Abstract Background Systemic sclerosis (SSc) is an autoimmune connective tissue disease with a high risk of organ damage and mortality. Objectives To investigate whether tirabrutinib, an inhibitor of Bruton tyrosine kinase, is useful for treating SSc. Methods This randomized double-arm 52-week phase I study investigated the safety, efficacy and putative mechanism of action of once-daily tirabrutinib in adults with SSc (Japan Registry of Clinical Trials jRCT2031200315). The primary endpoints were safety, including treatment-emergent adverse events (TEAEs), and pharmacokinetics. Exploratory efficacy endpoints included the modified Rodnan skin score (mRSS) and mechanism of action determined via immunophenotyping and RNA sequencing (RNAseq). Results Sixteen patients were enrolled and treated with 40 mg or 80 mg tirabrutinib (n = 8 per group). All 16 patients experienced grade 1 or 2 TEAEs. Plasma tirabrutinib concentrations in steady-state conditions were within the expected ranges. The mean (SD) change in mRSS from baseline to week 52 was −4.0 (6.1) and −4.7 (3.6) in the 40-mg and 80-mg groups, respectively. The percentage of naïve B cells tended to increase, and the percentages of nonswitched memory B cells, activated memory CD95+ B cells, and plasmablasts tended to decrease in both groups. Immunophenotyping and RNAseq suggested that suppression of B-cell activity was involved in the mechanism of action of tirabrutinib. Conclusions This study suggests that tirabrutinib is tolerable in patients with SSc and acts by suppressing B-cell activity.
Matsuda et al. (Mon,) studied this question.
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