Seladelpar: an investigational drug for the treatment of early-stage primary biliary cholangitis (PBC)

ABSTRACT

Introduction

Generic fibrates are used off-label as add-in therapy for the management of primary biliary cholangitis (PBC) but with unproven long-term liver-related survival benefits. The recently developed fibrate, seladelpar, has shown promising results in clinical trials, but these outcomes have been previously marred by safety concerns.

Areas covered

We summarize existing treatment options in PBC and evaluate current trial data for seladelpar in relation to liver biochemistry, symptomology, and safety.

Expert opinion

Seladelpar leads to marked improvement in liver biochemistry and may improve symptoms. Safety concerns around liver toxicity appear to have been addressed. With likely increasing evidence compared to existing off-label fibrates, seladelpar has the potential as an attractive future second-line agent in PBC.

KEYWORDS:

• Primary biliary cholangitis
• fibrates
• seladelpar
• peroxisome proliferator-activated receptor agonists
• PPAR
• fatigue
• pruritus

Article highlights

• Generic fibrates are used off-label as add-in therapy for the management of primary biliary cholangitis (PBC) but with unproven long-term liver-related survival benefits.

• Seladelpar is a potent and selective PPAR-δ agonist that has anti-inflammatory and anti-fibrotic effects on Kupffer cells and hepatic stellate cells.

• Clinical trials, including the ENCHANCE trial, have demonstrated that seladelpar is well tolerated, including in those with compensated cirrhosis, and can lead to marked improvements in liver biochemistry in patients with PBC.

• Symptomatic PBC remains a significant unmet need. Emerging evidence suggests that seladelpar improves pruritus and may potentially result in improvements in fatigue.

• Safety concerns around liver toxicity appear to have been addressed, with dose adjustment in PBC and an independent review into liver histology from the NASH studies.

• Seladelpar is likely to have more robust underpinning evidence than existing off-licensed fibrates and may improve symptomatic PBC, making it an attractive potential future second-line agent in PBC.

This box summarizes key points contained in the article.

Declaration of Interest

D Jones has received consultancy fees from Novartis, Umecrine, and Exscientia, consultancy fees, and a grant from Intercept Pharmaceuticals, and speaker fees from Dr Falk and Abbott Laboratories. The authors have no other 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 apart from those disclosed.

Reviewer disclosures

A peer reviewer on this manuscript is an employee and stockholder of Bristol-Myers Squibb. Peer reviewers on this manuscript have no other relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.