An update on novel investigational agents for the treatment of primary biliary cholangitis

Primary biliary cholangitis (PBC) is a chronic autoimmune liver disease characterized by progressive bile duct destruction that can lead to liver cirrhosis and liver failure. While ursodeoxycholic acid (UDCA) remains the first-line treatment, up to 40% of patients show an inadequate response. In such cases, second-line therapies are explored. Obeticholic acid (OCA), a farnesoid X receptor agonist, was initially approved but recently lost its marketing authorization in the EU due to an unfavorable risk-benefit balance. Fibrates, particularly bezafibrate and fenofibrate, have shown promising results in improving biochemical markers and reducing pruritus, although they remain off-label.

We here focus on new FDA- and EMA-approved therapies, including the PPAR agonists elafibranor and seladelpar, which demonstrate improved biochemical response and, in the case of seladelpar, a significant reduction in pruritus. Additional investigational agents include NOX inhibitors such as setanaxib, IBAT inhibitors like linerixibat and odevixibat, and golexanolone, targeting fatigue through modulation of GABAergic neurotransmission.

Despite advances, challenges remain in treatment personalization, access to new drugs, and identification of robust endpoints beyond ALP normalization, including quality of life improvements. Future directions emphasize a personalized approach, long-term outcome studies, and broader access to effective therapies.