Navigating the liver landscape: upcoming pharmacotherapies for primary sclerosing cholangitis

ABSTRACT

Introduction

Primary sclerosing cholangitis (PSC) is a bile duct disorder characterized by ductular reaction, hepatic inflammation, and liver fibrosis. The pathogenesis of PSC is still undefined, and treatment options for patients are limited. Previous clinical trials evaluated drug candidates targeting various cellular functions and pathways, such as bile acid signaling and absorption, gut bacteria and permeability, and lipid metabolisms. However, most of phase III clinical trials for PSC were disappointing, except vancomycin therapy, and there are still no established medications for PSC with efficacy and safety confirmed by phase IV clinical trials.

Areas covered

This review summarizes the currently ongoing or completed clinical studies for PSC, which are phase II or further, and discusses therapeutic targets and strategies, limitations, and future directions and possibilities of PSC treatments. A literature search was conducted in PubMed and ClinicalTrials.gov utilizing the combination of the searched term ‘primary sclerosing cholangitis’ with other keywords, such as ‘clinical trials,’ ‘antibiotics,’ or drug names. Clinical trials at phase II or further were included for consideration.

Expert opinion

Only vancomycin demonstrated promising therapeutic effects in the phase III clinical trial. Other drug candidates showed futility or inconsistent results, and the search for novel PSC treatments is still ongoing.

KEYWORDS:

• Primary sclerosing cholangitis
• clinical studies
• cholestatic liver injury
• ductular reaction
• liver fibrosis
• hepatic inflammation

Article highlights

• Various phase II and III clinical studies are ongoing or completed to evaluate candidate medications for primary sclerosing cholangitis.

• Most of phase III trials were terminated or withdrawn due to futility. Only vancomycin showed promising therapeutic effects for PSC patients in a phase III clinical trial.

• Some of phase II studies showed inconclusive or not significant effects, and results could be inconsistent between phase II and III trials, indicating the challenges in the development of novel medications for this disorder.

• Further clinical studies and trials are required for novel candidate drugs targeting signaling pathways associated with the pathogenesis of the disorder.

Declaration of Interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Author contribution

H Nam Pham critically reviewed the manuscript and elaborated descriptions.

L Pham critically reviewed the manuscript and elaborated descriptions.

K Sato designed the study and prepared the manuscript.

Additional information

Funding

This manuscript was funded by Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine Strategic Research Initiative.