Seladelpar treatment reduces IL-31 and pruritus in patients with primary biliary cholangitis

Andreas E Kremer; Marlyn J Mayo; Gideon M Hirschfield; Cynthia Levy; Christopher L Bowlus; David E Jones; Jeff D Johnson; Charles A McWherter; Yun-Jung Choi

doi:10.1097/HEP.0000000000000728

Seladelpar treatment reduces IL-31 and pruritus in patients with primary biliary cholangitis

Hepatology. 2023 Dec 20. doi: 10.1097/HEP.0000000000000728. Online ahead of print.

Authors

Andreas E Kremer¹, Marlyn J Mayo², Gideon M Hirschfield³, Cynthia Levy^{4

5}, Christopher L Bowlus⁶, David E Jones⁷, Jeff D Johnson⁸, Charles A McWherter⁸, Yun-Jung Choi⁸

Affiliations

¹ Department of Gastroenterology and Hepatology, University Hospital Zürich, University of Zürich, Zürich, Switzerland.
² Division of Digestive and Liver Diseases, University of Texas SW Medical Center, Dallas, Texas, USA.
³ Toronto Centre for Liver Disease, Toronto General Hospital, University Health Network, Toronto, Ontario, Canada.
⁴ Division of Digestive Health and Liver Diseases, University of Miami Miller School of Medicine, Miami, Florida, USA.
⁵ Schiff Center for Liver Diseases, University of Miami, Miami, Florida, USA.
⁶ Department of Internal Medicine, Division of Gastroenterology and Hepatology, University of California Davis, Sacramento, California, USA.
⁷ Clinical and Translation Research Institute, Newcastle University, Newcastle upon Tyne, UK.
⁸ CymaBay Therapeutics, Inc., Fremont, California, USA.

PMID: 38117036
DOI: 10.1097/HEP.0000000000000728

Abstract

Background and aims: Pruritus is a debilitating symptom for many people living with primary biliary cholangitis (PBC). In studies with seladelpar, a selective peroxisome proliferator-activated receptor-delta agonist, patients with PBC experienced significant improvement in pruritus and reduction of serum bile acids. Interleukin-31 (IL-31) is a cytokine known to mediate pruritus, and blocking IL-31 signaling provides relief in pruritic skin diseases. This study examined the connection between seladelpar's antipruritic effects and IL-31 and bile acid levels in patients with PBC.

Approach and results: IL-31 levels were quantified in serum samples from the ENHANCE study of patients with PBC receiving daily oral doses of placebo (n = 55), seladelpar 5 mg (n = 53) or 10 mg (n = 53) for 3 months, and for healthy volunteers (n = 55). IL-31 levels were compared with pruritus using a numerical rating scale (NRS, 0-10) and with bile acid levels. Baseline IL-31 levels closely correlated with pruritus NRS ( r = 0.54, p < 0.0001), and total ( r = 0.54, p < 0.0001) and conjugated bile acids (up to 0.64, p < 0.0001). Decreases in IL-31 were observed with seladelpar 5 mg (-30%, p = 0.0003) and 10 mg (-52%, p < 0.0001) versus placebo (+31%). Patients with clinically meaningful improvement in pruritus (NRS ≥ 2 decrease) demonstrated greater dose-dependent reductions in IL-31 compared to those without pruritus improvement (NRS < 2 decrease). Strong correlations were observed for the changes between levels of IL-31 and total bile acids ( r = 0.63, p < 0.0001) in the seladelpar 10 mg group.

Conclusions: Seladelpar decreased serum IL-31 and bile acids in patients with PBC. The reductions of IL-31 and bile acids correlated closely with each other and pruritus improvement, suggesting a mechanism to explain seladelpar's antipruritic effects.