Repositioning of a novel GABA-B receptor agonist, AZD3355 (Lesogaberan), for the treatment of non-alcoholic steatohepatitis

Dipankar Bhattacharya,Joel T Dudley,Ryan Hicks,Björn Magnusson,Anna Backmark,Christine Becker,Scott L Friedman,Nicolas Goossens,Jacqueline Novik,Maria Isabel Fiel,Benjamin Readhead,Leslie P Cousens

doi:10.1038/s41598-021-99008-2

Abstract

Non-alcoholic steatohepatitis (NASH) is a rising health challenge, with no approved drugs. We used a computational drug repositioning strategy to uncover a novel therapy for NASH, identifying a GABA-B receptor agonist, AZD3355 (Lesogaberan) previously evaluated as a therapy for esophageal reflux. AZD3355’s potential efficacy in NASH was tested in human stellate cells, human precision cut liver slices (hPCLS), and in vivo in a well-validated murine model of NASH. In human stellate cells AZD3355 significantly downregulated profibrotic gene and protein expression. Transcriptomic analysis of these responses identified key regulatory nodes impacted by AZD3355, including Myc, as well as MAP and ERK kinases. In PCLS, AZD3355 down-regulated collagen1α1, αSMA and TNF-α mRNAs as well as secreted collagen1α1. In vivo, the drug significantly improved histology, profibrogenic gene expression, and tumor development, which was comparable to activity of obeticholic acid in a robust mouse model of NASH, but awaits further testing to determine its relative efficacy in patients. These data identify a well-tolerated clinical stage asset as a novel candidate therapy for human NASH through its hepatoprotective, anti-inflammatory and antifibrotic mechanisms of action. The approach validates computational methods to identify novel therapies in NASH in uncovering new pathways of disease development that can be rapidly translated into clinical trials.

Highlights

Nonalcoholic steatohepatitis (NASH) is a serious and escalating health threat in the United States, affecting between 6.5 million to 16.3 million A mericans[1], with a rising incidence paralleling the obesity epidemic
We explored the potential efficacy of AZD3355 (Lesogaberan)[17,18], an agent that previously failed in a Phase 2b human trial for treatment of gastroesophageal reflux disease (GERD)[19], as a novel treatment for NASH using a combination of culture and in vivo studies
To further evaluate whether the transcriptomic relationship between AZD3355 and the NASH gene expression signature was unusually strong, we performed the same repurposing analysis for all 1,309 compounds in Connectivity Map against the NASH signature and found that the connectivity score for AZD3355 was in the top 2% of predictions for NASH when ranked among all 1,309 compounds

Summary

Introduction

Nonalcoholic steatohepatitis (NASH) is a serious and escalating health threat in the United States, affecting between 6.5 million to 16.3 million A mericans[1], with a rising incidence paralleling the obesity epidemic. (OCA or INT-747 or 6alpha-ethylchenodeoxycholic acid (6-ECDCA)) is the most advanced investigational drug for NASH far, but is not yet FDA-approved due to safety concerns This agent improves NASH fibrosis in only 23.1% of patients in a phase 3 trial, compared to 11.9% of placebo-treated patients[7]. Many drugs that have clean safety profiles are shelved because of insufficient efficacy or commercial decisions related to the available market and competitive landscape Some of these agents can be repurposed for treating diseases unrelated to their original clinical indication based on an emerging understanding of pathobiology, and enhanced by computational tools to search vast databases of publicly available knowledge[13,14]. Drug repurposing reduces risk of failure from toxicity and can lower the cost of drug development since these FDA-approved drugs have passed regulatory scrutiny and sometimes post-market surveillance as well

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Conclusion