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

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.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.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.