Linerixibat quells cholestatic itch in PBC, enabling better sleep

The ileal bile acid transporter (IBAT) inhibitor linerixibat provides rapid and substantial relief from cholestatic pruritus, in turn reducing associated sleep disturbances, in patients with primary biliary cholangitis (PBC), as shown in the global, phase III GLISTEN trial.

The primary endpoint was met, with the reduction in monthly itch score (measured on a 1–10 numerical rating scale for worst itch [WI-NRS]) over 24 weeks being significantly greater with linerixibat than with placebo (–2.86 vs –2.15; adjusted mean difference, –0.72, 95 percent confidence interval [CI], –1.15 to –0.28; p=0.001). [EASL 2025, abstract GS-011]

First study author Dr Gideon Hirschfield from the Toronto General Hospital in Toronto, Ontario, Canada, reported the results at an oral presentation during the EASL Congress. He noted that the itch relief was rapid, with the reduction in itch scores already more pronounced with linerixibat vs placebo at week 2 (–1.78 vs –1.07; adjusted mean difference, –0.71, 95 percent CI, –1.07 to –0.34; p<0.001).

The IBAT inhibitor also proved superior to placebo in terms of reducing pruritus-related sleep interference over 24 weeks (–2.77 vs –2.24; adjusted mean difference, –0.53, 95 percent CI, –0.98 to –0.07; p=0.024).

There was a significant placebo effect consistent with previous pruritus studies, Hirschfield noted. But despite this, a clear distinction between the linerixibat and placebo curves emerged as early as week 2 and continued through week 24, he said.

Meaningful improvement

At week 24, significantly more patients on linerixibat than those on placebo achieved a clinically meaningful itch improvement, defined as a ≥3-point reduction in the WI-NRS score (56 percent vs 43 percent; nominal p=0.043).

Furthermore, based on the Patient Global Impression of Severity, more patients reported their itch as absent with linerixibat vs placebo (21 percent vs 9 percent; p<0.0001).

In an 8-week blinded crossover period, patients who initially received placebo and crossed over to linerixibat experienced pruritus improvement, whereas those who initially received the IBAT inhibitor and crossed over to placebo experienced worsening. Hirschfield emphasized the importance of these findings, saying that they are pivotal to understanding the GLISTEN data.

Well-tolerated

“Safe drugs are very important to patients and providers, and linerixibat demonstrated … a safety profile consistent with prior studies,” Hirschfield noted.

Adverse events (AEs) occurred more frequently with the IBAT inhibitor vs placebo (92 percent vs 74 percent), with the most common being diarrhoea and abdominal pain, as expected, he added.

“Gastrointestinal AEs do occur more frequently with linerixibat. This is entirely consistent with the mechanism of action,” according to Hirschfield. “[Diarrhoea] did not normally need significant intervention, and it was a rare reason to stop the drug.”

Changes in ALT or AST were also more common with linerixibat than with placebo, but they were asymptomatic and minor changes.

Addressing an unmet need

“Cholestatic pruritus is debilitating [and] persists as an unmet need despite the use of current guideline-recommend therapies,” Hirschfield said.

“First-line PBC treatment [with] ursodeoxycholic acid does not treat itch, and second-line treatments have only been studied in patients who were selected based on PBC biochemical entry criteria,” he noted. “[Additionally,] guideline-recommended pruritus therapies for PBC have limited evidence of efficacy or have poor tolerability.”

Linerixibat is a minimally absorbed oral IBAT inhibitor that reduces key mediators of pruritus, according to Hirschfield. He emphasized that the GLISTEN data point to the potential of linerixibat to be the first global therapy indicated for pruritus in PBC.

When asked about his clinical experience with linerixibat given the presence of other effective therapies for PBC such as PPAR agonists, Hirschfield pointed out that the patients generally “love” the IBAT inhibitor, with their itch going away much more than what the numerical scale rating showed. “When the treatment stops, [the patients] complain bitterly about how bad their pruritus becomes.”

Looking ahead, Hirschfield anticipates a future where PPAR agonists—with their anticholestatic effect and secondary antipruritic effect—and IBAT inhibitors—a new class of drugs which clearly are antipruritic—are prescribed together. “What I take away from [GLISTEN] is the optimism that we’re making so much progress here.”

GLISTEN was conducted in 19 countries across Asia, Europe, North America, and other regions. A total of 238 PBC patients with moderate-to-severe pruritus were randomly assigned to receive either linerixibat 40 mg twice daily (n=119; mean age 54.7 years, 95 percent female, median PBC duration 4.6 years, mean WI-NRS score 7.33) or placebo (n=119; mean age 57.0 years, 95 percent female, median PBC duration 5.7 years, mean WI-NRS score 7.36) for 24 weeks. Concomitant medications for PBC and/or pruritus were permitted.