Basic Study
Copyright ©The Author(s) 2018. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Jan 14, 2018; 24(2): 195-210
Published online Jan 14, 2018. doi: 10.3748/wjg.v24.i2.195
INT-767 improves histopathological features in a diet-induced ob/ob mouse model of biopsy-confirmed non-alcoholic steatohepatitis
Jonathan D Roth, Michael Feigh, Sanne S Veidal, Louise KD Fensholdt, Kristoffer T Rigbolt, Henrik H Hansen, Li C Chen, Mathieu Petitjean, Weslyn Friley, Niels Vrang, Jacob Jelsing, Mark Young
Jonathan D Roth, Mark Young, Intercept Pharmaceuticals, Intercept Pharmaceuticals, San Diego, CA 92121, United States
Michael Feigh, Sanne S Veidal, Louise KD Fensholdt, Kristoffer T Rigbolt, Henrik H Hansen, Niels Vrang, Jacob Jelsing, Gubra, Hoersholm DK-2970, Denmark
Li C Chen, Mathieu Petitjean, PharmaNest, Genesis Imaging Services, Princeton, NJ 08540, United States
Weslyn Friley, Qualyst Transporter Solutions, Durham, NC 27713, United States
Author contributions: Studies were designed by Roth JD, Feigh M, Petitjean M and Young M; Fensholdt LKD Fensholdt, Veidal SS, Rigbolt KT, Chen LC and Friley W performed the majority of experiments; Hansen HH and Roth JD wrote the paper with significant contributions to data analyses and editing by all co-authors.
Institutional animal care and use committee statement: All animal experiments conformed to the internationally accepted principles for the care and use of laboratory animals (licence no. 2013-15-2934-00784, The Animal Experiments Inspectorate, Denmark).
Conflict-of-interest statement: Jonathan Roth and Mark Young are employed by and hold equity in Intercept Pharmaceuticals, Inc. All other authors have nothing to disclose.
Data sharing statement: No additional data are available.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:
Correspondence to: Henrik H Hansen, PhD, Principal Scientist, Pharmacology, Gubra, Kongevej 11B, Hoersholm DK-2970, Denmark.
Telephone: +45-23-1522651
Received: October 23, 2017
Peer-review started: October 25, 2017
First decision: November 14, 2017
Revised: November 24, 2017
Accepted: December 5, 2017
Article in press: December 5, 2017
Published online: January 14, 2018

To characterize the efficacy of the dual FXR/TGR5 receptor agonist INT-767 upon histological endpoints in a rodent model of diet-induced and biopsy-confirmed non-alcoholic steatohepatitis (NASH).


The effects of INT-767 on histological features of NASH were assessed in two studies using Lepob/ob (ob/ob) NASH mice fed the AMLN diet (high fat with trans-fat, cholesterol and fructose). In a proof-of-concept study, Lepob/ob (ob/ob) NASH mice were first dosed with INT-767 (3 or 10 mg/kg for 8 wk). A second ob/ob NASH study compared INT-767 (3 and 10 mg/kg) to obeticholic acid (OCA) (10 or 30 mg/kg; 16 wk). Primary histological endpoints included qualitative and quantitative assessments of NASH. Other metabolic and plasma endpoints were also assessed. A comparative assessment of INT-767 and OCA effects on drug distribution and hepatic gene expression was performed in C57Bl/6 mice on standard chow. C57Bl/6 mice were orally dosed with INT-767 or OCA (1-30 mg/kg) for 2 wk, and expression levels of candidate genes were assessed by RNA sequencing and tissue drug levels were measured by liquid chromatography tandem-mass spectrometry.


INT-767 dose-dependently (3 and 10 mg/kg, PO, QD, 8 wk) improved qualitative morphometric scores on steatohepatitis severity, inflammatory infiltrates and fibrosis stage. Quantitative morphometric analyses revealed that INT-767 reduced parenchymal collagen area, collagen fiber density, inflammation (assessed by Galectin-3 immunohistochemistry) and hepatocyte lipid droplet area following INT-767 treatment. In a comparative study (16 wk), the FXR agonists OCA (10 and 30 mg/kg) and INT-767 (3 and 10 mg/kg) both improved NASH histopathology, with INT-767 exerting greater therapeutic potency and efficacy than OCA. Mechanistic studies suggest that both drugs accumulate similarly within the liver and ileum, however, the effects of INT-767 may be driven by enhanced hepatic, but not ileal, FXR function.


These findings confirm the potential utility of FXR and dual FXR/TGR5 activation as disease intervention strategies in NASH.

Keywords: Non-alcoholic steatohepatitis, INT-767, Obeticholic acid, Liver biopsy, FXR, TGR5, Mouse model

Core tip: The studies contained herein evaluated the preclinical efficacy of INT-767, a dual FXR/TGR5 agonist, in a mouse model of diet-induced and biopsy-confirmed non-alcoholic steatohepatitis (NASH). Rigorous analyses for NASH histological endpoints and markers were conducted including blinded qualitative and quantitative scoring using standard microscopy as well as advanced morphometric fibrosis and steatosis features using second harmonic generation imaging and two-photon fluorescence excitation. INT-767 promoted dose-dependent improvements in fibrosis, steatosis, inflammation and ballooning degeneration. The effects of INT-767 and obeticholic acid (OCA) were also compared for histological efficacy, gene expression and tissue distribution. The preclinical data suggest that INT-767 is a more potent FXR receptor agonist, and is expected to have therapeutic effects at lower doses than OCA.