Icosabutate: targeting metabolic and inflammatory pathways for the treatment of NASH

ABSTRACT

Introduction

Via pleiotropic targeting of membrane and nuclear fatty acid receptors regulating key metabolic and inflammatory pathways in the liver, long-chain omega-3 fatty acids could offer a unique therapeutic approach for the treatment of metabolic-inflammatory diseases such as NASH. However, they lack efficacy for the treatment of NASH, likely due to unfavorable distribution, metabolism, and susceptibility to peroxidation.

Areas covered

Structurally engineered fatty acids (SEFAs), as exemplified by icosabutate, circumvent the inherent limitations of unmodified long-chain fatty acids, and demonstrate markedly enhanced pharmacodynamic effects without sacrificing safety and tolerability. We cover icosabutate’s structural modifications, their rationale and the fatty acid receptor and pathway targeting profile. We also provide an overview of the clinical data to date, including interim data from a Phase 2b trial in NASH subjects.

Expert opinion

Ideally, candidate drugs for NASH and associated liver fibrosis should be pleiotropic in mechanism and work upstream on multiple drivers of NASH, including lipotoxic lipid species, oxidative stress, and key modulators of inflammation, liver cell injury, and fibrosis. Icosabutate has demonstrated the ability to target these pathways in preclinical NASH models with interim data from the ICONA trial supporting, at least noninvasively, the clinical translation of highly promising pre-clinical data.

KEYWORDS:

• NASH
• icosabutate
• FFAR4
• omega-3 fatty acid
• steatohepatitis
• liver
• fibrosis
• antifibrotic
• inflammation
• macrophage

Declaration of interest

NorthSea Therapeutics BV acquired the commercial rights for icosabutate. D. Schuppan and S.A. Harrison are paid consultants and have stock options in NorthSea Therapeutics. D. Fraser is an employee of NorthSea Therapeutics BV. NorthSea Therapeutics BV but has no role in data collection. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

List of abbreviations

AA, arachidonic acid; ALT, alanine aminotransferase; AST, aspartate transaminase; CD, choline deficient; CVD, cardiovascular disease; CYP450, Cytochrome P450; ELF score, enhanced liver fibrosis score; EPA, eicosapentaenoic acid; fatty acid synthase, FASN; FIB-4, Fibrosis-4 index; FFA, free fatty acid; FGF, fibroblast growth factor; FFAR, free fatty acid receptor; GLP-1, glucagon-like peptide-1; GGT, gamma-glutamyl transferase; GPCRs, G protein-coupled receptors; HETEs, hydroxyeicosatetraenoic acids; HSD17B13, 17-β hydroxysteroid dehydrogenase 13; hsCRP, high sensitivity C-reactive protein; IL, interleukin; LCFAs, long-chain fatty acids; LCn-3FA, long-chain omega-3 fatty acid; PLA2, phospholipase 2; PPAR, peroxisome proliferator activated receptor; PRO-C3, procollagen type III N-propeptide; SEFA, structurally engineered fatty acid; THR, thyroid hormone receptor; TG, triglycerides; TNFα, tumor necrosis factor alpha; TLR, toll-like receptor.

Additional information

Funding

D. Schuppan receives project-related support from the German Research Foundation (DFG) Collaborative Research Center (CRC) grants SFB 1066 project B3 and CRC 1292 project B10, and by EU Horizon 2020 projects under grant agreement nr. 634413 (EPoS, European Project on Steatohepatitis)