Sanofi's tolebrutinib, an investigational brain-penetrant Bruton's tyrosine kinase (BTK) inhibitor, has shown positive results in a Phase III study for non-relapsing secondary progressive multiple sclerosis (nrSPMS). The HERCULES trial demonstrated a 31% delay in the time to onset of confirmed disability progression (CDP) compared to placebo (HR 0.69; 95% CI 0.55-0.88; p=0.0026). These findings, presented at the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) 2024 conference, suggest tolebrutinib may address disability accumulation independent of relapse activity in nrSPMS. Sanofi is preparing for global regulatory submissions in the second half of 2024.
HERCULES Trial Results
The HERCULES trial enrolled patients with nrSPMS, defined as having no clinical relapses for the previous 24 months and documented evidence of disability accumulation in the previous 12 months. Participants were randomized (2:1) to receive either tolebrutinib or placebo for up to approximately 48 months. The primary endpoint was 6-month CDP, defined as an increase of ≥1.0 point from the baseline Expanded Disability Status Scale (EDSS) score when the baseline score is ≤5.0, or an increase of ≥0.5 point when the baseline EDSS score was >5.0.
In addition to the primary endpoint, secondary endpoint analysis revealed that 10% of participants treated with tolebrutinib experienced confirmed disability improvement, compared to 5% in the placebo group (HR 1.88; 95% CI: 1.10 to 3.21; nominal p=0.021).
Robert Fox, MD, Vice Chair of Research at Cleveland Clinic’s Neurological Institute and Chair of the HERCULES Global Steering Committee, noted, "The results of HERCULES show clearly that tolebrutinib delayed disability progression in people with nrSPMS – and some people even improved disability – by uniquely targeting the biological processes driving disease progression in the brain."
Safety Profile and Monitoring
Preliminary analysis of the HERCULES study indicated a slight increase in adverse events among tolebrutinib-treated patients. Liver enzyme elevations (>3xULN) were observed in 4.1% of participants receiving tolebrutinib compared with 1.6% in the placebo group. A small proportion (0.5%) of participants in the tolebrutinib group experienced peak ALT increases of >20xULN, all occurring within the first 90 days of treatment. Sanofi has implemented more frequent monitoring to mitigate serious liver sequelae. One participant in the tolebrutinib arm received a liver transplant and died due to post-operative complications prior to the implementation of the revised study protocol.
GEMINI 1 and 2 Trials in Relapsing MS
Data from the GEMINI 1 and 2 phase 3 studies, which evaluated tolebrutinib versus teriflunomide (Aubagio) in relapsing multiple sclerosis (RMS), were also presented at ECTRIMS. While the studies did not meet their primary endpoints of statistically significant improvement in annualized relapse rates (ARR) compared to Aubagio, a pooled analysis of data from GEMINI 1 and 2 showed that tolebrutinib delayed the time to onset of 6-month confirmed disability worsening (CDW) by 29% (HR 0.71; 95% CI: 0.53-0.95; nominal p=0.023).
Future Directions
Sanofi is also evaluating tolebrutinib in primary progressive MS in the Phase III PERSEUS trial, with results anticipated in H2 2025. The company plans to discuss the HERCULES results with healthcare authorities and initiate global regulatory submissions for tolebrutinib in nrSPMS in the second half of 2024.
Houman Ashrafian, MD, PhD, Head of Research & Development at Sanofi, stated, "With no treatment options currently available for the broad population of patients with secondary progressive multiple sclerosis, tolebrutinib has demonstrated its ability to delay disability by targeting underlying drivers of the disease."
