Tolebrutinib slows disability worsening in relapsing MS

In the phase 3 GEMINI 1 and 2 studies, tolebrutinib did not reach the primary endpoint of reduced annualised relapse rate (ARR) in relapsing MS compared with teriflunomide. However, the studies did show a positive result on a key secondary endpoint: tolebrutinib significantly delayed the time to onset of worsening.

“Current MS therapies very effectively reduce focal inflammation but are less effective at slowing pathophysiological processes responsible for disability accumulation,” said Dr Jiwon Oh (St. Michael's Hospital, Canada), to address a large unmet clinical treatment need [1]. The Bruton’s tyrosine kinase (BTK) inhibitors may offer a solution. The BTK inhibitor tolebrutinib is a potent small molecule that is brain-penetrant in bioactive concentrations. “It modulates persistent immune activation in the CNS, including disease-associated B cells and microglia.”

The phase 3 GEMINI 1 (NCT04410978) and GEMINI 2 (NCT04410991) trials evaluated the efficacy and safety of tolebrutinib compared with teriflunomide in participants with relapsing MS. The 1,873 participants (974 in GEMINI 1 and 899 in GEMINI 2) were randomised to oral tolebrutinib (60 mg/day) or oral teriflunomide (14 mg/day), each with a matching placebo. The primary endpoint was ARR.

“Disappointingly, but perhaps not surprisingly, both trials showed no significant difference between teriflunomide and tolebrutinib in ARR,” Dr Oh observed. In the pooled analysis, the ARR was 0.12 in both treatment arms. The overall ARR rate ratio was 1.03 (95% CI 0.84–1.25; P=0.80). However, for time to confirmed disability worsening (6-month CDW), tolebrutinib showed a clear separation from teriflunomide. In the pooled data this amounted to a 29% risk reduction (HR 0.71; 95% CI 0.53–0.95; P=0.023), in a population with very low disease activity (see Figure). “This result suggests that tolebrutinib may have an impact on progression independent of relapse activity [PIRA],” commented Dr Oh. Liver enzyme elevations were observed in 5.6% of tolebrutinib users, a signal also reported with other BTK inhibitors in MS. All cases resolved without sequelae.

Figure: Time to 6-month confirmed disability worsening in GEMINI [1]



CDW, confirmed disability worsening; CI, confidence interval; HR, hazard ratio.

Dr Oh concluded that these results are consistent with the hypothesis that acute focal inflammation and smouldering neuroinflammation are 2 distinct biological processes.

1. Oh J, et al. Efficacy and safety of tolebrutinib versus teriflunomide in relapsing multiple sclerosis: Results from the phase 3 GEMINI 1 and 2 trials. Abstract O135, ECTRIMS 2024, 18–20 September, Copenhagen, Denmark.

 

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Posted on 18 November 202419 November 2024