.757 (95% Confidence Interval: 0.607 to 0.944) with a p-value of 0.0134.

Regarding MRI lesions, the mean number of new and/or enlarging T2-hyperintense lesions per year was 2.948 for placebo and 1.835 for tolebrutinib 60 mg. A negative binomial model analysis showed a Relative Risk of 0.622 (95% Confidence Interval: 0.432 to 0.897) with a p-value of 0.011, demonstrating a significant reduction in lesion activity with tolebrutinib.

For physical function, the time to onset of sustained 20% increase in the Timed 25-foot Walk (T25-FW) for at least 3 months had a median of 9.25 months for placebo and 9.54 months for tolebrutinib 60 mg. The Cox regression analysis showed an HR of 0.767 (95% Confidence Interval: 0.64 to 0.919) with a p-value of 0.004.

However, for the time to onset of 6-month confirmed disability improvement (CDI), the median was 12.04 months for placebo and 11.89 months for tolebrutinib 60 mg. The Cox regression analysis showed an HR of 1.882 (95% Confidence Interval: 1.102 to 3.214) with a p-value of 0.0206, suggesting a lower likelihood of confirmed disability improvement with tolebrutinib compared to placebo.

What this means

The results from the HERCULES trial suggest that tolebrutinib may offer a significant benefit in slowing the progression of disability and reducing new inflammatory lesions in patients with non-relapsing secondary progressive multiple sclerosis. The statistically significant reduction in both 6-month and 3-month confirmed disability progression, alongside a decrease in T2-hyperintense lesions, indicates a positive impact on key markers of disease activity and progression. While the data also showed a lower likelihood of confirmed disability improvement with tolebrutinib, the primary focus for NRSPMS is often on delaying progression, where the drug demonstrated a favorable outcome.

Source

The information regarding these trial results was obtained from ClinicalTrials.gov, a public database of clinical studies. The results for study NCT04411641, titled "Nonrelapsing Secondary Progressive Multiple Sclerosis (NRSPMS) Study of Bruton's Tyrosine Kinase (BTK) Inhibitor Tolebrutinib (SAR442168) (HERCULES)," were posted on 2025-06-18 on clinicaltrials.gov.