Tolebrutinib delays disability progression by 31% in phase 3 study on non-relapsing secondary progressive MS

Positive results from the HERCULES phase 3 study in non-relapsing secondary progressive multiple sclerosis (nrSPMS) show that tolebrutinib significantly delayed the onset of 6-month confirmed disability progression (CDP) by 31% compared to a placebo. The study, presented at the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) 2024 conference in Copenhagen, also highlighted that the number of participants who experienced confirmed disability improvement nearly doubled, with 10% on tolebrutinib versus 5% on placebo.

Dr. Robert Fox, Vice Chair of Research at Cleveland Clinic’s Neurological Institute and Chair of the HERCULES Global Steering Committee, emphasized that secondary progressive multiple sclerosis represents a significant unmet medical need due to its gradual worsening of disability without effective treatments. The HERCULES results indicate that tolebrutinib delays disability progression and even improves disability in some patients by targeting the biological processes in the brain driving disease progression.

A preliminary analysis of HERCULES revealed a slight increase in adverse events among tolebrutinib-treated patients, including liver enzyme elevations observed in 4.1% of participants compared to 1.6% in the placebo group. One case required a liver transplant but subsequent stringent monitoring has mitigated serious liver issues. Deaths in the trial were balanced between the placebo and tolebrutinib groups, with each at 0.3%.

Dr. Houman Ashrafian, Head of Research & Development at Sanofi, highlighted the lack of treatment options for secondary progressive multiple sclerosis. Tolebrutinib's ability to delay disability progression by targeting disease drivers offers hope. Sanofi plans to discuss these findings with health authorities and anticipates results for tolebrutinib in primary progressive MS next year.

The GEMINI 1 and 2 phase 3 studies, also presented at ECTRIMS, compared tolebrutinib to Aubagio (teriflunomide) in relapsing multiple sclerosis (RMS) patients. Although the primary endpoints of statistically significant improvement in annualized relapse rates (ARR) were not met, a pooled analysis showed that tolebrutinib delayed the onset of 6-month confirmed disability worsening (CDW) by 29%, consistent with the 31% delay in CDP for nrSPMS. This suggests tolebrutinib addresses ongoing neuroinflammation independent of relapses.

The GEMINI studies showed similar relapse rates for Aubagio and tolebrutinib, approximating one relapse every eight years. Preliminary safety analyses indicated balanced adverse events between the two groups, with liver enzyme elevations in 5.6% of tolebrutinib participants and 6.3% of Aubagio participants, resolving without further medical intervention. Deaths were evenly distributed and determined unrelated to the treatment.

These results will guide future discussions with global regulatory authorities, with submissions starting in the second half of 2024. Tolebrutinib remains under clinical investigation, and its safety and efficacy have yet to be evaluated by any regulatory body. The ongoing PERSEUS phase 3 study in primary progressive MS is expected to provide results in the second half of 2025.

Multiple sclerosis is a chronic, immune-mediated, neurodegenerative disease causing irreversible disabilities over time. It affects physical and cognitive functions, leading to a decline in health status and quality of life. Disability accumulation is a significant medical challenge in MS, as current therapies mainly target the peripheral adaptive immune system and do not address the central nervous system's innate immunity, which drives disability accumulation.

RMS involves episodes of new or worsening symptoms (relapses) followed by recovery, while nrSPMS features ongoing disability accumulation without confirmed relapses. The HERCULES study focused on nrSPMS patients meeting specific criteria, while GEMINI 1 and 2 evaluated RMS patients. Both studies underscore the potential of tolebrutinib in addressing disability progression in multiple sclerosis.