Hepatic and renal improvements with FXR agonist vonafexor in individuals with suspected fibrotic NASH

International audienceBACKGROUND & AIMS : The LIVIFY trial investigated the safety, tolerability, and efficacy of vonafexor, a second-generation, non-bile acid farnesoid X receptor agonist in patients with suspected fibrotic non-alcoholic steatohepatitis (NASH). METHODS : This double-blind phase IIa study was conducted in two parts. Patients were randomised (1:1:1:1) to receive placebo, vonafexor 100 mg twice daily (VONA-100BID), vonafexor 200 mg once daily (VONA-200QD), or 400 mg vonafexor QD (VONA-400QD) in Part A (safety run-in, pharmacokinetics/pharmacodynamics) or placebo, vonafexor 100 mg QD (VONA-100QD), or VONA-200QD (1:1:1) in Part B. The primary efficacy endpoint was a reduction in liver fat content (LFC) by MRI-proton density fat fraction, while secondary endpoints included reduced corrected T1 values and liver enzymes, from baseline to Week 12.RESULTS : One hundred and twenty patients were randomised (Part A, n = 24; Part B, n = 96). In Part B, there was a significant reduction in least-square mean (SE) absolute change in LFC from baseline to Week 12 for VONA-100QD (-6.3% [0.9]) and VONA-200QD (-5.4% [0.9]), vs. placebo (-2.3% [0.9], p = 0.002 and 0.012, respectively). A >30% relative LFC reduction was achieved by 50.0% and 39.3% of patients in the VONA-100QD and VONA-200QD arms, respectively, but only in 12.5% in the placebo arm. Reductions in body weight, liver enzymes, and corrected T1 were also observed with vonafexor. Creatinine-based glomerular filtration rate improved in the active arms but not the placebo arm. Mild to moderate generalised pruritus was reported in 6.3%, 9.7%, and 18.2% of participants in the placebo, VONA-100QD, and VONA-200QD arms, respectively.CONCLUSIONS : In patients with suspected fibrotic NASH, vonafexor was safe and induced potent liver fat reduction, improvement in liver enzymes, weight loss, and a possible renal benefit

The farnesoid X receptor induces fetuin-B gene expression in human hepatocytes

FXR (farnesoid X receptor), a nuclear receptor activated by BAs (bile acids), is a key factor in the regulation of BA, lipid and carbohydrate metabolism. The recent development of synthetic FXR agonists and knockout mouse models has accelerated the discovery of FXR target genes. In the present study, we identify human fetuin-B as a novel FXR target gene. Treatment with FXR agonists increased fetuin-B expression in human primary hepatocytes and in the human hepatoma HepG2 cell line. In contrast, fetuin-B expression was not responsive to FXR agonist treatment in murine primary hepatocytes. Fetuin-B induction by FXR agonist was abolished upon FXR knockdown by siRNA (small interfering RNA). In addition to the previously described P1 promoter, we show that the human fetuin-B gene is also transcribed from an alternative promoter, termed P2. Transcription via the P2 promoter was induced by FXR agonist treatment, whereas P1 promoter activity was not sensitive to FXR agonist treatment. Two putative FXR-response elements [IR-1 (inverted repeat-1)] were identified in the region –1.6 kb upstream of the predicted P2 transcriptional start site. Both motifs bound FXR–RXR (retinoid X receptor) complexes in vitro and were activated by FXR in transient transfection reporter assays. Mutations in the IR-1 sites abolished FXR–RXR binding and activation. Taken together, these results identify human fetuin-B as a new FXR target gene in human hepatocytes

Viruses traverse the human proteome through peptide interfaces that can be biomimetically leveraged for drug discovery

International audienceSignificance Viruses have designed small protein interfaces to interact with human proteins. These viral peptides are original molecules to modulate the activity of host targets and an inspiration to create original drugs. Here, the wealth of virus-host protein interactions existing in the literature is integrated in an substantial database. A sample peptide library is screened against several pathogens, highlighting peptides modulators of replication. From one of them, a drug discovery program identifies highly potent antiviral molecules interacting with human metabolic targets. These molecules are proven to be active for treatment of mouse model of nonalcoholic steatohepatitis with chronic kidney disease. Our approach validates an original biomimetic framework to address cellular functions for fundamental applications and drug discovery