Comprehensive Monograph on Linerixibat (GSK2330672): An Investigational IBAT Inhibitor for Cholestatic Pruritus in Primary Biliary Cholangitis

Executive Summary

Linerixibat, also known by its developmental code GSK2330672, is an investigational, orally administered, small-molecule drug designed as a selective and minimally absorbed inhibitor of the ileal bile acid transporter (IBAT).[1] Its primary therapeutic target is the treatment of moderate to severe cholestatic pruritus, a debilitating form of internal itching, in adult patients with the rare autoimmune liver disease Primary Biliary Cholangitis (PBC).[4] This indication addresses a significant unmet medical need, as pruritus affects up to 90% of individuals with PBC, severely degrading quality of life through sleep disruption, fatigue, and psychological distress, and is often inadequately managed by current therapeutic options.[4]

The mechanism of action of Linerixibat is localized to the terminal ileum, where it inhibits IBAT to interrupt the enterohepatic circulation of bile acids. This blockade increases the fecal excretion of bile acids, thereby reducing the systemic bile acid load that is believed to be a primary driver of cholestatic pruritus.[2]

Pivotal clinical evidence is derived from the Phase 3 GLISTEN trial (NCT04950127), in which Linerixibat successfully met its primary endpoint. The trial demonstrated a statistically significant, albeit modest, reduction in itch severity compared to placebo over a 24-week period.[5] Furthermore, the study achieved a key secondary endpoint, showing a significant improvement in itch-related sleep interference.[5]