甲状腺激素受体β激动剂simedeutirom（HSK31679）治疗代谢功能障碍相关脂肪性肝炎中国患者的52周、多中心、随机、双盲、安慰剂对照、2b期试验。
完整摘要 · 中文译文
背景：Simedeutirom 是一种选择性甲状腺激素受体β激动剂，此前已显示可降低代谢功能障碍相关脂肪性肝病患者的肝脏脂肪含量。我们评估了simedeutirom 在经活检证实的代谢功能障碍相关脂肪性肝炎（MASH）且伴有 F2 或 F3 纤维化的亚裔患者中的疗效和安全性。 方法：这项多中心、随机、双盲、安慰剂对照的 2b 期试验在中国 42 个临床中心开展。患有经活检证实的 MASH、非酒精性脂肪性肝病活动性评分（NAS）至少为 4 分、F2 或 F3 纤维化，且 MRI 质子密度脂肪分数测得的肝脏脂肪含量至少为 8% 的成人（18-74 岁）通过中央网络系统按区组随机化（区组大小为 6；无分层）以 1:1:1 的比例被随机分配至接受每日一次 simedeutirom 80 mg、simedeutirom 160 mg 或安慰剂治疗，共 52 周。参与者及研究人员对治疗分组设盲。主要终点为第 52 周时 MASH 改善（即 NAS 降低至少 2 分，肝细胞气球样变改善至少 1 分，且脂肪变性评分无增加）且无纤维化加重（即纤维化分期无增加）。疗效分析在全分析集进行，该分析集包括所有随机分配且接受至少一次给药并在基线后拥有至少一次疗效评估的参与者；治疗后无肝活检数据或使用了影响疗效的禁用药物的参与者被视为无应答者。 该试验已在ClinicalTrials.gov注册（NCT06168383），且试验已完成。 结果：在2024年1月5日至2026年1月16日期间，186名参与者被随机分组（每组62人）。在完整分析集（n=179）中，中位年龄为42·0岁（IQR 35·0-54·0），116名（65%）参与者为男性，63名（35%）为女性。在80 mg组59名参与者中有22名（37%）、160 mg组60名参与者中有18名（30%）、安慰剂组60名参与者中有6名（10%）在第52周达到MASH改善且纤维化未加重。与安慰剂相比，80 mg组的比值比为4·87（95% CI 1·76-13·48；p=0·0023），160 mg组的比值比为5·24（1·74-15·72；p=0·0032），绝对差异分别为27·3个百分点（95% CI 12·2-41·1）和20·0个百分点（5·7-33·6）。3级治疗中出现的不良事件发生在simedeutirom 80 mg组61名参与者中的3名（5%）、simedeutirom 160 mg组62名参与者中的5名（8%）以及安慰剂组62名参与者中的3名（5%）；没有单个3级事件影响超过一名参与者，且未发生4-5级治疗中出现的不良事件。严重不良事件发生在simedeutirom 80 mg组3名（5%）参与者、simedeutirom 160 mg组4名（6%）参与者以及安慰剂组3名（5%）参与者中；均与治疗无关。未发生死亡或导致治疗中断的不良事件。 解读：与安慰剂相比，simedeutirom在52周后MASH改善且纤维化未加重的比率更高，值得在3期试验中进一步研究。 资助：海思科医药集团。
完整摘要 · 英文原文
BACKGROUND: Simedeutirom is a selective thyroid hormone receptor-β agonist that has previously been shown to reduce hepatic fat content in metabolic dysfunction-associated steatotic liver disease. We assessed the efficacy and safety of simedeutirom in patients of Asian descent with biopsy-confirmed metabolic dysfunction-associated steatohepatitis (MASH) and F2 or F3 fibrosis. METHODS: This multicentre, randomised, double-blind, placebo-controlled, phase 2b trial was conducted at 42 clinical sites in China. Adults (aged 18-74 years) with biopsy-confirmed MASH, a non-alcoholic fatty liver disease activity score (NAS) of at least 4, F2 or F3 fibrosis, and MRI-proton density fat fraction liver fat content of at least 8% were randomly assigned (1:1:1) by block randomisation (block size of six; no stratification) via a centralised web-based system to receive once-daily simedeutirom 80 mg, simedeutirom 160 mg, or placebo for 52 weeks. Participants and study personnel were masked to treatment assignment. The primary endpoint was MASH improvement (ie, two-point or more reduction in NAS, one-point or more improvement in hepatocellular ballooning, and no increase in steatosis score) without worsening of fibrosis (ie, no increase in fibrosis stage) at week 52. Efficacy was analysed in the full analysis set, which included all randomly assigned participants who received at least one dose and had at least one efficacy assessment after baseline; participants without liver biopsy data after treatment or who used prohibited medications affecting efficacy were considered non-responders. The trial is registered with ClinicalTrials.gov (NCT06168383) and is complete. FINDINGS: Between Jan 5, 2024, and Jan 16, 2026, 186 participants were randomly assigned (62 per group). In the full analysis set (n=179), the median age was 42·0 years (IQR 35·0-54·0), 116 (65%) participants were men, and 63 (35%) were women. 22 (37%) of 59 participants in the 80 mg group, 18 (30%) of 60 in the 160 mg group, and six (10%) of 60 in the placebo group had MASH improvement without worsening of fibrosis at week 52. ORs versus placebo were 4·87 (95% CI 1·76-13·48; p=0·0023) in the 80 mg group and 5·24 (1·74-15·72; p=0·0032) in the 160 mg group, with absolute differences of 27·3 percentage points (95% CI 12·2-41·1) and 20·0 percentage points (5·7-33·6), respectively. Grade 3 treatment-emergent adverse events occurred in three (5%) of 61 participants in the simedeutirom 80 mg group, five (8%) of 62 in the simedeutirom 160 mg group, and three (5%) of 62 in the placebo group; no individual grade 3 event affected more than one participant, and no grade 4-5 treatment-emergent adverse events occurred. Serious adverse events occurred in three (5%) participants in the simedeutirom 80 mg group, four (6%) in the simedeutirom 160 mg group, and three (5%) in the placebo group; none were treatment related. No deaths or adverse events leading to treatment discontinuation occurred. INTERPRETATION: Simedeutirom led to higher rates of MASH improvement without worsening of fibrosis than placebo after 52 weeks, warranting further investigation in phase 3 trials. FUNDING: Haisco Pharmaceutical Group.