IL‐31 levels correlate with pruritus in patients with cholestatic and metabolic liver diseases and is farnesoid X receptor responsive in NASH

Abstract

Background and Aims: Pruritus is associated with multiple liver diseases, particularly those with cholestasis, but the mechanism remains incompletely understood. Our aim was to evaluate serum IL-31 as a putative biomarker of pruritus in clinical trials of an farnesoid X receptor (FXR) agonist, cilofexor, in patients with NASH, primary sclerosing cholangitis (PSC), and primary biliary cholangitis (PBC). Approach and Results: Serum IL-31 was measured in clinical studies of cilofexor in NASH, PSC, and PBC. In patients with PSC or PBC, baseline IL-31 was elevated compared to patients with NASH and healthy volunteers (HVs). IL-31 correlated with serum bile acids among patients with NASH, PBC, and PSC. Baseline IL-31 levels in PSC and PBC were positively correlated with Visual Analog Scale for pruritus and 5-D itch scores. In patients with NASH, cilofexor dose-dependently increased IL-31 from Week (W)1 to W24. In patients with NASH receiving cilofexor 100 mg, IL-31 was higher in those with Grade 2-3 pruritus adverse events (AEs) than those with Grade 0-1 pruritus AEs. IL-31 weakly correlated with C4 at baseline in patients with NASH, and among those receiving cilofexor 100 mg, changes in IL-31 and C4 from baseline to W24 were negatively correlated. IL-31 messenger RNA (mRNA) was elevated in hepatocytes from patients with

Discovery of the First-in-Class Intestinal Restricted FXR and FABP1 Dual Modulator ZLY28 for the Treatment of Nonalcoholic Fatty Liver Disease

“…Gilead Sciences' latest research shows that the pruritus of FXR agonists (such as OCA) is because of the increased levels of interleukin-31 (IL-31) in the liver but not in the intestine. 36 Moreover, intestinal FXR agonists have some unique advantages, such as promoting white fat browning, reducing body weight, and improving insulin resistance in diet-induced obesity (DIO) mice. 54 Thus, we speculated that the intestine-specific activation of FXR might be a better therapeutic strategy to effectively relieve NASH without systemic adverse effects.…”

“…Indeed, the side effect of pruritus severely limited the use of FXR agonists for the treatment of NASH, and reducing the incidence of pruritus is crucial to the development of FXR agonists. Gilead Sciences’ latest research shows that the pruritus of FXR agonists (such as OCA) is because of the increased levels of interleukin-31 (IL-31) in the liver but not in the intestine . Moreover, intestinal FXR agonists have some unique advantages, such as promoting white fat browning, reducing body weight, and improving insulin resistance in diet-induced obesity (DIO) mice .…”

“…34,35 Therefore, intestinal restriction of FXR agonists is considered as an important strategy to decrease the side effect by reducing systemic exposure of the drug. 36 Fatty acid binding protein 1 (FABP1), a member of the lipidbinding protein family, mainly coordinates lipid responses in cells as lipid chaperones. 37 FABP1 is primarily expressed in the liver and intestine.…”

“… ,− Although OCA revealed excellent therapeutic effects in phase III trials for the treatment of NASH, it was not approved due to severe pruritus. Moreover, the side effect of pruritus was also observed in clinical trials for several nonsteroidal FXR agonists, such as cilofexor and TERN-101. , Therefore, intestinal restriction of FXR agonists is considered as an important strategy to decrease the side effect by reducing systemic exposure of the drug …”

FXR Friend-ChIPs in the Enterohepatic System

“…Utilization of global FXR agonists in primary biliary cholangitis and NASH patients remains controversial due to severe adverse effects such as pruritus, fatigue, and increased serum low density lipoprotein (123)(124)(125). In pre-clinical settings, inhibition of mast cell FXR reduces serum histamine levels and prevents bile duct damage in a murine model of mast cell-induced cholestasis (58).…”