Amplifying Impact: Efruxifermin Plus GLP-1RA Elevates MASH Outcomes

Efruxifermin (EFX; AKR-001) taken in conjunction with a glucagon-like peptide-1 receptor agonist (GLP-1RA) is both a tolerable and safe dual therapy for patients with metabolic dysfunction-association steatohepatitis (MASH) and type 2 diabetes (T2D). A double-blind, placebo-controlled study published in Clinical Gastroenterology and Hepatology informed these findings, where patients also exhibited markedly reduced levels of noninvasive fibrosis markers and hepatic fat fraction (HFF).¹

T2D and obesity are more prevalent among patients with metabolic disorders, such as metabolic dysfunction-associated steatotic liver disease (MASLD), which progresses to MASH.² Additional research also suggests that fibrosis can progresses more quickly in MASLD populations when they also live with T2D, compared with those without T2D.³

The present authors outline the risks of having these conditions simultaneously, including a higher likelihood of cardiovascular disease and hepatocellular carcinoma (HCC).¹ Weight loss, bolstering insulin sensitivity, and lifestyle modifications can counteract these risks to a degree; these interventions and outcomes have benefited from the advent of glycogen ligand peptide 1 receptor agonists (GLP-1RAs). In fact, “GLP-1RAs indirectly improve liver health by reducing calorie intake and redirecting energy away from liver, mediated by increased peripheral uptake of dietary energy,” the authors wrote.¹

GLP-1RA plus efruxifermin was found to be safe, tolerable, and effective for managing MASH | image credit: TensorSpark - stock.adobe.com

Fibroblast growth factor 21 (FGR21) can also improve patients’ conditions, due to its ability to regulate lipid and glucose metabolism, limit cellular stress, among other effects. Research on the efficacy of EFX, an Fc-FGF21 analog, has demonstrated the drug’s capacity to address steatosis, liver fibrosis, hepatocyte injury, fibrogenesis, insulin resistance and more, in the treatment of MASH. Considering these findings, the authors hypothesized that EFX could have an additive effect to the pharmacologic impact of GLP-1RAs.

Between May 2022 and December 2022, this multicenter study recruited a cohort of 31 patients (29 of whom completed the study) from 24 clinics throughout the US. The treatment period lasted 12 weeks and featured a follow-up 4 weeks later. Eligible patients had MASH and T2D, and were receiving steady GLP-1RA doses at a minimum of 90 days before their initial screening. Those with fibrosis stage 4 (F4), or histories of HCC, liver transplant, decompensated liver disease, or other influences of liver disease were excluded from the analysis.

Patients were randomized 2:1 to either receive 50 mg of EFX (n = 21) or placebo (n = 10) in addition to their GLP-1RA therapy once weekly. Reports of adverse-events, as well as electrocardiograms, clinical laboratory tests, immunogenicity assessment, and more were used to evaluate tolerability and safety measures. Outcomes related to HFF, fibrosis, insulin sensitivity, changes in weight, and various liver makers were also assessed.

Patients were aged 57.4 years and weighed just over 99 kg (218 lbs) on average. The GLP-1RAs used were liraglutide, semaglutide, and dulaglutide.

Nausea was the most prevalently reported treatment-emergent AE (33% for treatment group vs 10% for placebo). Other common reports included appetite increases (24% vs 0%), diarrhea (19% vs 30%), and appetite decreases (14% vs 20%). No serious drug-related AEs were reported, although there were 2 participants who withdrew.

The authors additionally noted that there were significantly higher baseline heart rates observed in the treatment group vs placebo (6 beats/min vs 4 beats/min; P = .0042). However, by week 12, there were no significant differences in systolic nor diastolic blood pressure between groups. No significant clinical differences were observed in the other laboratory tests or safety measures considered in the analysis.

Notably, after 12 weeks of adding EFX to patients’ dosage of GLP-1RA, patients exhibited significantly lower levels of liver fat, and HFF reached normal levels (≤ 5%) for 88% of those in the treatment group vs 10% in placebo (P = .002). The treatment group’s HFF was also reduced by 65% compared with baseline measurements vs 10% in the placebo group (P < .0001). The authors added that 88% of those in the treatment group compared with 0% in placebo experienced at least a 50% reduction of HFF (P < .0001).

Compared with placebo, EFX was linked to improvements in fibrosis, lipid metabolism, glucose, and noninvasive liver injury markers; all the while, patients were still able to maintain weight loss that was mediated by their GLP-1RA.

With these results, the authors conclude, “There are preliminary indications that combining these 2 mechanistic classes could accelerate resolution of MASH and regression of fibrosis.”

References

1. Harrison SA, Frias JP, Lucas KJ, et al. 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. Clin Gastroenterol Hepatol. 2025;23(1):103-113. doi:10.1016/j.cgh.2024.02.022

2. Rinella ME, Neuschwander-Tetri BA, Siddiqui MS, et al. AASLD practice guidance on the clinical assessment and management of nonalcoholic fatty liver disease. Hepatology. 2023;77(5):1797-1835. doi:10.1097/HEP.0000000000000323

3. Huang DQ, Wilson LA, Behling C, et al. Fibrosis progression rate in biopsy-proven nonalcoholic fatty liver disease among people with diabetes versus people without diabetes: a multicenter study. Gastroenterol. 2023;165(2):463-472.e5. doi:10.1053/j.gastro.2023.04.025