Phase 1b study of miricorilant in patients with presumed metabolic dysfunction-associated steatohepatitis (MASH)

BACKGROUND AND AIMS: Miricorilant, an oral nonsteroidal selective glucocorticoid receptor modulator, is being investigated as a therapy that modulates hepatic cortisol activity in patients with metabolic dysfunction-associated steatohepatitis (MASH). This phase 1b study evaluated miricorilant's efficacy and safety. APPROACH AND RESULTS: Seventy patients with presumed MASH received oral miricorilant daily (30-150 mg) or intermittent (100-200 mg once, twice, or thrice weekly) dosing regimens for 12 or 24 weeks. Across dosing regimens, reductions in relative liver fat content (LFC) ranged from 10.1% to 76.6%. Improvements in MASH liver function markers and the enhanced liver fibrosis (ELF) score were observed across regimens. Treatment-emergent adverse events (TEAE) leading to drug interruption/discontinuation occurred in 12.9% of patients (n=9) each; most were due to aminotransferase elevations during an excessively rapid drop in LFC (up to 70.2% at week 6) and in patients receiving daily dosing. Intermittent dosing enabled more patients to complete 12 weeks of treatment without discontinuation due to TEAEs. Intermittent dosing with miricorilant 100 mg twice weekly had the best benefit-risk profile; this cohort demonstrated a mean LFC reduction of 28.2% at week 12, with a corresponding decline in liver enzymes (ALT, -3.8 U/L; AST, -6.0 U/L). Patients in this cohort also had numerical improvement in lipid profiles, glycemic markers, and fibrosis biomarkers. CONCLUSIONS: Intermittent miricorilant dosing of 100 mg twice weekly achieved meaningful reductions in LFC and improved liver health markers with a favorable safety profile. This regimen is being evaluated in the phase 2b MONARCH study (NCT06108219).