Journal Article

Licogliflozin for nonalcoholic steatohepatitis: a randomized, double-blind, placebo-controlled, phase 2a study

Zuckerman, Eli, Charatcharoenwitthaya, Phunchai, Smith, William B., Ben-Ari, Ziv, Sicard, Eric, Zhang, Yiming, Cheng, Pin-Nan, Alpenidze, Diana, Aizenberg, Diego, He, YanLing, Tanner, Sandra, Badman, Michael K., Klarenbeek, Naomi, Klein, Samuel, Pachori, Alok, Martic, Miljen, Kao, Sheena, Ma, Shenglin, Mendonza, Anisha E., Chen, Chi-Yi, Ukomadu, Chinweike, Harrison, Stephen A., Ravussin, Eric, Manghi, Federico Perez, Katchman, Helena

2022

Overview

Nonalcoholic steatohepatitis (NASH) is a common chronic liver disease that may advance to fibrosis and lead to mortality; however, no pharmacotherapy is currently available. We tested the hypothesis that inhibition of both the sodium–glucose cotransporters 1 and 2 with licogliflozin would lead to improvement in NASH. A total of 107 patients with phenotypic or histologic NASH were randomized (1:2:2) to receive oral administration of either placebo ( n  = 21), licogliflozin 30 mg ( n  = 43) or 150 mg ( n  = 43) once daily for 12 weeks. Licogliflozin 150 mg showed a significant 32% (80% confidence interval (CI): 21–43%; P  = 0.002) placebo-adjusted reduction in serum alanine aminotransferase after 12 weeks of treatment, the primary endpoint of the study. However, the 30 mg dose of licogliflozin did not meet the primary endpoint (placebo-adjusted reduction 21% (80% CI: 7–32%; P  = 0.061)). Diarrhea occurred in 77% (33 of 43), 49% (21 of 43) and 43% (9 of 21) of patients treated with licogliflozin 150 mg, 30 mg and placebo, respectively, which was mostly mild in severity. No other major safety concerns were identified. Treatment with 150 mg licogliflozin led to reductions in serum alanine aminotransferase in patients with NASH. Studies of longer duration and in combination with drugs that have different mechanisms of action are needed to validate these findings and to define a role of licogliflozin as a therapeutic option for NASH. ClinicalTrials.gov identifier: NCT03205150. In a phase 2a clinical trial in patients with nonalcoholic steatohepatitis, dual inhibition of sodium–glucose cotransporters 1 and 2 with 150 mg of licogliflozin led to reductions in serum alanine aminotranferase levels.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 692/699/1503/1607/2750 / 692/699/1503/1607/2751 / Alanine / Alanine Transaminase / Anhydrides - pharmacology / Anhydrides - therapeutic use / Biomedical and Life Sciences / Biomedical research / Biomedicine / Cancer Research / Clinical trials / Diarrhea / Double-Blind Method / Double-blind studies / Drug dosages / Drug therapy / Fibrosis / Gastrointestinal surgery / Glucose / Health services / Hospitals / Humans / Infectious Diseases / Liver diseases / Metabolic Diseases / Molecular Medicine / Neurosciences / Non-alcoholic Fatty Liver Disease - drug therapy / Non-alcoholic Fatty Liver Disease - pathology / Obesity / Oral administration / Patients / Peptides / Placebos / Reduction / Sodium / Sodium-glucose cotransporter / Sorbitol - analogs & derivatives / Sorbitol - pharmacology / Sorbitol - therapeutic use / Transaminases / Treatment Outcome / Weight control