Tolebrutinib potential in MS: Phase 3 trials

By Lily Fitzgerald

Three phase 3 trials show that tolebrutinib reduces the risk of disability progression in non-relapsing secondary progressive multiple sclerosis (SPMS), but is not superior to teriflunomide at reducing annualized relapse rates (ARR) in relapsing MS (RMS).

In HERCULES, a double-blind study published in The New England Journal of Medicine (NEJM), 22.6% of the 754 patients with non-relapsing SPMS given tolebrutinib, a Bruton’s kinase (BTK) inhibitor, (60 mg once daily) for 133 weeks had confirmed disability progression sustained for at least 6 months. This was a significantly lower than the rate of 30.7% observed among the 377 participants given placebo.

Robert Fox (Cleveland Clinic, Ohio, USA) and co-authors suggest this demonstrates “the role of tolebrutinib in slowing disability accrual in persons with non-relapsing SPMS, a population with an unmet need for treatments that delay disability.”

In GEMINI 1 and GEMINI 2, also published in NEJM, researchers randomly assigned people with RMS to either tolebrutinib (60 mg once daily) or teriflunomide (14 mg once daily). There was no significant difference between the treatment groups in ARR, which was 0.13 for tolebrutinib (n=486) and 0.12 for teriflunomide (n=488) in GEMINI 1, and 0.11 for both tolebrutinib (n=447) and teriflunomide (n=452) in GEMINI 2.

Nevertheless, in the pooled population, confirmed disability worsening sustained for at least 6 months was lower with tolebrutinib (8.3%) than with teriflunomide (11.3%).

As the primary endpoint was nonsignificant, this secondary endpoint was not tested for statistical significance, and Jiwon Oh (University of Toronto, Ontario, Canada) and co-researchers therefore say that for RMS, “[w]hether the rates of disability worsening with tolebrutinib are significantly better than comparator agents will require further study.”

Serious adverse events (SAEs) were observed in 15.0% of people treated with tolebrutinib and 10.4% with placebo in HERCULES, including serious infections in 5.2% versus 3.5%. In GEMINI 1 and 2, AEs were similar across both treatment groups, although minor bleeding was higher with tolebrutinib.

Elevated alanine aminotransferase levels more than three times the upper limit of the normal range occurred in 4% of the HERCULES tolebrutinib group, 1.6% with placebo, 5.6% of the GEMINI 1 and 2 tolebrutinib group, and 6.3% with teriflunomide. The researchers note that elevated liver-enzyme levels have been seen with other BTK inhibitors, and that most cases resolved without sequelae across both studies.

The effects of tolebrutinib are thought to be due to its ability to penetrate the blood–brain barrier, affecting chronic inflammation in the central nervous system (CNS). The researchers say that additional analyses will investigate tolebrutinib’s effect on pathophysiological substrates involved in chronic CNS inflammation in non-relapsing disease, such as microglial activity.

They add that continued follow-up is still needed to fully understand the long-term efficacy and safety of tolebrutinib in MS.

Developed by EPG Health, for Medthority. The article has been developed independently of any sponsor.