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Review
. 2023 Jan 5:6:100188.
doi: 10.1016/j.jtauto.2023.100188. eCollection 2023.

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

Francesca Colapietro  1   2 , M Eric Gershwin  3 , Ana Lleo  1   2
Affiliations
Review

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

Francesca Colapietro et al. J Transl Autoimmun. .

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.

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Conflict of interest statement

The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Ana Lleo reports a relationship with Gilead Sciences Inc that includes: speaking and lecture fees. Ana Lleo reports a relationship with Intercept Pharmaceuticals that includes: consulting or advisory and speaking and lecture fees. Ana Lleo reports a relationship with Alfasigma SpA that includes: consulting or advisory and speaking and lecture fees. Ana Lleo reports a relationship with Albireo Pharma Inc that includes: consulting or advisory. Ana Lleo reports a relationship with GSK that includes: speaking and lecture fees. Ana Lleo reports a relationship with AstraZeneca Pharmaceuticals LP that includes: consulting or advisory. Ana Lleo reports a relationship with Incyte Corporation that includes: speaking and lecture fees. Ana Lleo reports a relationship with Takeda Pharmaceutical Co Ltd that includes: consulting or advisory. Ana Lleo reports a relationship with Kowa Pharmaceutical Europe Co Ltd that includes: consulting or advisory. Ana Lleo reports a relationship with Merck Sharp & Dohme UK Ltd that includes: speaking and lecture fees. Ana Lleo reports a relationship with AbbVie Inc that includes: speaking and lecture fees. Francesca Colapietro reports a relationship with Intercept Pharmaceuticals Inc that includes: speaking and lecture fees. Research Grants: EU Project D-LIVER, EU COST Action EURO-Cholangio-Net, Italian Ministry of Health, Italian Association for Cancer Research (AIRC) Support for sponsored studies (via Humanitas Research Hospital): Falk, Intercept Pharma.

Figures

Fig. 1
Fig. 1
Mechanisms and effects of peroxisome proliferator-activated receptor (PPAR) activation in the liver.
Fig. 2
Fig. 2
Chemical structure of Peroxisome Proliferator-Activated Receptor (PPAR) agonists.
See this image and copyright information in PMC

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References

    1. European e. e. e. Association for the study of the liver. Electronic address, L. European association for the study of the. EASL clinical practice guidelines: the diagnosis and management of patients with primary biliary cholangitis. J. Hepatol. 2017;67:145–172. doi: 10.1016/j.jhep.2017.03.022. - DOI - PubMed
    1. Lleo A., Wang G.Q., Gershwin M.E., Hirschfield G.M. Primary biliary cholangitis. Lancet. 2020;396:1915–1926. doi: 10.1016/S0140-6736(20)31607-X. - DOI - PubMed
    1. Corpechot C., Carrat F., Bahr A., Chretien Y., Poupon R.E., Poupon R. The effect of ursodeoxycholic acid therapy on the natural course of primary biliary cirrhosis. Gastroenterology. 2005;128:297–303. doi: 10.1053/j.gastro.2004.11.009. - DOI - PubMed
    1. Harms M.H., van Buuren H.R., Corpechot C., Thorburn D., Janssen H.L.A., Lindor K.D., et al. Ursodeoxycholic acid therapy and liver transplant-free survival in patients with primary biliary cholangitis. J. Hepatol. 2019;71:357–365. doi: 10.1016/j.jhep.2019.04.001. - DOI - PubMed
    1. Poupon R.E., Lindor K.D., Cauch-Dudek K., Dickson E.R., Poupon R., Heathcote E.J. Combined analysis of randomized controlled trials of ursodeoxycholic acid in primary biliary cirrhosis. Gastroenterology. 1997;113:884–890. doi: 10.1016/s0016-5085(97)70183-5. - DOI - PubMed

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