Author information

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

Abstract

Background and aims: Pruritus is a debilitating symptom for many people living with primary biliary cholangitis (PBC). In studies with seladelpar, a selective PPAR-delta agonist, PBC patients 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 anti-pruritic effects, IL-31 and bile acid levels in PBC patients.

Approach and results: IL-31 levels were quantified in serum samples from the ENHANCE study of PBC patients 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 PBC patients. The reductions of IL-31 and bile acids correlated closely with each other and pruritus improvement suggesting a mechanism to explain seladelpar's anti-pruritic effects.