Tolebrutinib slows disability in non-relapsing SPMS

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 (SP)MS. It makes this oral Bruton’s tyrosine kinase (BTK) inhibitor the first agent to slow disability in patients with progressive MS.

The phase 3 HERCULES trial (NCT04411641) evaluated the efficacy and safety of tolebrutinib in participants with non-relapsing SPMS. 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 had 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. In the words of Prof. Robert Fox (Cleveland Clinic, OH, USA) this made it “a very quiescent population in terms of the focal inflammation manifested by clinical relapse” [1]. 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 was associated with a significant change in disability accumulation. Six-month CDP occurred in 26.9% versus 37.2% of tolebrutinib- and placebo-treated participants, respectively: a 31% risk reduction (HR 0.69; 95% CI 0.55–0.88; P=0.0026; see Figure). Rates of 3-month CDP were 32.6% and 41.5%, respectively; a 24% risk reduction. 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.”

Figure: Time to 6-month confirmed disability progression in HERCULES [1]



CI, confidence interval; CDP, confirmed disability progression; HR, hazard ratio.

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 participants (0.5%) in the tolebrutinib group experienced very severe elevations (>20 times ULN), all during the first 12 weeks of treatment. All but 1 case resolved without medical intervention. It is now recommended that patients undergo weekly liver enzyme monitoring during the first 12 weeks of treatment.

Prof. Fox concluded: “We have finally found a therapy that can alter the compartmentalised inflammation that is driving progressive MS.”

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, 18–20 September, Copenhagen, Denmark.

 

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Posted on 18 November 202419 November 2024