Emerging pharmacologic therapies for primary sclerosing cholangitis

Abstract

Purpose of review: The only currently approved treatment for primary sclerosing cholangitis (PSC) is liver transplantation, with a median time to transplant of 12-18 years after diagnosis. There are a number of emerging drugs that have the potential to meet this critically unmet need that will be summarized and discussed herein.

Recent findings: Although the cause of PSC is unknown, there are a number of novel therapeutics under development. These drugs target presumed pathogenic mechanisms largely extrapolated from ex-vivo and in-vivo preclinical models, as well as translational observations.

Summary: Future therapeutic strategies for PSC may include a multitude of complex pathogenic mechanisms encompassing pathways of immunomodulation, the microbiome and inflammation-related fibrosis.

Figure 1

Current and emerging therapies for primary sclerosing cholangitis that modulate bile acid synthesis, detoxification, secretion and reabsorption. AE2, Cl⁻/HCO₃⁻ anion exchanger 2; ASBT, apical sodium-bile acid transporter; ASBT–, apical sodium-bile acid transporter inhibitor; BA, bile acids; BSEP, bile salt export pump; CaCl, Ca²⁺-dependent chloride channel; CB, conjugated bilirubin; CFTR, cystic fibrosis transmembrane conductance regulator; FGF19, fibroblast growth factor 19; FGFR4, fibroblast growth factor receptor 4; FXR, farsenoid X receptor; MDR2/3, multidrug resistance 2/3; MRP2, multidrug resistance-associated protein 2; MRP3, multidrug resistance-associated protein 3; MRP4, multidrug resistance-associated protein 4; NTCP, sodium/taurocholate cotransporting polypeptide; norUDCA, 24-norUrsodeoxycholic acid; OCA, obetichoic acid; OSTα/β, organic solute transporter α/β; PC, phosphatidylcholine; PSC, primary sclerosing cholangitis; RXR, retinoid X receptor; SULT2A1, sulfotransferase family 2A member 1; UDCA, ursodeoxycholic acid; UGT1A1, uridine diphosphate-glucoronosyltransferase family 1 member A1. Modified from [5].

Figure 2

Therapies that are proposed to inhibit the transmigration of gut-derived lymphocytes into the hepatic environment in primary sclerosing cholangitis. In primary sclerosing cholangitis, mucosal vascular address in cell adhesion molecule 1 is aberrantly expressed. This allows aberrant binding and transmigration of gut-derived lymphocytes via α4β7 integrin. Binding and transmigration is further enhanced by vascular adhesion protein-1, which is constitutively present on hepatic endothelial cells and allows lymphocyte recruitment. CCR9–, chemokine receptor 9 inhibitor; MAdCAM-1, mucosal vascular addressin cell adhesion molecule 1; PSC, primary sclerosing cholangitis; VAP-1, vascular adhesion protein-1.