Efruxifermin Side Effects: What Studies Report

What the published record covers

Efruxifermin is an engineered long-acting Fc-FGF21 fusion protein that has been evaluated in randomised trials in non-alcoholic/metabolic dysfunction-associated steatohepatitis (NASH/MASH), and a 2023 expert review discussed its development status, engineering and clinical programme as an investigational agent rather than a marketed medicine (PMID 37376813). A 2025 systematic review pooled the available efruxifermin trials in MASH and reported that adverse events were predominantly gastrointestinal and mostly mild to moderate in severity across studies (PMID 40937291). Because every safety observation below comes from a controlled clinical trial in a specific liver-disease population, the tolerability picture described here does not extend to other populations, settings or uses.

This page is for educational purposes only and is not medical advice; consult a licensed physician about any medical question, medication or investigational therapy. It summarises what researchers wrote about adverse events; it does not describe how any compound should be used.

Gastrointestinal Events: What Studies Report

Gastrointestinal complaints dominate the reported adverse-event tables. In the phase 2a BALANCED trial, participants with NASH received efruxifermin at 28 mg, 50 mg or 70 mg once weekly for 16 weeks, and the study reported that the most common adverse events were grade 1 or 2 gastrointestinal events including increased frequency of bowel movements, diarrhoea and nausea, alongside increased appetite (PMID 34239138).

In the phase 2b HARMONY trial, which randomised participants with MASH and fibrosis to efruxifermin 28 mg, 50 mg or placebo once weekly, researchers reported that diarrhoea and nausea were the most frequent treatment-emergent adverse events and were generally mild to moderate, with more of these events on active treatment than on placebo (PMID 37802088). The same pattern recurred in the trial of participants with compensated cirrhosis caused by MASH, in which the investigators reported diarrhoea and nausea as the adverse events occurring more often with efruxifermin 28 mg or 50 mg once weekly than with placebo (PMID 40341827).

Several reports characterised these events as transient. The phase 2a publication described the gastrointestinal effects as low-grade and temporary in most participants (PMID 34239138), and the 2025 systematic review of efruxifermin in MASH reached a similar conclusion when it summarised tolerability across trials (PMID 40937291).

Appetite and Metabolic Laboratory Changes: What Studies Report

Increased appetite was listed among the more frequently reported adverse events in the phase 2a trial of efruxifermin at 28 mg, 50 mg and 70 mg weekly (PMID 34239138). Alongside adverse-event reporting, that study reported reductions in hepatic fat fraction measured by MRI-PDFF in the efruxifermin groups compared with placebo, and improvements in markers of liver injury and lipid metabolism (PMID 34239138). HARMONY similarly reported improvements in non-invasive markers of liver injury and in lipoprotein and glycaemic measures over 24 weeks of once-weekly dosing at 28 mg and 50 mg (PMID 37802088). These are efficacy and biomarker findings rather than harms, but they sit in the same publications and are part of how researchers judged the overall risk–benefit balance.

Serious Adverse Events and Discontinuations: What Studies Report

Trial reports distinguished common low-grade events from serious adverse events and from events leading to withdrawal. HARMONY reported that serious adverse events occurred in a minority of participants across groups and that a small number of participants discontinued treatment because of adverse events, with gastrointestinal intolerance among the reasons (PMID 37802088). In the compensated-cirrhosis trial, the investigators reported that adverse events were mostly mild or moderate and that discontinuations attributed to adverse events were uncommon but occurred (PMID 40341827).

The earlier phase 2a study in compensated NASH cirrhosis reported that efruxifermin 50 mg once weekly was generally well tolerated over the treatment period, with gastrointestinal events again the most common category and a small number of withdrawals (PMID 36644237). Individual trial abstracts did not resolve whether rarer events cluster with any particular dose level, and the 2025 systematic review noted that sample sizes across the efruxifermin programme remained modest for detecting uncommon harms (PMID 40937291).

Longer-Term Exposure: What the 96-Week Data Report

The longest published exposure comes from the extension of HARMONY. The 96-week results reported that once-weekly efruxifermin at 28 mg and 50 mg continued to show a tolerability profile dominated by gastrointestinal events, with sustained effects on fibrosis and steatohepatitis endpoints in the analysed population (PMID 40818852). Researchers reported no new safety signal category emerging between the 24-week and 96-week analyses in that trial (PMID 40818852). Data beyond 96 weeks of continuous exposure were not reported in any of the publications cited on this page (PMID 40937291).

Cirrhosis Populations: What Studies Report

Two publications addressed compensated cirrhosis specifically. The phase 2a trial in compensated NASH cirrhosis administered efruxifermin 50 mg once weekly against placebo and reported tolerability broadly consistent with the non-cirrhotic trials, with gastrointestinal adverse events most frequent (PMID 36644237). The larger 2025 trial in compensated cirrhosis caused by MASH randomised participants to 28 mg, 50 mg or placebo and reported fibrosis-stage outcomes together with an adverse-event profile in which diarrhoea and nausea were more common on active treatment (PMID 40341827). A 2023 systematic review of emerging pharmacotherapy for fatty liver disease placed FGF21-pathway agents, including efruxifermin, among investigational candidates whose safety databases were still accumulating at the time of publication (PMID 37701920).

Combination With a GLP-1 Receptor Agonist: What Studies Report

One randomised phase 2 study examined efruxifermin added to background GLP-1 receptor agonist therapy in participants with NASH/MASH and type 2 diabetes, and the investigators reported that the combination was generally well tolerated with adverse events that were mostly mild to moderate and predominantly gastrointestinal (PMID 38447814). That study also reported reductions in liver fat content in the efruxifermin groups relative to placebo when added to GLP-1 receptor agonist treatment (PMID 38447814). Because both drug classes commonly produce gastrointestinal effects, overlapping tolerability was the main safety question the researchers addressed in that report (PMID 38447814).

Trials at a Glance

Class Context: FGF21 Biology and Other MASLD Candidates

Efruxifermin acts on the FGF21 pathway, and a 2025 review of FGF21 in heart failure described the hormone's broader roles in cardiac and systemic metabolism and its study as a biomarker and therapeutic target outside the liver (PMID 41198096). That review examined FGF21 biology rather than efruxifermin safety, so it does not report adverse events for the drug (PMID 41198096).

For comparison within the wider MASLD development field, trials of pemvidutide, a GLP-1/glucagon dual receptor agonist, reported reductions in liver fat content alongside adverse events that were mostly mild to moderate and gastrointestinal, chiefly nausea and vomiting (PMID 39002641). A separate 24-week randomised controlled trial of pemvidutide in MASLD reported a comparable tolerability pattern (PMID 41113119). These were independent studies of a different mechanism; no head-to-head safety comparison between efruxifermin and pemvidutide appeared in the publications cited here (PMID 40937291).

What the Published Literature Does Not Report

Several gaps are worth stating plainly as absences rather than as reassurance:

• No outcomes were reported for efruxifermin outside randomised clinical trials in liver-disease populations; the trial reports cover only their enrolled participants and stated durations (PMID 37802088).
• The abstracts and reviews cited here did not report bone mineral density, fertility, pregnancy or paediatric outcomes for efruxifermin (PMID 40937291).
• Exposure beyond the 96-week HARMONY analysis was not reported (PMID 40818852).
• Cardiovascular outcome trials for efruxifermin were not reported in this set; the FGF21 heart-failure review addressed pathway biology only (PMID 41198096).
• A 2023 expert review noted that the agent remained investigational, meaning no approved product labelling with a regulator-reviewed adverse-reaction table existed at that time (PMID 37376813).

How This Page Relates to the Efruxifermin Course

This page is limited to what trial publications and reviews reported about adverse events, discontinuations and safety gaps. The mechanism, trial design, endpoint definitions and the wider MASH research context are taught separately in the PeptideU efruxifermin course at /learn/efruxifermin/, which covers background rather than the adverse-event record summarised above. Readers comparing the two should expect the course to explain FGF21 pathway pharmacology and study methodology, while this page stays with reported tolerability findings and their limits (PMID 40937291).

References

• Efruxifermin in non-alcoholic steatohepatitis: a randomized, double-blind, placebo-controlled, phase 2a trial (Nature Medicine, 2021)
• Safety and efficacy of once-weekly efruxifermin versus placebo in non-alcoholic steatohepatitis (HARMONY): a multicentre, randomised, double-blind, placebo-controlled, phase 2b trial (The Lancet Gastroenterology & Hepatology, 2023)
• Safety and efficacy of once-weekly efruxifermin versus placebo in metabolic dysfunction-associated steatohepatitis (HARMONY): 96-week results from a multicentre, randomised, double-blind, placebo-controlled, phase 2b trial (Lancet, 2025)
• Efruxifermin in Compensated Liver Cirrhosis Caused by MASH (The New England Journal of Medicine, 2025)
• A randomized, double-blind, placebo-controlled phase IIa trial of efruxifermin for patients with compensated NASH cirrhosis (JHEP Reports, 2023)
• Safety and Efficacy of Efruxifermin in Combination With a GLP-1 Receptor Agonist in Patients With NASH/MASH and Type 2 Diabetes in a Randomized Phase 2 Study (Clinical Gastroenterology and Hepatology, 2025)
• Safety and efficacy of efruxifermin in metabolic dysfunction-associated steatohepatitis: A systematic review (World Journal of Gastrointestinal Pharmacology and Therapeutics, 2025)
• Efruxifermin, an investigational treatment for fibrotic or cirrhotic nonalcoholic steatohepatitis (NASH) (Expert Opinion on Investigational Drugs, 2023)
• Emerging therapeutic options for non-alcoholic fatty liver disease: A systematic review (World Journal of Hepatology, 2023)
• Effect of pemvidutide, a GLP-1/glucagon dual receptor agonist, on MASLD: A randomized, double-blind, placebo-controlled study (Journal of Hepatology, 2025)
• Safety and efficacy of 24 weeks of pemvidutide in metabolic dysfunction-associated steatotic liver disease: A randomized, controlled clinical trial (JHEP Reports, 2025)
• Role of FGF21 in Heart Failure: Molecular Insights and Therapeutic Implications (Cardiology in Review, 2025)