Sanofi's tolebrutinib, an oral Bruton's tyrosine kinase (BTK) inhibitor, has demonstrated a significant impact on slowing disability progression in patients with non-relapsing secondary progressive multiple sclerosis (nrSPMS). The phase 3 HERCULES trial (NCT04411641) revealed that tolebrutinib delayed the time to onset of 6-month confirmed disability progression (CDP) by 31% compared to placebo (HR, 0.69; 95% CI, 0.55-0.88; P = .0026). These findings, presented at the 2024 European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) Congress, mark a potential breakthrough in addressing the unmet need for therapies that effectively slow disability progression in this patient population.
HERCULES Trial: Key Findings
The HERCULES trial enrolled 1131 patients aged 18 to 60 years with nrSPMS, defined as having an Expanded Disability Status Scale (EDSS) score between 3.0 and 6.5 and documented disability progression in the prior 12 months without clinical relapses in the prior 24 months. Participants were randomized 2:1 to receive 60-mg once daily oral tolebrutinib or placebo. The primary endpoint was time to onset of 6-month CDP, as measured by EDSS.
Robert J. Fox, MD, a staff neurologist at the Mellen Center for Multiple Sclerosis at Cleveland Clinic, emphasized the clinical significance of the results: "What's exciting to me about these results from the HERCULES trial is that we finally have identified a therapy that slows progression of disability in a population of patients without relapses, the non-relapsing, secondary progressive MS population."
Additional secondary endpoint results indicated that the number of patients experiencing confirmed disability improvement nearly doubled in the tolebrutinib group compared to placebo (10% vs. 5%; HR, 1.88; 95% CI, 1.10-3.21; nominal P = .021).
Safety Profile and Monitoring
Preliminary analysis of the HERCULES trial indicated a slight increase in adverse events among tolebrutinib-treated patients. Liver enzyme elevations (>3xULN) were observed in 4.1% of patients receiving tolebrutinib compared with 1.6% in the placebo group. A small proportion (0.5%) of patients in the tolebrutinib group experienced peak ALT increases of >20xULN, all occurring within the first 90 days of treatment. With the exception of one case, all liver enzyme elevations resolved without further medical intervention.
GEMINI 1 and 2 Trials: Relapsing MS Data
Additional data from the phase 3 GEMINI 1 (NCT04410978) and GEMINI 2 (NCT04410991) trials, also presented at ECTRIMS 2024, showed that tolebrutinib did not meet its primary endpoint of reducing annualized relapse rate (ARR) compared with teriflunomide. However, pooled data from the two trials showed a 29% risk reduction in time to 6-month confirmed disability worsening (CDW) for the tolebrutinib group (9.9%) compared with the teriflunomide group (13.2%) (HR, 0.71; 95% CI, 0.53-0.95; P = .023).
Implications for MS Treatment
The HERCULES trial results suggest that tolebrutinib may address the underlying mechanisms of disability accumulation in MS, linked to smoldering neuroinflammation in the brain and spinal cord. Houman Ashrafian, MD, PhD, head of research and development at Sanofi, stated, "Tolebrutinib represents an unprecedented breakthrough as a potential first-in-disease treatment option with clinically meaningful benefit in disability accumulation."
With no approved therapies currently available for nrSPMS, tolebrutinib offers a potential new approach to managing disability progression in this patient population. Sanofi plans to discuss these results with global regulatory authorities, with potential submissions starting in the second half of 2024. The PERSEUS phase 3 study in primary progressive MS is ongoing, with results anticipated in 2025.
