PPAR agonists for the treatment of primary biliary cholangitis: Old and new tales

Francesca Colapietro; M Eric Gershwin; Ana Lleo

doi:10.1016/j.jtauto.2023.100188

PPAR agonists for the treatment of primary biliary cholangitis: Old and new tales

J Transl Autoimmun. 2023 Jan 5:6:100188. doi: 10.1016/j.jtauto.2023.100188. eCollection 2023.

Authors

Francesca Colapietro^{1

2}, M Eric Gershwin³, Ana Lleo^{1

2}

Affiliations

¹ Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy.
² Division of Internal Medicine and Hepatology, Department of Gastroenterology, Humanitas Research Hospital IRCCS, Rozzano, Milan, Italy.
³ Division of Rheumatology, Allergy, and Clinical Immunology, University of California at Davis, Davis, CA, USA.

Abstract

Introduction: Primary biliary cholangitis (PBC) is an autoimmune liver disease involving the small intrahepatic bile ducts; when untreated or undertreated, it may evolve to liver fibrosis and cirrhosis. Ursodeoxycholic Acid (UDCA) is the standard of care treatment, Obeticholic Acid (OCA) has been approved as second-line therapy for those non responder or intolerant to UDCA. However, due to moderate rate of UDCA-non responders and to warnings recently issued against OCA use in patients with cirrhosis, further therapies are needed.Areas covered. Deep investigations into the pathogenesis of PBC is leading to proposal of new therapeutic agents, among which peroxisome proliferator-activated receptor (PPAR) ligands seem to be highly promising given the preliminary, positive results in Phase 2 and 3 trials. Bezafibrate, the most evaluated, is currently used in clinical practice in combination with UDCA in referral centers. We herein describe completed and ongoing trials involving PPAR agonists use in PBC, analyzing pits and falls.

Expert opinion: Testing new therapeutic opportunities in PBC is challenging due to its low prevalence and slow progression. However, new drugs including PPAR agonists, are currently under investigation and should be considered for at-risk PBC patients.

Keywords: AEs, adverse events; AIH, Autoimmune Hepatitis; ALP, Alkaline Phosphatase; AMA, Antimitochondrial antibodies; BZF, Bezafibrate; CKD, chronic kidney disease; Elafibranor; FDA, Food and Drug; FF, Fenofibrate; FXR, Farnesoid X Receptor; Fibrates; GGT, γ-glutamil transferase; HCC, Hepatocellular Carcinoma; HDL, high-density lipoprotein; HR, Hazard Ratio; HSC, Hepatic Stellate Cells; IL-1β, Interleukin-1; IgM, Immunoglobulin M; LDL, low-density- lipoprotein; LT, Liver Transplant; MDR3, multidrug resistance protein 3; NASH, Non Alcoholic Steato-Hepatits; NRS, Numerical Raing Scale; OCA, Obeticholic Acid; OR, Odds Ratio; PAR, protease-activated receptors; PBC, Primary Biliary Cholangitis; PC, phosphatidylcholine; PH, Portal Hypertension; PPAR agonists; PPAR, peroxisome proliferator-activated receptor; Primary biliary cholangitis; QoL, Quality of Life; RCT, randomized controlled trial; SAE, Severe Adverse Event; Saroglitazar; Seladelpar; TGR, transmembrane G protein-coupled receptor; TLR, Toll Like Receptor; TNF-α, Tumor Necrosis Factor- α; UDCA; UDCA, ursodeoxycholic acid; UK, United Kingdom; ULN, upper limit of normal; VAS, Visual Analogue Scale; VRS, Verbal Rating Scale.

Publication types

Review