Utility and variability of three non-invasive liver fibrosis imaging modalities to evaluate efficacy of GR-MD-02 in subjects with NASH and bridging fibrosis during a phase-2 randomized clinical trial

PLoS One. 2018 Sep 7;13(9):e0203054. doi: 10.1371/journal.pone.0203054. eCollection 2018.

Abstract

Background: Given the worldwide prevalence of NAFLD and NASH, there is a need to develop treatments to slow or reverse disease progression. GR-MD-02 (galactoarabino-rhamnogalaturonate) has been shown to reduce hepatic fibrosis in animal studies, and lower serum biomarkers of NASH fibrogenesis in humans. The primary aim of this study was to determine the difference between four-months of treatment with GR-MD-02 or placebo in liver inflammation and fibrosis as measured by iron-corrected T1 (cT1) mapping, a non-invasive magnetic resonance imaging (MRI) biomarker that correlates with the extent of hepatic fibro-inflammatory disease. The secondary aims were to determine change in liver stiffness as measured by magnetic resonance elastography (MRE) and shear-wave ultrasonic elastography (LSM), and to explore test-retest repeatability of the three biomarkers.

Materials and methods: Thirty subjects (13 females, 46-71 years) with NASH and advanced fibrosis were recruited. Subjects were randomized to receive 8 mg.kg-1 GR-MD-02 (via IV infusion) or placebo, administered biweekly over a 16-week period. Therapeutic efficacy was examined using cT1, MRE, and LSM. Statistical analyses on group differences in the biomarkers were performed using robust ANCOVA models adjusting for baseline measurement and additional covariates.

Results: There was no significant difference in cT1 (p = 0.16) between GR-MD-02 and placebo groups following a 16-week intervention. There was also no significant difference in liver stiffness, measured by MRE (p = 0.80) or LSM (p = 0.63), between groups. Examination of repeatability of the cT1, MRE and LSM revealed coefficient of variations of 3.1%, 11% and 40% respectively.

Conclusions: 8 mg.kg-1 of GR-MD-02 had no significant effect on non-invasive biomarkers of liver inflammation or fibrosis over a 4-month period. Histological confirmation was not available in this study. The high reproducibility of the primary outcome measure suggests that cT1 could be utilized for monitoring longitudinal change in patients with NASH.

Publication types

  • Clinical Trial, Phase II
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Double-Blind Method
  • Elasticity
  • Female
  • Humans
  • Liver / diagnostic imaging
  • Liver / drug effects
  • Liver Cirrhosis / diagnostic imaging*
  • Liver Cirrhosis / drug therapy*
  • Liver Cirrhosis / physiopathology
  • Magnetic Resonance Imaging* / methods
  • Male
  • Middle Aged
  • Non-alcoholic Fatty Liver Disease / diagnostic imaging
  • Non-alcoholic Fatty Liver Disease / drug therapy
  • Non-alcoholic Fatty Liver Disease / physiopathology
  • Pectins / therapeutic use*
  • Protective Agents / therapeutic use*
  • Treatment Outcome
  • Ultrasonography* / methods

Substances

  • Protective Agents
  • Pectins
  • belapectin

Grants and funding

SN acknowledges support from the Oxford NIHR Biomedical Research Centre. This study was sponsored by Galectin Therapeutics. Galectin Therapeutics did not play a role in the data collection and analysis, but were consulted on the study design, decision to publish and with the preparation of the manuscript. Galectin Therapeutics provided support in the form of salaries for author PGT. Perspectum Diagnostics provided support in the form of salaries for authors AD, MMF, MDK, CJK SN and RB, and performed analysis of the data, but did not have any additional role in the study design or data collection. The specific roles of these authors are articulated in the ‘author contributions’ section.