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

Hepatology. 2024 Jul 1;80(1):27-37. doi: 10.1097/HEP.0000000000000728. Epub 2023 Dec 20.

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.

Publication types

  • Randomized Controlled Trial

MeSH terms

  • Adult
  • Aged
  • Azetidines / administration & dosage
  • Azetidines / therapeutic use
  • Bile Acids and Salts / blood
  • Double-Blind Method
  • Female
  • Humans
  • Interleukins* / blood
  • Liver Cirrhosis, Biliary* / blood
  • Liver Cirrhosis, Biliary* / complications
  • Liver Cirrhosis, Biliary* / drug therapy
  • Male
  • Methylamines
  • Middle Aged
  • PPAR delta / agonists
  • Pruritus* / blood
  • Pruritus* / drug therapy
  • Pruritus* / etiology
  • Thiazepines

Substances

  • IL31 protein, human
  • Interleukins
  • 3-((((3R,5R)-3-butyl-3-ethyl-7-(methyloxy)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,4-benzothiazepin-8-yl)methyl)amino)pentanedioic acid
  • Bile Acids and Salts
  • PPAR delta
  • Azetidines
  • Methylamines
  • Thiazepines