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

Introduction: 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.

Areas covered: 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.

Expert opinion: 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.