Thyroid hormone receptor-β agonist simedeutirom (HSK31679) for Chinese patients with metabolic dysfunction-associated steatohepatitis: a 52-week, multicentre, randomised, double-blind, placebo-controlled, phase 2b trial.

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.