Elafibranor: a potential drug for the treatment of nonalcoholic steatohepatitis (NASH)

ABSTRACT

Introduction: Nonalcoholic fatty liver disease (NAFLD) encompasses a progressive disease phenotype starting from simple steatosis, which can progress to nonalcoholic steatohepatitis (NASH). It is component of the metabolic syndrome with a large impact on mortality in these patients. Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors that regulate lipid and insulin metabolism, two key components in pathophysiology of NAFLD and NASH. Elafibranor acts as an agonist of PPAR-α and PPAR-δ and is currently under development for the treatment of NAFLD.

Areas covered: This review summarizes the pharmacological aspects, the preclinical and clinical effectivity, and safety data of elafibranor for the treatment of nonalcoholic steatohepatitis and fibrosis.

Expert opinion: Current data support an effect of elafibranor on the resolution on NASH and the improvement of two key drivers of NASH progression – insulin resistance and serum lipid normalization. The safety profile is favorable, though reversible serum creatinine elevations occur with use, potentially limiting its use in patients with concurrent renal disease. The modest effect sizes in different NAFLD disease stages of elafibranor and other drugs in development for NASH, will likely lead to pursuing of drug combinations personalized to each stage of the NAFLD disease spectrum.

KEYWORDS:

• Elafibranor
• PPAR-α
• PPAR-δ
• nonalcoholic steatohepatitis
• nonalcoholic fatty liver disease

Article Highlights

• Nonalcoholic fatty liver disease has a progressive disease phenotype starting at steatosis, which leads to steatohepatitis and eventually fibrosis.

• There is no dedicated pharmacological treatment for NAFLD/NASH.

• Elafibranor is a combined PPAR-α and PPAR-δ agonist in development for the treatment of NAFLD/NASH.

• Elafibranor has shown a modest effect in a phase 2 trial on histological resolution of NASH, but not on histological resolution of fibrosis.

• Elafibranor has shown small reversible creatinine elevations in the safety results of phase 2 trials.

• The results on efficacy and safety of the dedicated RESOLVE-IT phase 3 trial and the phase 3 trials on combinations with other developmental drugs, will decide if elafibranor has role in the future treatment of NAFLD/NASH.

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Declaration of interest

J Drenth has received honoraria or research grants from Novartis, Ipsen, Abbvie, and Gilead. In the last 2 years, J Drenth has been member of advisory boards of Abbvie.

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. 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

Additional information

Funding

This paper was not funded.