S103 Change in Total Serum Bile Acids Correlates With Improvement in Itch in Patients With Primary Biliary Cholangitis (PBC) Receiving Linerixibat

Introduction: Cholestatic pruritus (itch) affects up to 80% of patients with PBC. Bile acids are an important pathophysiological mediator of cholestatic itch. Linerixibat, a selective small-molecule inhibitor of the ileal bile acid transporter, reduced circulating TSBA levels and improved itch in patients with PBC. Here, we analyse the linerixibat dose-TSBA relationship and explore the correlation between change in TSBA and change in itch. Methods: Data from Phase 1/2 studies of healthy volunteers or patients with PBC were used to develop a population dose–pharmacodynamic (k-PD) model. Simulations were performed to explore the effect of linerixibat dose and regimen on daily TSBA profiles. Modelling was used post hoc to derive the area under the TSBA concentration-curve (AUC0-24) for patients in GLIMMER, a Phase 2b study of linerixibat in patients with PBC and itch (NCT02966834). AUC0-24 estimates were correlated with change in weekly itch score (previously mean worst daily itch) and monthly itch score (MIS) reported on a 0–10 numerical rating scale (NRS). In GLIMMER, 4 weeks single-blind placebo (PBO; baseline [BL]=Week 4) was followed by a 12-week treatment period with linerixibat or PBO (to Week 16), then 4 weeks single-blind PBO (to Week 20). Itch responders were defined as having a ≥2 point improvement in MIS at Week 16. Results: The final population k-PD model successfully described the effect of linerixibat on TSBA in PBC. Linerixibat treatment resulted in a dose-dependent decrease in TSBA AUC0-24; the reduction in TSBA AUC0-24 was apparent after a single dose. BL TSBA concentrations did not correlate with change from BL in MIS at Week 16 (r=-0.13, P=0.14). At Week 16, there was a moderate correlation between change in TSBA AUC0-24 and change in MIS from BL (r=0.27, P=0.002), which dissipated during PBO washout (Week 20; r=0.011, P=0.91). Change in TSBA AUC0-24 significantly correlated with improvement in weekly itch score from BL over the 12-week treatment period (r=0.52, P< 0.0001). A ≥30% decrease in TSBA AUC0-24 was associated with 64% of participants having an itch response. Conclusion: Linerixibat treatment leads to rapid and dose-dependent reductions in TSBA. BL TSBA levels do not correlate with on-treatment change in NRS itch score, suggesting they do not predict linerixibat response. Change in TSBA over the 12-week treatment period correlates significantly with, and can be predictive of, improvement in itch in patients with PBC. Encore: A modified version of this abstract was presented at EASL and UEGW 2023.