Inhibition of 11β-Hydroxysteroid dehydrogenase-1 with AZD4017 in patients with nonalcoholic steatohepatitis or nonalcoholic fatty liver disease: A randomized, double-blind, placebo-controlled, phase II study.

Abstract

AIM:

To evaluate whether short-term treatment with a selective 11β-Hydroxysteroid dehydrogenase-1 (11β-HSD1) inhibitor, AZD4017, would block hepatic cortisol production and thereby decrease hepatic fat in patients with nonalcoholic fatty liver disease (NAFLD)/nonalcoholic steatohepatitis (NASH), with or without type 2 diabetes (T2D).

MATERIALS AND METHODS:

This was a randomized, double-blind, placebo-controlled, phase 2 study conducted at two sites. Key inclusion criteria were the presence of NAFLD or NASH on magnetic resonance imaging (MRI) or recent biopsy positive for NASH. Enrolled patients were randomly assigned (1:1) to AZD4017 or placebo for 12 weeks. Primary outcomes were between-group differences in mean change from baseline to week 12 in liver fat fraction (LFF) and conversion of 13 C cortisone to 13 C cortisol in the liver.

RESULTS:

A total of 93 patients were randomized; 85 patients completed treatment. The mean (standard deviation [SD]) change in LFF was -0.667 (5.246) and 0.139 (4.323) in the AZD4017 and placebo groups (P = 0.441). For patients with NASH and T2D, the mean (SD) change in LFF was significantly improved in the AZD4017 versus the placebo group (-1.087 [5.374] vs. 1.675 [3.318]; P = 0.033). Conversion of 13 C cortisone to 13 C cortisol was blocked in all patients in the AZD4017 group. There were no significant between-group differences (AZD4017 vs. placebo) in changes in fibrosis, weight, levels of liver enzymes or lipids, or insulin sensitivity.

CONCLUSION:

Although the study did not meet one of the primary outcomes, AZD4017 blocked the conversion of 13 C cortisone to 13 C cortisol in the liver in all patients who received the drug. In patients with NASH and T2D, AZD4017 improved liver steatosis versus placebo.

• Authors: Yogesh Yadav, Kelly Dunagan, Rachita Khot, Sudhakar K Venkatesh, John Port, Alfonso Galderisi, Claudio Cobelli, Craig Wegner, Ananda Basu, Rickey Carter, Rita Basu
• Journal: Diabetes, obesity & metabolism (Diabetes Obes Metab) Vol. 24 Issue 5 Pg. 881-890 (05 2022) ISSN: 1463-1326 [Electronic] England
• PMID: 35014156 (Publication Type: Clinical Trial, Phase II, Journal Article, Randomized Controlled Trial, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2022 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.

Chemical References

• 2-(1-(5-(cyclohexylcarbamoyl)-6-propylsulfanylpyridin-2-yl)-3-piperidyl)acetic acid
• Piperidines
• Niacinamide
• 11-beta-Hydroxysteroid Dehydrogenase Type 1

Topics

• 11-beta-Hydroxysteroid Dehydrogenase Type 1
• Diabetes Mellitus, Type 2 (complications, drug therapy, pathology)
• Double-Blind Method
• Humans
• Liver (pathology)
• Niacinamide (analogs & derivatives)
• Non-alcoholic Fatty Liver Disease (complications, drug therapy, pathology)
• Piperidines (therapeutic use)