Mechanisms and molecules: What are the treatment targets for primary biliary cholangitis?

Abstract

Treatment of primary biliary cholangitis (PBC) with ursodeoxycholic acid (UDCA) is not always sufficient to prevent progression to hepatic decompensation and/or need for liver transplant. Adjuvant therapy with obeticholic acid may provide additional biochemical improvements in some patients, but it is not well-tolerated by patients with significant itch or advanced cirrhosis. Thus, new and creative approaches to treating patients with PBC are important to identify. This review discusses major potential therapeutic targets in PBC and provides examples of some specific agents currently in development for the treatment of PBC. Targets are broadly classified into those which strive to modify bile, inflammation, cell survival, or fibrosis. In bile, shrinking the size of the bile acid pool or modifying the quality of the bile by making it more hydrophilic or enriched in phosphatidylcholine may ameliorate cholestatic injury.Biliary epithelial cell survival may be extended by fortifying the bicarbonate umbrella or improving cell membrane integrity. Autoimmunity and cholangitis have the potential to be improved via regulation of the immune system.Targeting cytokines, immune checkpoints, and anti-mitochondrial antibodies are examples of a more focused immunosuppression approach. Stem cell therapy and lymphocyte trafficking inhibition are more novel methods of broad immune regulation. Anti-fibrotic therapies are also potentially useful for preventing progression of PBC. The nuclear hormone receptors, farnesoid X receptor (FXR) and peroxisome proliferator-activated receptor (PPAR) regulate many of these pathways: cholestasis, inflammation, and fibrosis, which is why they are being enthusiastically pursued as potential therapeutic targets in PBC.

Update on the Pharmacological Treatment of Primary Biliary Cholangitis

“…The crucial point when designing clinical trials is the choice of a combination treatment with nuclear receptor ligands and other agents with different mechanism and therapeutic effects [ 89 ]. This huge armamentarium of new therapeutic options will likely lead to a novel treatment landscape for PBC in the near future, with novel therapies based on the combinations of multiple agents acting on different pathogenetic mechanisms [ 90 ]. Another crucial point is that the ideal therapy for PBC would achieve a complete biochemical remission, namely normalization of serum ALP and bilirubin, and would be well tolerated.…”

Discovery of the First Subnanomolar PPARα/δ Dual Agonist for the Treatment of Cholestatic Liver Diseases

“…Ursodeoxycholic acid (UDCA) ( 1 ) is the first-line therapy for PBC, but about 40% of patients do not respond to UDCA treatment . Obeticholic acid (OCA) ( 2 ) was approved for PBC treatment in 2016 by FDA; however, it is not tolerated by patients due to severe itching, and its long-term effect on survival is still unknown . In recent years, some investigational drugs for CLD have entered the clinical trials, including peroxisome proliferator-activated receptor agonists (e.g., elafibranor ( 3 ), seladelpar ( 4 )), farnesoid X receptor agonists (e.g., cilofexor (5) , tropifexor ( 6 )), NADPH oxidase inhibitors (e.g., setanaxib ( 7 )), and UDCA derivatives (e.g., norUDCA ( 8 ), HTD-1801 ( 9 )). − Despite the lack of deep understanding of CLD pathophysiology, therapeutic approaches based on decreasing BA synthesis, relieving inflammatory response, and delaying the fibrosis process are thought to be potentially effective intervention strategies …”

“…7−13 Despite the lack of deep understanding of CLD pathophysiology, therapeutic approaches based on decreasing BA synthesis, relieving inflammatory response, and delaying the fibrosis process are thought to be potentially effective intervention strategies. 6 Peroxisome proliferator-activated receptors (PPARs) belong to the nuclear receptor superfamily, which contains three isoforms, PPARα (NR1C1), PPARδ (NR1C2), and PPARγ (NR1C3). They are the ligand-regulated transcriptional factors, whose structures consist of the DNA-binding domain (DBD), the hinge region, and the ligand-binding domain (LBD).…”

Feasibility, safety and tolerability of the CREB-binding protein/β-catenin inhibitor OP-724 in patients with advanced primary biliary cholangitis: an investigator-initiated, open-label, non-randomised, two-centre, phase 1 study

“…OCA was conditionally approved by the US and EU regulatory authorities in 2016 for the treatment of PBC in patients with incomplete response or intolerance to UDCA. OCA is a synthetic bile acid derivative with a high affinity for farnesoid X receptor (FXR), a nuclear receptor that closely regulates bile acid synthesis and secretion, and has been shown to mediate anti-inflammatory and antifibrotic effects 9 11. Bezafibrate is also the third treatment option, after UDCA and OCA, to have shown clear beneficial effects in large, well-powered, placebo-controlled trials in PBC 12 13.…”

“…Bezafibrate is also the third treatment option, after UDCA and OCA, to have shown clear beneficial effects in large, well-powered, placebo-controlled trials in PBC 12 13. However, antifibrotic drugs for liver cirrhosis associated with PBC are yet to be put into practical use 3 7 11. Bile acid receptors, such as FXR (as well as its transporter system) and fibroblast growth factor 19, are attracting attention as therapeutic targets for cholestatic liver disease and liver fibrosis 14 15.…”