Tolebrutinib Delays Disability Progression by 31% in Phase 3 SPMS Study

Positive results from the HERCULES phase 3 study have shown that tolebrutinib, a brain-penetrant BTK inhibitor, delays the time to onset of six-month confirmed disability progression (CDP) in people with non-relapsing secondary progressive multiple sclerosis (nrSPMS) by 31% compared to a placebo. This significant delay was revealed in data presented at the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) 2024 conference in Copenhagen, Denmark. The findings were based on a hazard ratio (HR) of 0.69 with a 95% confidence interval (CI) of 0.55-0.88 and a p-value of 0.0026.

The study, led by Dr. Robert Fox, Vice Chair of Research at Cleveland Clinic’s Neurological Institute, highlighted that secondary progressive multiple sclerosis (SPMS) involves a slow and relentless worsening of disability without relying on relapse activity. This condition signifies a major unmet medical need as effective treatments are currently lacking. Tolebrutinib was shown to not only delay disability progression but also improve disability in some patients by uniquely targeting the biological mechanisms driving disease progression within the brain.

Secondary endpoints of the study indicated that tolebrutinib nearly doubled the rate of participants experiencing confirmed disability improvement, with 10% of the tolebrutinib group showing improvement compared to 5% in the placebo group (HR 1.88; 95% CI 1.10-3.21; nominal p=0.021).

Adverse events were slightly more common in the tolebrutinib-treated group, with liver enzyme elevations (>3xULN) reported in 4.1% of participants compared to 1.6% in the placebo group. A small percentage (0.5%) of tolebrutinib-treated participants experienced significant ALT increases (>20xULN) within the first 90 days of treatment. Most cases of liver enzyme elevations were resolved without further medical intervention. Prior to the implementation of stringent monitoring protocols, one participant required a liver transplant and subsequently died due to post-operative complications. Enhanced monitoring has since mitigated such serious liver complications.

Additionally, the GEMINI 1 and 2 phase 3 studies comparing tolebrutinib with Aubagio (teriflunomide) in participants with relapsing multiple sclerosis (RMS) were also presented at the ECTRIMS conference. Both studies failed to achieve the primary endpoints of reducing annualized relapse rates (ARR) more effectively than Aubagio. However, pooled data from GEMINI 1 and 2 showed that tolebrutinib delayed the onset of six-month confirmed disability worsening (CDW) by 29%, aligning with the delay observed in the HERCULES study for nrSPMS. The significant impact of tolebrutinib on disability accumulation, despite the lack of superior impact on relapses, suggests that the drug effectively addresses smoldering neuroinflammation related to MS progression independent of relapses.

Adverse events in GEMINI 1 and 2 were generally balanced between the tolebrutinib and Aubagio groups, with liver enzyme elevations reported in 5.6% of tolebrutinib participants and 6.3% of Aubagio participants. Death rates were comparable between the groups, both deemed unrelated to the treatment.

The results of these studies will support future discussions with global regulatory authorities, with submissions expected to begin in the second half of 2024. Tolebrutinib remains under clinical investigation, with its safety and efficacy yet to be evaluated by regulatory authorities.

The ongoing PERSEUS phase 3 study aims to evaluate the efficacy of tolebrutinib in primary progressive MS, with results anticipated in the second half of 2025. These studies are crucial as multiple sclerosis is a chronic, immune-mediated, neurodegenerative disease leading to irreversible disabilities over time. Existing therapies mainly target the adaptive immune system and do not address the innate immunity believed to drive disability accumulation within the central nervous system (CNS).

Overall, these findings suggest that tolebrutinib might become a valuable treatment option for various forms of multiple sclerosis, addressing the critical unmet need of delaying disability progression in patients.