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

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 twopart 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 log 10 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.

Recent Advances in the Digestive, Metabolic and Therapeutic Effects of Farnesoid X Receptor and Fibroblast Growth Factor 19: From Cholesterol to Bile Acid Signaling

“…Vonafexor was well tolerated overall with moderate gastrointestinal adverse effects (pruritus occurred in ~60% of subjects with twice-daily treatment compared with 16% in subjects with once-daily treatment). Vonafexor alone or combined with interferon-α2a showed an anti-viral effect by reducing HBV markers [ 252 ]. In non-diabetic NAFLD patients, a 4-weeks of treatment with the non-steroidal FXR agonist PX-104 improved liver enzymes and insulin sensitivity with no serious adverse events.…”

A perspective study of the possible impact of obeticholic acid against SARS-CoV-2 infection

“…In addition, OCA stops HIV-1 particle accumulation within the liver cells (Zhou et al 2019 ). A recent study displayed that FXR agonists potentially affect the proliferation of the hepatitis B virus (HBV) (Erken et al 2021 ). A double-blind placebo-controlled trial of 73 cases with HBV infection treated with FXR agonists for 35 days demonstrated that these agents efficiently lessened the hepatitis B surface antigen (HBsAg) level relative to the placebo impact (Erken et al 2021 ).…”

“…A recent study displayed that FXR agonists potentially affect the proliferation of the hepatitis B virus (HBV) (Erken et al 2021 ). A double-blind placebo-controlled trial of 73 cases with HBV infection treated with FXR agonists for 35 days demonstrated that these agents efficiently lessened the hepatitis B surface antigen (HBsAg) level relative to the placebo impact (Erken et al 2021 ). FXR agonists interact with HBV viral proteins preventing their transcription and triggering off the reduction of HBV viral protein (Erken et al 2021 ).…”

“…A double-blind placebo-controlled trial of 73 cases with HBV infection treated with FXR agonists for 35 days demonstrated that these agents efficiently lessened the hepatitis B surface antigen (HBsAg) level relative to the placebo impact (Erken et al 2021 ). FXR agonists interact with HBV viral proteins preventing their transcription and triggering off the reduction of HBV viral protein (Erken et al 2021 ). These findings may explain the role of FXR agonists against viral infections, including OCA, to antagonize HBV infection.…”

RNA interference as a novel treatment strategy for chronic hepatitis B infection

“…Multiple novel therapeutics, broadly classified as virus-targeting agents and immunomodulators, are being actively investigated as strategies for achieving functional cure [ 5 ]. Virus-targeting agents inhibit different steps of the HBV lifecycle and agents in development include: 1) entry inhibitors: which inhibit HBV docking and hepatocyte entry [ 6 ]; 2) polymerase inhibitors: which inhibit HBV polymerase competitively (conventional NAs) or non-competitively (novel active site polymerase inhibitor nucleotide) [ 7 ]; 3) RNA silencers: which inhibit HBV messenger RNA (mRNA) translation and viral protein production [ 8 ]; 4) capsid assembly modulators: which inhibit HBV nucleocapsid assembly and pregenomic RNA encapsidation [ 9 ]; 5) viral protein export inhibitors: which inhibit HBV antigen release from hepatocytes [ 10 , 11 ]; and 6) farnesoid X receptor (FXR) agonist: which reverses the interaction between FXR and the HBV X protein to interfere with transcription regulation [ 12 ]. Immunomodulators utilize an alternative strategy which is different from virus-targeting agents.…”