Population Dose-Response-Time Analysis of Itch Reduction and Patient-Reported Tolerability Supports Phase 3 Dose Selection for Linerixibat.

Increase in serum bile acids (BA) in patients with primary biliary cholangitis (PBC) may play a causal role in cholestatic pruritus (itch). Linerixibat, is a selective small molecule inhibitor of the ileal bile acid transporter, which blocks reabsorption of BA in the gastrointestinal tract thereby lowering BA in the systemic circulation and reducing itch. One consequence is excess BA in the colon, leading to diarrhea and abdominal pain. GLIMMER (NCT02966834) was a placebo-controlled Phase 2b dose-ranging trial of linerixibat once (QD) or twice daily (BID) in adults with moderate to severe pruritus and PBC. To determine the optimal dose for maximum itch reduction while minimizing diarrhea, a kinetic-pharmacodynamic (k-PD) model was developed using data from GLIMMER. The PD endpoint modeled was worst daily itch, derived from itch score reported by patients BID. A proportional odds model was developed post hoc to indicate the probability of diarrhea occurrence, a patient-reported outcome (GI-5) recorded weekly. The final k-PD model successfully described the effects of linerixibat and placebo on itch. Model simulations were consistent with the observed dose-dependent increase in the average number of itch responders (patients with a ≥2-point improvement in itch). This was paralleled by a dose-dependent increase in the probability of higher diarrhea frequency scores. BID dosing regimens led to a modest increase in the number of itch responders as compared with QD dosing. This quantitative framework highlights the trade-off between benefit and tolerability and supported the selection of 40 mg BID in the Phase 3 GLISTEN trial (NCT04950127).