AAN 2026 | Efficacy of tolebrutinib in non-relapsing and relapsing MS: insights from pivotal Phase III trials

The HERCULES study was a Phase III study that focused on non-relapsing secondary progressive MS. It was a randomized, placebo-controlled, double-blind, event-driven study. It entered 1,131 individuals. They had to have been free of any clinical relapse in the prior two years and had to have progressed in the year prior to entry. They ranged in age from 18 to 60 with an EDSS of 3 to 6.5. The primary outcome was six-month confirmed disability progression that was significantly slowed in favor of the BTK inhibitor, a 31% decrease in progression with the oral BTK inhibitor. The interesting thing in the two Phase III relapsing trials that read out at the same time, they failed because there was a direct comparator, teriflunomide, and the primary outcome was annualized relapse rate. And it didn’t beat teriflunomide, although the annualized relapse rate was low across the board. But when you looked at confirmed disability worsening in this relapsing cohort, the graph separated in favor of the BTK inhibitor. So even though you can’t count that because the primary outcome was negative, it really indicated that you were likely seeing an effect on PIRA in those relapsing patients, confirming an impact on progression in MS.

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