| A better understanding of the molecular mechanisms of bile formation and cholestasis has significantly advanced our therapeutic approaches beyond ursodeoxycholic acid (UDCA) as current first line therapy in many cholestatic diorders such as primary biliary cholangitis (PBC) and intrahepatic cholestasis of pregnancy (ICP). The role of UDCA in PSC is still under debate since so far no clear impact on hard clinical endpoints such as patient survival could be demonstrated. The identification of specific bile acid (BA) transport systems and dedicated BA receptors such as the nuclear hormone receptor for BA/farnesoid X receptor (FXR) and Takeda G protein coupled receptor 5 (TGR5) now allows a more specific targeting of impaired BA homeostasis and inflammation/immunity. Novel BA-based therapeutic options include 24-norursodeoxycholic acid (norUDCA), a side chain-shortened C23 homologue of UDCA, sterodial and non-steroidal bile acid receptor/farnesoid X receptor (FXR) agonists (e.g., obeticholic acid (OCA), cilofexor, tropifexor) as well as the FXR-downstream target FGF19 (non-tumorigenic recombinant FGF-19/NGM-282). OCA is the first approved second line therapy or PBC patients with inadequate biochemical response /intolerance to UDCA. Phase 2 studies with OCA and cilofexor in PSC have also been successful. Other nuclear receptors such as peroxisome proliferator-activated receptors (PPARs), vitamin D receptor (VDR) and vitamin A receptors (RAR, RXR) are also of considerable interest and can be targeted by already available drugs (e.g. fibrates for PPARalpha). Recent studies have also shown the efficacy of fibrates as second line treatment in PBC. Moreover, BA transporters and signaling within the enterohepatic circulation can be targeted by inhibitors blocking intestinal/hepatic BA uptake or chaperones restoring transporter function. norUDCA, a side-chain shortened and thereby conjugation resistant 23-C homologue of UDCA, undergoes cholehepatic shunting (instead of an enterohepatic circulation) which results in stimulation of biliary bicarbonate secretion/umbrella and allows ductular/ductal targeting with direct anti-inflammatory and anti-fibrotic effects. Although attempts with classic immunosuppressive strategies and biologicals have so far been rather disappointing in PBC and PSC, novel immunomodulatory approaches are currently explored. In particular, drugs targeting the gut-liver axis (e.g. intregrin blockers such as vedolizumab, antibiotics such as vancomycin) represent interesting approaches based on the close link of PSC to inflammatory bowel disease and the emerging role of the gut microbiome in PSC. A major challenge will be to test the multitude of novel therapeutic options in a rare ophan disease such as PBC and PSC. Moreover, due to complexity of these diseases most likely combination of different pharmacological strategies may be necessary. |
