Inhibition of apoptosis signal–regulating kinase 1, a serine/threonine kinase, leads to improvement in inflammation and fibrosis in animal models of nonalcoholic steatohepatitis. We evaluated the safety and efficacy of selonsertib, a selective inhibitor of apoptosis signal–regulating kinase 1, alone or in combination with simtuzumab, in patients with nonalcoholic steatohepatitis and stage 2 or 3 liver fibrosis. In this multicenter phase 2 trial, 72 patients were randomized to receive 24 weeks of open‐label treatment with either 6 or 18 mg of selonsertib orally once daily with or without once‐weekly injections of 125 mg of simtuzumab or simtuzumab alone. The effect of treatment was assessed by paired pretreatment and posttreatment liver biopsies, magnetic resonance elastography, magnetic resonance imaging–estimated proton density fat fraction, quantitative collagen content, and noninvasive markers of liver injury. Due to the lack of effect of simtuzumab on histology or selonsertib pharmacokinetics, selonsertib groups with and without simtuzumab were pooled. After 24 weeks of treatment, the proportion of patients with a one or more stage reduction in fibrosis in the 18‐mg selonsertib group was 13 of 30 (43%; 95% confidence interval, 26‐63); in the 6‐mg selonsertib group, 8 of 27 (30%; 95% confidence interval, 14‐50); and in the simtuzumab‐alone group, 2 of 10 (20%; 95% confidence interval, 3‐56). Improvement in fibrosis was associated with reductions in liver stiffness on magnetic resonance elastography, collagen content and lobular inflammation on liver biopsy, as well as improvements in serum biomarkers of apoptosis and necrosis. There were no significant differences in adverse events between the treatment groups. Conclusion: These findings suggest that selonsertib may reduce liver fibrosis in patients with nonalcoholic steatohepatitis and stage 2‐3 fibrosis. (Hepatology 2018;67:549‐559).

中文翻译：

---

ASK1 抑制剂 Selonsertib 在非酒精性脂肪性肝炎患者中的应用：一项随机、2 期试验

抑制细胞凋亡信号调节激酶 1（一种丝氨酸/苏氨酸激酶）可改善非酒精性脂肪性肝炎动物模型的炎症和纤维化。我们评估了 selonsertib（一种凋亡信号调节激酶 1 的选择性抑制剂）单独或与 simtuzumab 联合治疗非酒精性脂肪性肝炎和 2 或 3 期肝纤维化患者的安全性和有效性。在这项多中心 2 期试验中，72 名患者随机接受 24 周的开放标签治疗，每天一次口服 6 或 18 mg selonsertib，有或没有每周一次注射 125 mg simtuzumab 或单独 simtuzumab。通过对治疗前和治疗后的肝活检、磁共振弹性成像、磁共振成像-估计的质子密度脂肪分数、定量胶原蛋白含量和肝损伤的非侵入性标志物。由于 simtuzumab 对组织学或 selonsertib 药代动力学没有影响，合并了有和没有 simtuzumab 的 selonsertib 组。治疗 24 周后，18 毫克 selonsertib 组中纤维化减少一个或多个阶段的患者比例为 30 人中的 13 人（43%；95% 置信区间，26-63）；在 6 毫克 selonsertib 组中，27 人中有 8 人（30%；95% 置信区间，14-50）；在 simtuzumab 单药组中，10 个中有 2 个（20%；95% 置信区间，3-56）。纤维化的改善与磁共振弹性成像显示的肝脏硬度、肝活检中胶原含量和小叶炎症的降低以及细胞凋亡和坏死的血清生物标志物的改善有关。治疗组之间的不良事件没有显着差异。结论：这些发现表明 selonsertib 可以减少非酒精性脂肪性肝炎和 2-3 期纤维化患者的肝纤维化。（肝病学 2018 年；67：549-559）。