Eleni Karatza, 1, Fernando Carreño, 2, Sumanta Mukherjee, 2, Linda Casillas, 2, James Fettiplace, 3, Philip J.F. Troke, PhD3, Megan M. McLaughlin, 2, Brandon Swift, 4 1University of North Carolina at Chapel Hill, Chapel Hill, NC; 2GSK, Collegeville, PA; 3GSK, London, England, United Kingdom; 4GSK, Durham, NC
Introduction: Cholestatic pruritus (itch) affects up to 80% of pts 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 pts 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 pts in GLIMMER, a Phase 2b study of linerixibat in pts 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.
Discussion: 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 pts with PBC.
Encore: A modified version of this abstract was presented at EASL and UEGW 2023.
Disclosures:
Eleni Karatza: GSK – Grant/Research Support. Janssen – Stock Options. Johnson & Johnson – Stock Options.
Fernando Carreño: GSK – Employee, Stock-publicly held company(excluding mutual/index funds).
Sumanta Mukherjee: GSK – Employee, Stock-publicly held company(excluding mutual/index funds).
Linda Casillas: GSK – Employee, Stock-publicly held company(excluding mutual/index funds).
James Fettiplace: GSK – Employee, Stock-publicly held company(excluding mutual/index funds).
Philip J.F. Troke: GSK – Employee, Stock-publicly held company(excluding mutual/index funds).
Megan McLaughlin: GSK – Employee, Stock-publicly held company(excluding mutual/index funds).
Brandon Swift: GSK – Employee, Stock-publicly held company(excluding mutual/index funds).
Eleni Karatza, 1, Fernando Carreño, 2, Sumanta Mukherjee, 2, Linda Casillas, 2, James Fettiplace, 3, Philip J.F. Troke, PhD3, Megan M. McLaughlin, 2, Brandon Swift, 4. P1463 - Change in Total Serum Bile Acids Correlates With Improvement in Itch in Patients With Primary Biliary Cholangitis (PBC) Receiving Linerixibat, ACG 2023 Annual Scientific Meeting Abstracts. Vancouver, BC, Canada: American College of Gastroenterology.
