IOT-022

Drug combinations have potential for additive or synergistic efficacy in patients with metabolic dysfunction–associated steatohepatitis (MASH).

To assess the safety, efficacy and pharmacokinetics of single or combination treatments in patients with MASH.

In this multicentre, open‐label, platform phase 2 study, patients ( N  = 41) were randomised 1:1 to LYS006 20 mg twice‐daily (bid) monotherapy or LYS006 20 mg bid+tropifexor 200 μg once‐daily (qd) combination therapy for 12 weeks. The primary endpoint was safety; secondary endpoints were efficacy and pharmacokinetics.

Pruritus adverse events (AEs) were reported in 62% of patients in the combination arm. Other AEs were similar between the treatment arms. A greater reduction in alanine aminotransferase (ALT) and liver fat was observed in the combination versus monotherapy arm (ALT: 43% vs. 13% reduction; liver fat: 37% vs. 20% reduction, respectively). No significant impact on biomarkers for liver fibrosis was observed in either treatment arm, but there was an indication for lower plasma exposure to LYS006 upon co‐administration with tropifexor.

LYS006 20 mg bid monotherapy and LYS006 20 mg bid+tropifexor 200 μg qd therapy were well tolerated with the exception of a high frequency of pruritus in the combination arm, consistent with the now known pharmacologic effect of farnesoid X receptor agonists. The greater reductions in ALT and liver fat in the combination arm versus monotherapy arm were similar to those observed with tropifexor as monotherapy in a previously reported phase 2 clinical trial, and clear additional benefit was not observed in combination treatment with LYS006. This study design allowed for rapid screening of potentially high efficacy drug combinations in MASH.

ClinicalTrials.gov identifier: NCT04147195

As intracellular organisms, viruses exploit host metabolism to replicate and propagate. The farnesoid X receptor alpha (FXRα) is a bile acid-activated nuclear receptor that regulates bile acid, glucose and lipid metabolism, as well as inflammation and immunity. Since its discovery in 1995, numerous ligands have been developed to treat metabolism-related syndromes. More recently, FXRα has been shown to modulate the life cycle of various viruses that infect human. This review provides a comprehensive summary of the literature regarding the effect of FXRα agonism in viral infections caused by hepatotropic viruses, enteric viruses and other viral pathogens. Rather than acting through a single antiviral mechanism, FXRα has been reported to influence many steps of viral replication, including entry, transcription and particle secretion. The established safety profiles of FXRα agonists and their clinical use for other pathologies could pave the way for their re-purposing as broad-spectrum antivirals.