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Review
. 2024 Dec 20;9(1):e0612.
doi: 10.1097/HC9.0000000000000612. eCollection 2025 Jan 1.

PPAR agonists for the treatment of cholestatic liver diseases: Over a decade of clinical progress

Colleen M Hayes  1 , Gina M Gallucci  1 , James L Boyer  2 , David N Assis  2 , Nisanne S Ghonem  1
Affiliations
Review

PPAR agonists for the treatment of cholestatic liver diseases: Over a decade of clinical progress

Colleen M Hayes et al. Hepatol Commun. .

Abstract

Primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) are characterized by the destruction of the small bile ducts and the formation of multifocal biliary strictures, respectively, impairing bile flow. This leads to the hepatic accumulation of bile acids, causing liver injury and the risk of progression to cirrhosis and liver failure. First-line therapy for PBC is ursodeoxycholic acid, although up to 40% of treated individuals are incomplete responders, and there is no effective therapy for PSC, highlighting the need for better therapeutic options in these diseases. In addition, pruritus is a common symptom of cholestasis that has severe consequences for quality of life and is often undertreated or untreated. Nuclear receptors are pharmacological targets to treat cholestasis due to their multifactorial regulation of hepatic enzymatic pathways, particularly in bile acid metabolism. The peroxisome proliferator-activated receptor (PPAR) is of significant clinical interest due to its role in regulating bile acid synthesis and detoxification pathways. PPAR agonism by fibrates has traditionally been explored due to PPARα's expression in the liver; however, recent interest has expanded to focus on newer PPAR agonists that activate other PPAR isoforms, for example, δ, γ, alone or in combination. Several PPAR agonists have been investigated as second-line therapy for people living with PBC, including the recent accelerated United States Food and Drug Administration approval of elafibranor and seladelpar. This review evaluates available data on the efficacy and safety of the five PPAR agonists investigated for the treatment of cholestasis and associated pruritus in PBC and PSC, namely fenofibrate, bezafibrate, saroglitazar, elafibranor, and seladelpar.

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Conflict of interest statement

Gina Gallucci is employed by Boehringer Ingelheim. James Boyer serves on clinical events committees for IPSEN. He received grants from Mirum Pharmaceuticals.

Figures

FIGURE 1
FIGURE 1
Overview of PPAR agonists that have received accelerated FDA approval as second-line therapy for PBC (elafibranor and seladelpar) and PPAR agonists under clinical investigation to treat PBC and PSC (fenofibrate, bezafibrate, and saroglitazar). Created in BioRender.com. Abbreviations: FDA, Food and Drug Administration; PBC, primary biliary cholangitis; PPAR, peroxisome proliferator-activated receptor; PSC, primary sclerosing cholangitis.
See this image and copyright information in PMC

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