The U.S. Food and Drug Administration (FDA) has granted Breakthrough Therapy designation to tolebrutinib, an investigational oral Bruton's tyrosine kinase (BTK) inhibitor, for the treatment of adults with non-relapsing secondary progressive multiple sclerosis (nrSPMS). This designation aims to expedite the development and review of tolebrutinib, marking a significant step forward in addressing the unmet needs of patients with this debilitating condition. The decision is based on positive results from the Phase 3 HERCULES study, where tolebrutinib demonstrated a significant delay in disability progression compared to placebo.
HERCULES Trial Results
The HERCULES trial (NCT04411641) was a double-blind, randomized, Phase 3 study evaluating the efficacy and safety of tolebrutinib in participants with nrSPMS. Participants were randomized (2:1) to receive either an oral daily dose of tolebrutinib or a matching placebo for up to approximately 48 months. The study defined nrSPMS at baseline as having an SPMS diagnosis with an Expanded Disability Status Scale (EDSS) between 3.0 and 6.5, no clinical relapses for the previous 24 months, and documented evidence of disability accumulation in the previous 12 months.
The primary endpoint was the time to onset of 6-month confirmed disability progression (CDP), defined as an increase of ≥1.0 point from the baseline EDSS score when the baseline score was ≤5.0, or an increase of ≥0.5 point when the baseline EDSS score was >5.0. Secondary endpoints included time to onset of 3-month CDP, total number of new or enlarging T2 hyperintense lesions as detected by MRI, time to onset of confirmed disability improvement, 3-month change in the 9-hole peg test, and the T25-FW test.
Results from the HERCULES study showed that tolebrutinib delayed the time to onset of 6-month CDP by 31% compared to placebo (HR 0.69; 95% CI 0.55-0.88; p=0.0026). Further analysis of secondary endpoints demonstrated that the number of participants who experienced confirmed disability improvement was nearly double with tolebrutinib (10%) compared to those on placebo (5%) (HR 1.88; 95% CI 1.10 to 3.21; nominal p=0.021).
Safety and Tolerability
While tolebrutinib was generally well-tolerated, 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. However, all but one case of liver enzyme elevations resolved without further medical intervention. The implementation of more frequent monitoring has helped mitigate serious liver sequelae.
Regulatory Status and Future Studies
Regulatory submissions of tolebrutinib are currently being finalized for the US and prepared for the EU. Sanofi plans to confirm once a regulatory submission for tolebrutinib has been accepted. The PERSEUS phase 3 study in primary progressive MS is currently ongoing, with study results anticipated in H2 2025.
Expert Commentary
Erik Wallström, MD, PhD, Global Head of Neurology Development at Sanofi, stated, "This Breakthrough Therapy designation demonstrates the potential for tolebrutinib to delay disability progression, a critical unmet need for people living with multiple sclerosis. We look forward to working with the FDA during the regulatory review of this first of its kind medicine in non-relapsing secondary progressive multiple sclerosis where there are currently no approved treatments available."
About Tolebrutinib
Tolebrutinib is an investigational, oral, brain-penetrant, and bioactive Bruton's tyrosine kinase (BTK) inhibitor that achieves cerebrospinal fluid concentrations predicted to modulate B lymphocytes and disease-associated microglia. It is currently being evaluated in phase 3 clinical studies for the treatment of various forms of multiple sclerosis, but its safety and efficacy have not been evaluated by any regulatory authority worldwide.
Multiple Sclerosis Overview
Multiple sclerosis is a chronic, immune-mediated, neurodegenerative disease that may result in the accumulation of irreversible disabilities over time. The physical and cognitive disability impairments translate into a gradual deterioration of health status, impacting patients' care and quality of life. Disability accumulation remains the significant unmet medical need in MS. nrSPMS refers to people with MS who have stopped experiencing relapses but continue to accumulate disability, experienced as symptoms such as fatigue, cognitive impairment, balance and gait impairment, loss of bowel and/or bladder function, and sexual dysfunction.
