GSK's linerixibat, an investigational ileal bile acid transporter (IBAT) inhibitor, has demonstrated positive results in the Phase III GLISTEN trial for treating cholestatic pruritus associated with primary biliary cholangitis (PBC). The trial met its primary endpoint, showing a statistically significant improvement in itch over 24 weeks compared to placebo, offering hope for a condition with limited treatment options.
The GLISTEN trial (NCT04950127) was a double-blind, randomized, placebo-controlled study involving PBC patients with moderate to severe itch. Participants were either receiving stable doses of guideline-suggested therapies for pruritus, were treatment-naive, or had been previously treated. The primary analysis evaluated the efficacy and safety of linerixibat compared with placebo, using the Numerical Rating Scale (NRS) for worst itch and itch-related sleep interference, and the PBC-40 questionnaire for quality of life.
Clinical Significance of Linerixibat
Kaivan Khavandi, SVP & Global Head, Respiratory/Immunology R&D, GSK, stated that linerixibat has the potential to be the first global therapy specifically developed to treat itch in PBC. The positive data suggest it could significantly improve the quality of life for patients severely affected by persistent itching. It is estimated that by 2030, over 240,000 people with PBC worldwide will experience relentless itch requiring treatment, highlighting a significant unmet need.
Understanding Cholestatic Pruritus and PBC
Primary biliary cholangitis (PBC) is a rare autoimmune liver disease affecting primarily women, characterized by disrupted bile flow from the liver. This leads to an excess of bile acids in circulation, thought to cause cholestatic pruritus, an internal itch unrelieved by scratching. Pruritus can occur at any stage of PBC and affects up to 90% of patients. Current therapies have limited impact on itch and are often poorly tolerated.
Carol Roberts, President of The PBCers Organization, emphasized that the itch associated with PBC is often overlooked but has a significant impact on quality of life and mental health. A treatment addressing the root cause of itch would fulfill a previously unmet need for people with PBC.
Mechanism of Action and Trial Design
Linerixibat inhibits the ileal bile acid transporter (IBAT), reducing bile acid re-uptake and addressing a root cause of cholestatic pruritus. The GLISTEN trial included multiple arms, allowing participants to receive either linerixibat or placebo, with potential crossover at one point. Stable use of guideline-suggested anti-itch therapy was permitted during the trial.
The ongoing Phase 3 GLISTEN study enrolled 238 adults, ages 18-80, with PBC and moderate or severe pruritus. Participants were randomly assigned to receive either linerixibat or the placebo, with some participants crossing over to the alternate treatment arm at some point in the study. During the trial, patients were allowed to continue on a stable regimen of recommended anti-itch therapies. The study’s main goal was to evaluate change in patients’ self-reported monthly itch severity after about six months of treatment.
Future Directions
Full results of the GLISTEN trial will be presented at a future scientific congress. Linerixibat has been granted Orphan Drug Designation in both the US and EU. PBC patients who complete previous linerixibat trials have the option to continue treatment in an open-label Phase 3 study (NCT04167358) evaluating the therapy’s long-term safety and tolerability.
