Farnesoid X receptor agonist for the treatment of chronic hepatitis B: A safety study

  • J Viral Hepat. 2021 Dec;28(12):1690-1698. doi: 10.1111/jvh.13608.
Robin Erken  1 ,  Patrice Andre  2 ,  Elise Roy  3 ,  Neeltje Kootstra  4 ,  Noelie Barzic  3 ,  Hugo Girma  3 ,  Christian Laveille  5 ,  Pauline Radreau-Pierini  3 ,  Raphael Darteil  3 ,  Jacky Vonderscher  3 ,  Pietro Scalfaro  3 ,  Pisit Tangkijvanich  6 ,  Robert Flisiak  7 ,  Henk Reesink  8
Affiliations
  • 1. Department of Gastroenterology and Hepatology, Amsterdam UMC, University of Amsterdam, Duivendrecht, The Netherlands.
  • 2. Inserm U1111, CNRS UMR5308, Université Lyon 1, and Ecole Normale Supérieure de Lyon, Lyon, France.
  • 3. Enyo Pharma SA, Lyon, France.
  • 4. Amsterdam UMC, University of Amsterdam, Department of Experimental Immunology, Amsterdam Infection & Immunity Institute, University of Amsterdam, Amsterdam, Netherlands.
  • 5. Calvagone, Liergues, France.
  • 6. Center of Excellence in Hepatitis and Liver Cancer, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand.
  • 7. Klinika Chorób Zakaźnych I Hepatologii UMB, Uniwersytecki Szpital Kliniczny w Białymstoku, Białystok, Poland.
  • 8. Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, The Netherlands.
PMID: 34467593 DOI: 10.1111/jvh.13608
Abstract

The nuclear farnesoid X receptor (FXR) regulates bile acid homeostasis and is a drug target for metabolic liver diseases. FXR also plays an important role in hepatitis B virus (HBV) DNA transcription. In vitro and in mice, FXR Agonist treatment leads to inhibition of viral replication and a decline in Viral Proteins, pregenomic RNA (pgRNA) and HBV DNA levels. We aimed to translate this to a clinical use by primarily evaluating the safety and secondary the anti-viral effect of Vonafexor, a FXR Agonist, in chronic hepatitis B (CHB) patients. In total, 73 CHB patients were enrolled in a two-part Phase Ib double-blind, placebo-controlled trial. Patients were randomized to receive oral Vonafexor (100, 200 and 400 mg once daily, or 200 mg twice daily), placebo, or entecavir (Part A, n = 48) or to receive Vonafexor (300 mg once daily or 150 mg twice daily), or placebo, combined with pegylated-interferon-α2a (Part B, n = 25) for 29 days. Patients were followed up for 35 days. Enrolled CHB patients were mostly HBeAg-negative. Vonafexor was overall well tolerated and safe. The most frequent adverse events were moderate gastrointestinal events. Pruritus was more frequent with twice-daily compared with once-daily regimens (56%-67% vs. 16%, respectively, p < 0.05). Vonafexor monotherapy of 400 mg once daily decreased HBsAg concentrations (-0.1 log10 IU/mL, p < 0.05), and Vonafexor/pegylated-IFN-α2a combination therapy decreased HBcrAg and pgRNA. In conclusion, Vonafexor was safe with a decline in HBV markers observed in CHB patients suggesting a potential anti-viral effect the therapeutic potential of which has to be evaluated in larger trials.

Keywords
HBV therapy; Vonafexor; cccDNA transcription; farnesoid X receptor; phase Ib.
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