Liver and Bile
J Hepatol. 2023;78(3):479–92
Hepatic and renal improvements with FXR agonist vonafexor in individuals with suspected fibrotic NASH
Background and aims: The LIVIFY trial investigated the safety, tolerability, and efficacy of vonafexor, a second-generation, non-bile acid farnesoid X receptor (FXR) agonist in patients with suspected fibrotic non-alcoholic steatohepatitis (NASH).
Methods: This double-blind phase 2a study was conducted in 2 parts. Patients were randomized (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 end point was a reduction in liver fat content (LFC) by magnetic resonance imaging (MRI)-proton density fat fraction, while secondary end points included reduced corrected T1 values and liver enzymes, from baseline to week 12.
Results: 120 patients were randomized (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]), versus 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 generalized 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 non-alcoholic steatohepatitis, vonafexor was safe and induced potent liver fat reduction, improvement in liver enzymes, weight loss, and a possible renal benefit.