Tolebrutinib slows disability in non-relapsing secondary progressive MS

In the phase 3 HERCULES study, tolebrutinib demonstrated a statistically significant delay in time to onset of confirmed disability progression (CDP) in patients with non-relapsing secondary progressive MS (nrSPMS). It makes this oral Bruton’s tyrosine kinase (BTK) inhibitor the first agent to slow disability in patients with progressive MS.

The results of the HERCULES trial (NCT04411641) were presented by Prof. Robert Fox (Cleveland Clinic, OH, USA) [1]. This phase 3 trial evaluated the efficacy and safety of tolebrutinib in participants with nrSPMS. To be enrolled, patients had to be 18–60 years of age, have SPMS with an Expanded Disability Status Scale (EDSS) score of 3.0–6.5, have had no clinical relapses for at least 24 months, and have documented evidence of disability progression in the year before screening. The 1,131 participants from 31 countries were randomised 2:1 to oral tolebrutinib (60 mg once daily) or a matching placebo for up to 48 months. They had a mean age of 48.9 years, and 62% were women. The mean EDSS score was 5.53, 12.8% of the participants had gadolinium-enhancing T1 lesions, and mean T2 lesion volume was 18.9 cm³. Importantly, the mean time since most recent relapse was 7.5 years. The primary endpoint was time to onset of 6-month CDP.

In the tolebrutinib and placebo arms, 580 and 289 participants completed the trial, respectively, meaning about 23% of each arm did not. Tolebrutinib demonstrated a significant effect on disability accumulation. Six-month CDP occurred in 26.9% versus 37.2% of tolebrutinib- and placebo-treated patients, respectively: a 31% risk reduction (HR 0.69; 95% CI 0.55–0.88; P=0.0026). In addition, 6-month confirmed disability improvement was seen in 10% in the tolebrutinib group versus 5% in the placebo group (HR 1.88; 95% CI 1.10–3.21; P=0.021). There was a 38% reduction in the annualised rate of new/enlarging T2-lesions (HR 0.62; 95% CI 0.43–0.90; P=0.011). There was no significant slowing of brain atrophy or brain volume loss, which Prof. Fox called “a bit of a head-scratcher.”

Regarding safety, liver enzyme elevations occurred at >3 times the upper limit of normal (ULN) in 4.1% of the tolebrutinib group versus 1.6% in the placebo group. Some patients (0.5%) in the tolebrutinib group experienced very severe elevations (>20 times ULN) in liver enzymes; all during the first 12 weeks of treatment. All but one case resolved without medical intervention.

1. Fox RJ, et al. Efficacy and safety of tolebrutinib versus placebo in non-relapsing secondary progressive multiple sclerosis: Results from the phase 3 HERCULES trial. Abstract O136, ECTRIMS 2024, 17–20 October 2024, Copenhagen, Denmark.

Medical writing support was provided by Michiel Tent

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Posted on 24 September 202424 September 2024