Efruxifermin, an investigational treatment for fibrotic or cirrhotic nonalcoholic steatohepatitis (NASH)

ABSTRACT

Introduction

Non-alcoholic fatty liver disease (NAFLD) is the most prevalent chronic liver disease and strongly associated with metabolic disorders: obesity, type 2 diabetes (T2D), cardiovascular disease. Persistent metabolic injury results in inflammatory processes leading to nonalcoholic steatohepatitis (NASH), liver fibrosis, and ultimately cirrhosis. To date, no pharmacologic agent is approved for the treatment of NASH. Fibroblast growth factor 21 (FGF21) agonism has been linked to beneficial metabolic effects ameliorating obesity, steatosis, and insulin resistance, supporting its potential as a therapeutic target in NAFLD.

Areas covered

Efruxifermin (EFX, also AKR-001 or AMG876) is an engineered Fc-FGF21 fusion protein with an optimized pharmacokinetic and pharmacodynamic profile, which is currently tested in several phase 2 clinical trials for the treatment of NASH, fibrosis and compensated liver cirrhosis. EFX improved metabolic disturbances including glycemic control, showed favorable safety and tolerability, and demonstrated antifibrotic efficacy according to FDA requirements for phase 3 trials.

Expert opinion

While some other FGF-21 agonists (e.g. pegbelfermin) are currently not further investigated, available evidence supports the development of EFX as a promising anti-NASH drug in fibrotic and cirrhotic populations. However, antifibrotic efficacy, long-term safety and benefits (i.e. cardiovascular risk, decompensation events, disease progression, liver transplantation, mortality) remain to be determined.

KEYWORDS:

• Efruxifermin (EFX, also AKR-001 or AMG876)
• Fibroblast growth factor 21 (FGF21)
• liver fibrosis
• liver cirrhosis
• Non-alcoholic fatty liver disease (NAFLD)
• Nonalcoholic steatohepatitis (NASH)

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. declares no conflict of interests. Outside the submitted work, FT’s lab has received research funding from Allergan, Bristol-Myers Squibb, Gilead and Inventiva. FT has received honoraria for consulting or lectures from Astra Zeneca, Gilead, AbbVie, BMS, Boehringer, Madrigal, Intercept, Falk, Ionis, Inventiva, Merz, Pfizer, Alnylam, NGM, CSL Behring, Novo Nordisk, Novartis.

Reviewer disclosures

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

Additional information

Funding

TP is supported by the BIH clinician scientist program and declares no conflict of interest. FT is supported by the German Research Foundation (DFG SFB/TRR 296 and CRC1382, Project-ID 403224013) and the German Ministry of Education and Research (BMBF DEEP-HCC consortium, BMBF Immun Avatar consortium).