Phase III, multicenter, randomized, double-blind, placebo-controlled study of norursodeoxycholic acid in metabolic dysfunction-associated steatotic liver disease patients

BACKGROUND The norursodeoxycholic acid (norUDCA), a side chain-shortened derivative of ursodeoxycholic acid, exhibits unique pharmacological properties that may benefit patients with metabolic dysfunction-associated steatotic liver disease (MASLD). AIM To evaluate the efficacy, safety, and tolerability of norUDCA 1500 mg compared to placebo in the patients with MASLD. METHODS This phase III, randomized, double-blind, multi-centric, placebo-controlled trial enrolled patients with MASLD, and were randomized in 2:1 ratio to receive either norUDCA 1500 mg or placebo for 24 weeks. Efficacy and safety were rigorously evaluated through clinical, biochemical, and imaging assessments. Primary endpoints assessed alanine aminotransferase (ALT) normalization and improvement in liver stiffness (FibroScan®) at week 12, while secondary endpoints included changes in nonalcoholic fatty liver disease fibrosis score, liver enzymes, lipid profile, glycosylated hemoglobin, and FibroScan-assessed liver stiffness. Safety was monitored throughout the study. RESULTS Of 165 randomized patients, 110 received norUDCA and 55 placebos. At week 12, ALT normalization was achieved in 89% of norUDCA-treated group compared to 76% of placebo-treated group (P = 0.022); with a statistically significant adjusted mean difference (P = 0.016). Fibrosis improvement was observed in 57% of norUDCA-treated vs 40% in placebo-treated (P = 0.035), with highly significant adjusted mean (P = 0.002). nonalcoholic fatty liver disease fibrosis score at week 18 and 24 (P = 0.041 and P = 0.032). Similarly, ALT reductions were significant at both week 18 and week 24 (P = 0.021 and P = 0.035). Improvements in lipid profile trended towards norUDCA without statistical significance. Liver stiffness has improved in 90 patients in norUDCA-treated vs 36 patients in placebo group (P = 0.009). NorUDCA demonstrated favorable safety profile, with no serious adverse events reported, and only mild to moderate adverse events were observed. CONCLUSION NorUDCA 1500 mg demonstrated clinically meaningful therapeutic efficacy in patients with MASLD, accompanied by consistently favorable safety profile.