Chung Lorinda, Silver Richard M, Steen Virginia, Furst Daniel E, Castelino Flavia V, Trojanowski Marcin, Spiera Robert, Domsic Robyn, Rodriguez-Pla Alicia, Katsumoto Tamiko R, Goulaouic Helene, Wang Hong, Espinasse Melanie, El-Chemaly Souheil, Wang Rui
Department of Medicine and Dermatology, Stanford University School of Medicine, Stanford, CA, USA.
Palo Alto VA Health Care System, Palo Alto, CA, USA.
Rheumatology (Oxford). 2025 Jul 1;64(7):4299-4308. doi: 10.1093/rheumatology/keaf062.
To determine the efficacy, safety and pharmacodynamics of belumosudil in patients with diffuse cutaneous systemic sclerosis (dcSSc) treated with background immunosuppressive therapies.
Eligible patients were randomised 1:1:1 to receive belumosudil 200 mg once daily (QD) or twice daily (BID), or placebo for 28 weeks (double-blind period). After unblinding, the patients who received belumosudil continued the same dose, whereas the patients who received placebo were re-randomised for one of the belumosudil doses for 24 weeks (open-label extension).
Thirty-five and 31 patients were treated in the double-blind and open-label periods, respectively. The study was terminated prematurely, and target enrolment was not met. The primary end point, of CRISS score ≥0.60 at week 24, did not exhibit an efficacy signal in the belumosudil vs placebo groups [odds ratio: 1.06 (0.19-5.82; P = 0.9472) for the QD, and 0.39 (0.07-2.35; P = 0.3078) for the BID group]. Belumosudil was well tolerated and exhibited similar safety profiles in both double-blind and open-label periods. Tissue-based RNA sequencing analysis revealed FOXP3 upregulation and STAT3, IL23A and TGF-β downregulation in patients with CRISS score ≥0.60, which supported the mechanism of action of belumosudil. In blood and tissue samples, trends of decreased fibrosis biomarker levels were seen in the belumosudil-treated group vs placebo.
Efficacy signal for belumosudil could not be detected. Signalling pathway modulation analysis supported the mechanism of action of belumosudil. A trend for decreased fibrosis-related biomarkers was observed in the belumosudil-treated group.
ClinicalTrials.gov, https://clinicaltrials.gov, NCT03919799.
确定在接受背景免疫抑制疗法治疗的弥漫性皮肤系统性硬化症（dcSSc）患者中，贝洛苏地尔的疗效、安全性和药效学。
符合条件的患者按1:1:1随机分组，接受贝洛苏地尔200mg每日一次（QD）或每日两次（BID），或安慰剂治疗28周（双盲期）。揭盲后，接受贝洛苏地尔治疗的患者继续使用相同剂量，而接受安慰剂治疗的患者重新随机分配接受其中一种贝洛苏地尔剂量治疗24周（开放标签延长期）。
双盲期和开放标签期分别有35例和31例患者接受治疗。该研究提前终止，未达到目标入组人数。主要终点，即第24周时CRISS评分≥0.60，在贝洛苏地尔组与安慰剂组之间未显示出疗效信号[QD组的优势比为1.06（0.19 - 5.82；P = 0.9472），BID组为0.39（0.07 - 2.35；P = 0.3078）]。贝洛苏地尔耐受性良好，在双盲期和开放标签期均表现出相似的安全性。基于组织的RNA测序分析显示，CRISS评分≥0.60的患者中FOXP3上调，STAT3、IL23A和TGF-β下调，这支持了贝洛苏地尔的作用机制。在血液和组织样本中，与安慰剂相比，贝洛苏地尔治疗组的纤维化生物标志物水平有下降趋势。
未检测到贝洛苏地尔的疗效信号。信号通路调节分析支持贝洛苏地尔的作用机制。在贝洛苏地尔治疗组中观察到纤维化相关生物标志物有下降趋势。
ClinicalTrials.gov，https://clinicaltrials.gov，NCT03919799
