Evaluating the safety and efficacy of seladelpar for adults with primary biliary cholangitis

ABSTRACT

Introduction

Seladelpar (MBX-8025) is a once-daily administered highly specific PPAR-δ agonist in Phase 3 and extension trials for use in patients with primary biliary cholangitis (PBC).

Areas covered

This review provides background on current treatment options for PBC, and summarizes clinical trial data regarding the safety and effectiveness of seladelpar within the context of these treatments.

Expert opinion

Clinical trials results demonstrate the safety and tolerability of seladelpar use for PBC, including in patients with cirrhosis. The primary composite endpoint (ALP <1.67 times ULN, decrease ≥ 15% from baseline, and TB ≤ULN) was met in 61.7% of the patients treated with seladelpar and in 20% receiving placebo (p < 0.001). Moreover, pruritus – a cardinal and often intractable symptom of PBC – was improved with seladelpar treatment, as were overall quality of life measurements. Improvements in markers of inflammation were likewise observed. These biochemical and clinical findings therefore represent landmark developments in PBC treatment and offer a therapeutic option for PBC.

KEYWORDS:

• Primary biliary cholangitis
• second-line therapy
• cirrhosis
• itch
• fibrates
• ursodeoxycholic acid
• UDCA
• elafibranor
• fezofibrate
• bezafibrate

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Article highlights

• There are currently few treatment options for the large proportion of patients with primary biliary cholangitis (PBC) who fail to respond to standard treatment with ursodeoxycholic acid, and none that comprehensively address pruritus, a common and distressing symptom

• The PPAR-ligand therapies fezofibrate and bezafibrate show promise in in decreasing markers of cholestasis in PBC patients, but concerns remain regarding side effects and potential hepatoxicity. Clinical trials of elafibranor, a dual PPAR-α/δ agonist, demonstrated significantly larger reductions in alkaline phosphatase than placebo, with ALP normalization in 15% of treated participants.

• Seladelpar is highly specific PPAR-δ agonist. Results from clinical trials show similar or slightly greater efficacy compared to elafibranor.

• Seladelpar treatment was also associated with significant and meaningful reductions in pruritus in a majority of patients who reported moderate-to-severe itch at baseline. This represents the first PBC therapy to effectively treat pruritus, a symptom with major impact on the quality of life for PBC patients.

Declaration of interest

S C Gordon receives grant/research support from AbbVie Pharmaceuticals, Arbutus Biopharma Corporation, COUR Pharmaceuticals, CymaBay, Genfit/IPSEN, Gilead Sciences, GlaxoSmithKline, Intercept Pharmaceuticals, and Takeda Development Center Americas, Inc., Viking Therapeutics. 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 reviewer on this manuscript has disclosed being a Consultant for IPSEN and CAMP4 therapeutics, as well as receiving speaker’s fees for ADVANZ PHARMA. Peer reviewers on this manuscript have no other relevant financial relationships or otherwise to disclose.

Additional information

Funding

This paper was not funded.