Gideon Hirshfield, FRCP, PhD: Developing Therapies to Address Pruritus in PBC

New research is calling attention to a significant unmet need for symptom-specific therapy targeting pruritus in primary biliary cholangitis (PBC), highlighting the shortcomings of currently available treatments and suggesting the potential utility of linerixibat for addressing itch.¹

Findings from the analysis of baseline data from the phase 3 Global Linerixibat Itch STudy of Efficacy and safety iN PBC (GLISTEN) trial were presented at The Liver Meeting 2024 from the American Association for the Study of Liver Diseases (AASLD) in San Diego, California, by Gideon Hirschfield, FRCP, PhD, Lily and Terry Horner Chair in Autoimmune Liver Disease Research, director of the Francis Family Liver Clinic, a staff hepatologist at Toronto General Hospital, and a professor at the University of Toronto.

“I think pruritus is one of the most important symptoms for a person living with PBC. Well over 30 to 40% of patients have itch,” Hirschfield said in an interview with HCPLive. “Within that, you have patients with mild itch, moderate itch, and severe itch, but I think all itch is impactful for a person living with PBC. It reduces their quality of life, it changes how they sleep, it affects their mood.”

For many years, ursodeoxycholic acid (UDCA) and obeticholic acid were the only treatment options available for patients living with PBC. Although both have shown efficacy for treating the disease itself, neither offers any meaningful benefit for addressing pruritus.

To date, disease modification has been the primary focus of PBC care, while symptom management has largely fallen by the wayside. However, linerixibat, an ileal bile acid transporter (IBAT) inhibitor, may offer an effective treatment for pruritus in PBC.

“We know from our experience with IBAT inhibitors in children that they can be very powerful anti-itch drugs,” Hirschfield explained to HCPLive. “Therefore, linerixibat has been undergoing a series of clinical trials to try and demonstrate its benefit for the treatment of cholestatic pruritis in PBC.”

An ongoing phase 3, placebo-controlled study in adults with PBC and moderate to severe pruritus, GLISTEN evaluated the efficacy and safety of linerixibat compared with placebo. Primary and secondary outcome measures were assessed using the Numerical Rating Scale (NRS) for worst itch and itch-related sleep interference, and the PBC-40 questionnaire for quality of life.¹

Positive headline results from the trial were announced on November 19, 2024, and showed GLISTEN met its primary endpoint, with linerixibat resulting in an improvement in itch, as demonstrated by a statistically significant reduction from baseline in monthly itch score over 24 weeks versus placebo.²

“One of the most important things to recognize about this particular poster and this trial is that it's international. It's global, so we recognize that patients living with PBC anywhere in the world are itchy, including patients who have access to different first- and second-line therapies,” Hirschfield emphasized.

The research he presented at AASLD showed that among 227 GLISTEN participants, at baseline, 58% had severe pruritus; 9% had compensated cirrhosis; 51% had alkaline phosphatase levels <1.67x upper limit of normal (ULN); and 13% had total bilirubin >1x ULN. Overall, 97% of participants were receiving UDCA. The most common prior therapies for pruritus were antihistamines (15%), bile acid-binding resins (13%), rifampin (6%), and fibrates (4%), which were most commonly discontinued due to lack of efficacy (83%, 55%, 69%, and 13%, respectively) and lack of tolerability/adverse events (9%, 45%, 38%, and 88%, respectively).¹

“In the field of PBC, we really hope to have an emerging toolbox. We hope that by understanding the disease and the burden for patients, both on disease progression and symptoms, we will have different drugs to give patients at different times and for the patient whose predominant symptoms are itch or itch plus disease control who will therefore benefit from having this choice,” Hirschfield said.

Editors’ note: Hirschfield has relevant disclosures with Intercept, GlaxoSmithKline, Cymabay, Ipsen, Falk, Pliant, Mirum, Chemomab, Advanz, Gilead, and Kowa.

References

1. ^{Hirschfield G, Bowlus C, Jones D, et al. Insufficient control of cholestatic pruritus in primary biliary cholangitis (PBC) with current therapies: baseline data from the ongoing Phase 3 GLISTEN (Global Linerixibat Itch STudy of Efficacy and safety iN PBC) trial. Paper presented at: AASLD’s The Liver Meeting 2024. San Diego, California. November 15-19, 2024.}
2. ^{GSK. Linerixibat shows positive Phase III results in cholestatic pruritus (relentless itch) in primary biliary cholangitis (PBC). November 19, 2024. Accessed November 25, 2024. https://www.gsk.com/en-gb/media/press-releases/linerixibat-shows-positive-phase-iii-results-in-cholestatic-pruritus/}