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In the GEMINI 1 and 2 studies, tolebrutinib did not reach the primary endpoint of reduced annualized relapse rates in relapsing MS compared with teriflunomide. The studies showed a positive result on a key secondary endpoint: tolebrutinib significantly delayed the time to onset of worsening MS.
The phase 3 GEMINI 1 (NCT04410978) and GEMINI 2 (NCT04410991) trials evaluated the efficacy and safety of the Bruton’s tyrosine kinase (BTK) inhibitor tolebrutinib compared with teriflunomide in participants with relapsing MS. Topline results of these trials were presented by Jiwon Oh, MD, PhD, from St. Michael’s Hospital, in Canada1. “Inclusion criteria were very typical for these kinds of trials,” Dr. Oh said. The 1,873 participants (974 in GEMINI 1 and 899 in GEMINI 2) were randomly assigned to oral tolebrutinib (60 mg/day) or oral teriflunomide (14 mg/day), each with a matching placebo. The primary endpoint was annualized relapse rate (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. “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.
Dr. Oh concluded that these results are consistent with the hypothesis that acute focal inflammation and smoldering neuroinflammation are two distinct biological processes.
Medical writing support was provided by Michiel Tent
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