Matsuda Kazuki M, Harada Tomohiro, Doi Masaaki, Io Toshiro, Kitani Akihiro, Hasegawa Minoru, Sato Shinichi, Yoshizaki Ayumi
Department of Dermatology, The University of Tokyo Graduate School of Medicine, Tokyo, Japan.
Clinical Development Planning III, Ono Pharmaceutical Co., Ltd., Osaka, Japan.
Br J Dermatol. 2025 Aug 18;193(3):434-441. doi: 10.1093/bjd/ljaf168.
Systemic sclerosis (SSc) is an autoimmune connective tissue disease with a high risk of organ damage and mortality.
To investigate whether tirabrutinib, an inhibitor of Bruton tyrosine kinase, is useful for treating SSc.
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).
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.
This study suggests that tirabrutinib is tolerable in patients with SSc and acts by suppressing B-cell activity.
系统性硬化症（SSc）是一种自身免疫性结缔组织疾病，具有器官损害和死亡的高风险。
研究布鲁顿酪氨酸激酶抑制剂替拉布替尼是否对治疗系统性硬化症有用。
这项为期52周的随机双臂I期研究调查了每日一次替拉布替尼在成年系统性硬化症患者中的安全性、疗效和可能的作用机制（日本临床试验注册中心jRCT2031200315）。主要终点是安全性，包括治疗中出现的不良事件（TEAE）和药代动力学。探索性疗效终点包括改良罗德南皮肤评分（mRSS）以及通过免疫表型分析和RNA测序（RNAseq）确定的作用机制。
16名患者入组并接受40mg或80mg替拉布替尼治疗（每组8例）。所有16例患者均经历1级或2级TEAE。稳态条件下血浆替拉布替尼浓度在预期范围内。40mg组和80mg组从基线到第52周mRSS的平均（标准差）变化分别为-4.0（6.1）和-4.7（3.6）。两组中未成熟B细胞百分比趋于增加，未转换记忆B细胞、活化记忆CD95+B细胞和成浆细胞百分比趋于下降。免疫表型分析和RNA测序表明，B细胞活性的抑制参与了替拉布替尼的作用机制。
本研究表明，替拉布替尼在系统性硬化症患者中耐受性良好，其作用机制是抑制B细胞活性。
