Tolebrutinib Reduces Disability Progression in Nonrelapsing Secondary Progressive Multiple Sclerosis: Phase 3 HERCULES Trial
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For the first time, a drug has shown a statistically significant ability to slow disability progression in people with nonrelapsing secondary progressive multiple sclerosis (nrSPMS), a form of MS for which no approved therapy had previously existed. In the phase 3 HERCULES trial, patients who took tolebrutinib, an oral brain-penetrant Bruton's tyrosine kinase (BTK) inhibitor, had a 31% lower risk of confirmed disability progression sustained for at least 6 months compared to those on placebo. These results, published in the New England Journal of Medicine, represent a major milestone for a patient population that has long had no targeted treatment options.
Abstract
Nonrelapsing secondary progressive multiple sclerosis (nrSPMS) is characterized by gradual, cumulative neurological deterioration driven not by acute inflammatory relapses but by ongoing smoldering neuroinflammation within the central nervous system, including persistent microglial activation. This pathological mechanism has been particularly difficult to target because most existing MS therapies act primarily on peripheral immune cells and have limited penetrance into the CNS. As a result, no therapy had previously demonstrated a statistically significant benefit on disability progression in nrSPMS in a phase 3 trial.
Tolebrutinib is an oral, brain-penetrant BTK inhibitor that modulates both peripheral B-cell activity and CNS-resident microglia. HERCULES was a phase 3, randomized, double-blind, placebo-controlled, event-driven trial in which 1,131 adults with nrSPMS were assigned in a 2:1 ratio to tolebrutinib 60 mg once daily (n=754) or matching placebo (n=377), with a median follow-up of 133 weeks. The primary endpoint was time to onset of 6-month confirmed disability progression (CDP), defined as a sustained worsening on the Expanded Disability Status Scale (EDSS).
Tolebrutinib significantly reduced the risk of 6-month CDP compared to placebo (22.6% vs. 30.7%; hazard ratio 0.69; 95% CI 0.55 to 0.88; P=0.003), representing a 31% relative risk reduction. A secondary endpoint of confirmed disability improvement also favored tolebrutinib. The most notable safety signal was drug-induced liver injury, which occurred in approximately 4.1% of participants receiving tolebrutinib and resolved in most cases with dose interruption or discontinuation. These results establish tolebrutinib as the first therapy to demonstrate a clear treatment effect on disability progression in nrSPMS in a phase 3 setting.