About the Trial
Trial Name: Global Linerixibat Itch Study of Efficacy and Safety in Primary Biliary Cholangitis (PBC) (GLISTEN)
ClinicalTrials.gov ID: NCT04950127
Sponsor: GlaxoSmithKline
Completion Date: December 20, 2024
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Linerixibat Significantly Improves PBC-Related Cholestatic Pruritus in Adult Patients
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Key Takeaways
- Linerixibat significantly improved cholestatic pruritus in PBC patients, meeting primary and secondary endpoints in the GLISTEN trial.
- The trial showed linerixibat reduced itch severity and itch-related sleep interference compared to placebo.
Compared with placebo, patients with cholestatic pruritus and primary biliary cholangitis (PBC) receiving linerixibat experienced improved itch and sleep interference.
Positive results from the phase 3 GLISTEN trial (NCT04950127) show that linerixibat (GSK2330672; GSK), when used in adult patients with cholestatic pruritus and primary biliary cholangitis (PBC), met its primary end point as well as key secondary end points.1,2 Full data were presented in a late-breaker oral presentation at the 2025 European Association for the Study of the Liver (EASL) Congress, according to a GSK news release.1
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PBC is a rare autoimmune cholestatic liver disease in which bile flow from the liver is disrupted. The resulting excess bile acids in circulation are believed to play a causal role in cholestatic pruritus, an internal itch that cannot be relieved by scratching. This itchiness can occur at any PBC disease stage or biochemical control and is experienced in varying degrees of severity by up to 90% of patients who have PBC. First-line PBC treatment controls disease in approximately 70% of patients; however, it does not reduce the severity or impact of the itch. Cholestatic pruritus is a serious condition that can be debilitating, with some patients experiencing sleep disturbance, fatigue, impaired quality of life, and, in the absence of liver failure, liver transplantation.1
Linerixibat is an investigational targeted ileal bile acid transporter inhibitor with the potential to treat PBC-associated cholestatic pruritus, or itch. Linerixibat reduces multiple mediators of pruritus in circulation by inhibiting bile acid reuptake. Previously, it was granted orphan drug designation by the FDA and European Medicines Agency for this indication.1
The GLISTEN trial is a double-blind, randomized, placebo-controlled, phase 3 trial in which 238 patients with PBC and cholestatic pruritus were randomly assigned to receive treatment with linerixibat or placebo (n = 119 per group). All patients had moderate-to-severe itch. Further, patients initially received either linerixibat or a placebo and had the potential to cross over in part B of the trial.1,2
The primary and secondary outcome measures were assessed via monthly itch scores that were assessed using a 0 to 10 numerical rating scale (NRS) for worst itch and itch-related sleep interference. Other secondary end points consisted of changes from baseline in PBC-40 domain, global impression of change, and impression of severity scores over 24 weeks.1,2
The findings demonstrated that linerixibat had significantly improved itch compared with placebo (least squares [LS] mean difference, 95% CI: -0.72 [-1.15, -0.28], P = .001). In addition, linerixibat met key secondary end points, including itch score at week 2 (LS mean difference, 95% CI: -0.71 [-1.07, -0.34], P < .001) and itch-related sleep interference NRS over 24 weeks (LS mean difference, 95% CI: -0.53 [-0.98, -0.07], P = .024). Notably, more patients receiving linerixibat (56%) had clinically meaningful itch improvement—defined as a worst itch NRS reduction of at least 3 points—compared with placebo (43%) at the 24-week period (treatment difference: 13% [95% CI 0%-27%]; nominal P =.043).1,2
“Relentless itch is present in the majority of patients with PBC and is a symptom that affects sleep, mental health, and quality of life. With linerixibat, we are 1 step closer to addressing the high unmet need of itch and its related sleep interference that are critically important to patients but historically under-treated,” Kaivan Khavandi, senior vice president and global head of respiratory, immunology & inflammation research and development at GSK, said in a news release.1
According to the findings, linerixibat’s safety profile was observed to be consistent with prior studies and the mechanism of IBAT inhibition. Gastrointestinal adverse events (AEs) were common in the active treatment group. The most common AE was diarrhea and was considered mostly mild in intensity. Discontinuation because of diarrhea was approximately 4% in the linerixibat group compared with less than 1% in the placebo group.1
“Currently there are very limited therapies for pruritus in PBC and previous attempts to develop new therapies have been unsuccessful. As an investigator who also sees many patients with PBC, and who has worked with this molecule from the early phase 2 studies, the clear improvements in itch and its related sleep interference seen in GLISTEN are meaningful and clinically important,” lead study author Gideon Hirschfield, Lily and Terry Horner chair in autoimmune liver disease research and director of the Autoimmune and Rare Liver Disease Programme at University Health Network, Toronto, said.1
REFERENCES
1. GSK. GLISTEN phase III trial results show linerixibat significantly improves cholestatic pruritus (relentless itch) in primary biliary cholangitis (PBC). News release. May 8, 2025. Accessed May 19, 2025. https://www.gsk.com/en-gb/media/press-releases/glisten-phase-iii-trial-results-show-linerixibat-significantly-improves-cholestatic-pruritus/
2. Global Linerixibat Itch Study of Efficacy and Safety in Primary Biliary Cholangitis (PBC) (GLISTEN). ClinicalTrials.gov identifier: NCT04950127. Updated February 26, 2025. Accessed May 19, 2025. https://clinicaltrials.gov/study/NCT04950127
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