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

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.

Seladelpar combined with complementary therapies improves fibrosis, inflammation, and liver injury in a mouse model of nonalcoholic steatohepatitis.

Seladelpar, a selective peroxisome proliferator-activated receptor δ (PPARδ) agonist, improves markers of hepatic injury in human liver diseases, but histological improvement of nonalcoholic steatohepatitis (NASH) and liver fibrosis has been challenging with any single agent. To discover how complementary agents could work with seladelpar to achieve optimal outcomes, this study evaluated a variety of therapeutics (alone and in combination) in a mouse model of NASH. Mice on a high-fat amylin liver NASH (AMLN) diet were treated for 12 wk with seladelpar, GLP-1-R (glucagon-like peptide-1 receptor) agonist liraglutide, apoptosis signal-regulating kinase 1 (ASK1) inhibitor selonsertib, farnesoid X receptor (FXR) agonist obeticholic acid, and with seladelpar in combination with liraglutide or selonsertib. Seladelpar treatment markedly improved plasma markers of liver function. Seladelpar alone or in combination resulted in stark reductions in liver fibrosis (hydroxyproline, new collagen synthesis rate, mRNA indices of fibrosis, and fibrosis staining) compared with vehicle and the other single agents. Robust reductions in liver steatosis were also observed. Seladelpar produced a reorganization of metabolic gene expression, particularly for those genes promoting peroxisomal and mitochondrial lipid oxidation. In summary, substantial improvements in NASH and NASH-induced fibrosis were observed with seladelpar alone and in combination with liraglutide in this model. Broad gene expression analysis suggests seladelpar should be effective in concert with diverse mechanisms of action.NEW & NOTEWORTHY NASH is a chronic, progressive, and increasingly problematic liver disease that has been resistant to treatment with individual therapeutics. In this study using a diet-induced mouse model of NASH, we found that the PPARδ agonist seladelpar reduced fibrosis and NASH pathology alone and in combinations with a GLP-1-R agonist (liraglutide) or an ASK1 inhibitor (selonsertib). Liver transcriptome analysis comparing each agent and coadministration suggests seladelpar should be effective in combination with a variety of therapeutics.