Efruxifermin, an investigational treatment for fibrotic or cirrhotic nonalcoholic steatohepatitis (NASH)

Introduction: Non-alcoholic fatty liver disease (NAFLD) is the most prevalent chronic liver disease and strongly associated with metabolic disorders: obesity, type 2 diabetes (T2D), cardiovascular disease. Persistent metabolic injury results in inflammatory processes leading to nonalcoholic steatohepatitis (NASH), liver fibrosis, and ultimately cirrhosis. To date, no pharmacologic agent is approved for the treatment of NASH. Fibroblast growth factor 21 (FGF21) agonism has been linked to beneficial metabolic effects ameliorating obesity, steatosis, and insulin resistance, supporting its potential as a therapeutic target in NAFLD. Areas covered: Efruxifermin (EFX, also AKR-001 or AMG876) is an engineered Fc-FGF21 fusion protein with an optimized pharmacokinetic and pharmacodynamic profile, which is currently tested in several phase 2 clinical trials for the treatment of NASH, fibrosis and compensated liver cirrhosis. EFX improved metabolic disturbances including glycemic control, showed favorable safety and tolerability, and demonstrated antifibrotic efficacy according to FDA requirements for phase 3 trials. Expert opinion: While some other FGF-21 agonists (e.g. pegbelfermin) are currently not further investigated, available evidence supports the development of EFX as a promising anti-NASH drug in fibrotic and cirrhotic populations. However, antifibrotic efficacy, long-term safety and benefits (i.e. cardiovascular risk, decompensation events, disease progression, liver transplantation, mortality) remain to be determined.