Linerixibat and the Future of Pruritus Therapy in Primary Biliary Cholangitis

Cholestatic pruritus significantly impairs quality of life in Primary Biliary Cholangitis (PBS) and is often refractory to ursodeoxycholic acid. This review explores Linerixibat, a gut-restricted ileal bile acid transporter (IBAT) inhibitor, as a targeted therapy for PBC-associated pruritus. By selectively blocking IBAT in the terminal ileum, Linerixibat reduces systemic bile acid (BA) accumulation—a key driver of itch via MAS-related G protein-coupled receptor X4 (MRGPRX4) activation on sensory neurons. Clinical trials demonstrate Linerixibat’s efficacy in lowering serum BAs and alleviating pruritus, with a safety profile characterized primarily by manageable, mechanism-driven diarrhea. Unlike IBAT inhibitors developed for paediatric cholestatic disorders (e.g., odevixibat for PFIC), Linerixibat is optimized for adult PBC. Future therapeutic strategies may involve combining Linerixibat with agents targeting BA homeostasis (e.g., dual FXR/TRG5 agonists like INT-767) or pruritus signaling (e.g., MRGPRX4 antagonists). Ongoing Phase III trials will further define its long-term role in PBC management.