ACTRIMS 2026 | Subgroup analysis of the HERCULES trial in NRSPMS: tolebrutinib in the North American cohort

The subgroup analysis of the Phase III tolebrutinib trial, HERCULES, which studied the BTK inhibitor tolebrutinib versus placebo in individuals with secondary progressive MS, had analyses that considered different subgroups, particularly from different regions, and this particular poster described the subgroup analysis involving North American participants, which were further split into U.S. and Canadian participants. So, of course, the HERCULES trial was a Phase III, multicenter, randomized, double-blind, placebo-controlled arm. It was event-driven. It randomized individuals with a diagnosis of secondary progressive MS who had absence of clinical relapses in the prior 24 months, but nonetheless demonstrated clinical progression in the 12 months prior. They were randomized two-to-one to either tolebrutinib or placebo and followed to the primary endpoint of six-month confirmed disability progression in an event-driven trial. And here the focus is on the subgroup analysis of the six-month confirmed disability progression by geographic region with a focus on North America and, again, U.S. and Canada. With respect to the baseline characteristics, when one considered all participants as compared to the North American participants, there were 1,131 participants in total and 162 individuals, so 14.3% from North America. They had a similar age at entry, a similar distribution of EDSS’s, about 5.5, a slightly higher female preponderance in the North American population, 73.5% versus 61.5% in all participants. There was a very similar time from RRMS symptom onset, perhaps a slightly longer duration from the most recent relapse in the North American subgroup, 8.7 years versus 7.5 years, and then a slightly higher proportion of individuals with gadolinium-enhancing lesions in the overall population compared to the North American subgroup, 4.4% in the North American subgroup, particularly low, and 12.7% in the total participant population, with fairly similar baseline burden of T2 volume and a similar history of prior DMTs. The outcome in terms of time to onset of six-month confirmed disability progression is that for the total population as previously reported, as well as for both the North American and the U.S. out of North American subgroups, point estimates were left of unity, meaning favoring tolebrutinib over placebo. And in fact, the point estimates for North America and particularly the U.S. had particularly lower hazard ratios as compared to the overall population, making the point that from the standpoint of the primary outcome measure, which was hit for the overall population, this was also the case and even more so for the subgroup in North America, including and particularly the U.S. subgroup. And this resulted in terms of the North American participants in a six-month CDP reduction by 54% in the tolebrutinib arm versus the placebo arm. So that was for the North American group. And within it, for U.S. participants, tolebrutinib reduced the risk of the six-month CDP by 62% versus placebo, which again makes the point that it acted well versus placebo in all groups analyzed, including in North America and within it in the United States population.

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