Tolebrutinib Delays Disability Progression in Secondary Progressive MS by 31%

Sanofi has announced promising results from the HERCULES phase 3 study examining the efficacy and safety of tolebrutinib in individuals with non-relapsing secondary progressive multiple sclerosis (nrSPMS). The study revealed that tolebrutinib, a brain-penetrant Bruton’s tyrosine kinase (BTK) inhibitor, delayed the onset of six-month confirmed disability progression (CDP) by 31% compared to a placebo. The findings were presented at the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) 2024 conference in Copenhagen, Denmark.

Dr. Robert Fox, Vice Chair of Research at Cleveland Clinic’s Neurological Institute and Chair of the HERCULES Global Steering Committee, highlighted the significance of these results. He noted that nrSPMS is marked by a gradual worsening of disability independent of relapses, and to date, there have been no effective treatments. The HERCULES study showed tolebrutinib's potential in addressing this unmet need by uniquely targeting the biological processes responsible for disease progression in the brain.

Preliminary analysis of the HERCULES study indicated some adverse events among patients treated with tolebrutinib. Notably, liver enzyme elevations were observed in 4.1% of participants receiving tolebrutinib, compared to 1.6% in the placebo group. A small proportion of participants experienced significant ALT increases, with most cases resolving without further medical intervention. One participant in the tolebrutinib group required a liver transplant and subsequently died due to post-operative complications. Enhanced monitoring protocols have since been implemented to mitigate such severe liver issues. Deaths in the trial were evenly distributed between the placebo and tolebrutinib groups, each at 0.3%.

Alongside the HERCULES trial, results from the GEMINI 1 and 2 phase 3 studies were also presented at ECTRIMS. These studies compared tolebrutinib with Aubagio (teriflunomide), a standard-of-care treatment, in participants with relapsing multiple sclerosis (RMS). While the primary endpoints of statistically significant improvement in annualized relapse rates (ARR) were not met, secondary endpoints showed that tolebrutinib delayed the onset of six-month confirmed disability worsening (CDW) by 29%, aligning with the 31% delay in CDP observed in nrSPMS participants. This suggests that tolebrutinib may address smoldering neuroinflammation, which contributes to disease progression independent of relapses.

The GEMINI studies also revealed a historically low ARR in the Aubagio arm, with no significant difference observed between Aubagio and tolebrutinib in a pooled analysis. Adverse events were generally balanced between the two treatment arms, with liver enzyme elevations being a common side effect. Death rates were similar across both groups, and adverse events were deemed unrelated to the treatment.

The findings from these studies will form the basis for discussions with global regulatory authorities, with submissions expected to begin in the second half of 2024. Tolebrutinib is still under clinical investigation, and its safety and efficacy have not yet been evaluated by any regulatory authority. Additionally, the PERSEUS phase 3 study in primary progressive MS is ongoing, with results anticipated in the second half of 2025.

Multiple sclerosis (MS) is a chronic, immune-mediated, neurodegenerative disease that leads to irreversible disability over time. Current treatments primarily target the adaptive immune system and peripheral B and T cells, leaving innate immunity—which drives disability accumulation—largely unaddressed. Tolebrutinib, an investigational, oral, brain-penetrant BTK inhibitor, is being evaluated for its potential to modulate B lymphocytes and disease-associated microglia within the CNS.

Sanofi, the company behind tolebrutinib's development, is committed to transforming medicine and improving patient outcomes through scientific innovation. The company’s global healthcare initiatives focus on providing life-changing treatment options and life-saving vaccine protection while prioritizing sustainability and social responsibility.