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

Abstract

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.

Keywords: 24-norursodeoxycholic acid; Fatty liver; Liver diseases; Steatosis; Fibrosis; Metabolic dysfunction-associated steatotic liver disease; Nonalcoholic fatty liver disease

Core Tip: This phase III trial demonstrated that norursodeoxycholic acid (norUDCA) 1500 mg significantly improved liver function in metabolic dysfunction-associated steatotic liver disease patients, with a majority of patients achieving alanine aminotransferase normalization and showing fibrosis regression on FibroScan. Notably norUDCA demonstrated favorable safety profile with no serious adverse events reported. All adverse events reported were mild or moderate in intensity and recovered over time. These findings highlight the norUDCA’s efficacy and safety addressing the need for more approved promising therapies in managing metabolic dysfunction-associated steatotic liver disease.