Linerixibat Improved Pruritus in Phase 3 PBC Trial

Key Takeaways

• Linerixibat was associated with greater pruritus improvement than placebo over 24 weeks.
• Gastrointestinal adverse events, especially diarrhea, were reported more often with linerixibat than with placebo.
• The randomized phase 3 comparison enrolled patients with primary biliary cholangitis and WI-NRS scores of at least 4.

In the phase 3 GLISTEN trial, linerixibat improved pruritus more than placebo over 24 weeks in patients with primary biliary cholangitis and moderate-to-severe cholestatic pruritus. The adjusted mean difference on the pruritus scale was -0.72 (95% CI, -1.15 to -0.28; p=0.0013). The ileal bile acid transporter inhibitor was evaluated as a specific antipruritic therapy in this late-stage setting. Gastrointestinal adverse events and serious adverse events were more frequent with linerixibat than with placebo. The 24-week results paired itch reduction with a clearly documented gastrointestinal tolerability burden.

GLISTEN was a randomized, multicenter, double-blind, placebo-controlled phase 3 trial conducted at 115 centers in 19 countries. It enrolled patients with primary biliary cholangitis and moderate-to-severe pruritus defined as WI-NRS 4 or higher. 238 patients were randomly assigned, with 119 in each group. Patients received oral linerixibat 40 mg twice daily or matching placebo, and the primary endpoint was change over 24 weeks on the Worst Itch Numerical Rating Scale. Randomization was stratified by pruritus severity and concomitant pruritus treatment; efficacy analyses included all randomly allocated patients, and safety analyses included treated patients.

The primary endpoint was change in pruritus over 24 weeks. Both groups improved from baseline, with a larger reduction in the linerixibat group during the 24-week analysis. Least-squares mean change from baseline on WI-NRS was -2.86 with linerixibat versus -2.15 with placebo. The arm-specific 95% confidence intervals were -3.23 to -2.50 for linerixibat and -2.51 to -1.78 for placebo. The between-group difference was statistically significant for the 24-week pruritus outcome.

Gastrointestinal adverse events were more frequent with linerixibat, with diarrhea in 61% (72/119) versus 18% (21/118) and abdominal pain in 18% (22/119) versus 3% (4/118). Treatment discontinuations due to gastrointestinal adverse events occurred in 7% (8/119) of linerixibat-treated patients and less than 1% (1/118) with placebo. Five discontinuations in the linerixibat group were due to diarrhea. Serious adverse events occurred in 12% (14/119) with linerixibat and 3% (4/118) with placebo, and no deaths occurred during the study.

The phase 3 results paired modest pruritus benefit with a clearly documented gastrointestinal tolerability burden.