A Long-Acting Farnesoid X Receptor (FXR) Agonist Prevents Fibrosis

Despite effective vaccines and antiviral therapies, patients with chronic hepatitis B (CHB) remain at risk of developing progressive liver fibrosis and cirrhosis. Vonafexor (VON), a second-generation synthetic non-steroidal, non-bile acid farnesoid X receptor agonist, has been shown to prevent liver fibrosis and target the HBV cccDNA reservoir. However, adherence to daily oral therapy is an established barrier to successful treatment of chronic infections. To overcome this barrier, VON was transformed into a long-acting (LA) prodrug nanosuspension. The LA prodrug formulation suppressed αSMA, TGFβ, and Col1A1 gene expression in the LX2 hepatic stellate cell line. The formulation was well tolerated and prevented liver and lung damage in a carbon tetrachloride-induced chronic liver injury model. The promising preclinical data support further development of LA VON prodrugs as potential treatments for liver and lung fibrosis.