Efruxifermin Plus GLP-1RA Shows Promise in MASH Treatment
Key Insights
A study reveals that combining efruxifermin (EFX) with a GLP-1 receptor agonist (GLP-1RA) is a safe and tolerable dual therapy for MASH (search) and type 2 diabetes (search) patients.
The dual therapy significantly reduces hepatic fat fraction (HFF) and noninvasive fibrosis markers in patients with metabolic dysfunction-associated steatohepatitis (search) (MASH (search)).
Efruxifermin enhances the impact of GLP-1RAs by improving lipid and glucose metabolism, potentially accelerating MASH (search) resolution and fibrosis regression.
A recent study published in Clinical Gastroenterology and Hepatology indicates that efruxifermin (EFX), when administered with a glucagon-like peptide-1 receptor agonist (GLP-1RA), presents a well-tolerated and safe dual therapy option for individuals grappling with metabolic dysfunction-associated steatohepatitis (search) (MASH (search)) and type 2 diabetes (search) (T2D). The research highlights notable reductions in noninvasive fibrosis markers and hepatic fat fraction (HFF) among patients.
MASH (search) and Type 2 Diabetes (search) Complications
Patients with metabolic disorders, such as metabolic dysfunction-associated steatotic liver disease (MASLD), often experience a higher prevalence of T2D and obesity, which can progress to MASH (search). Studies suggest that fibrosis can advance more rapidly in MASLD patients with T2D compared to those without it. The co-occurrence of these conditions elevates the risk of cardiovascular disease and hepatocellular carcinoma (HCC (search)).
GLP-1RAs and Fibroblast Growth Factor 21
Weight loss, improved insulin sensitivity, and lifestyle adjustments can mitigate these risks, with GLP-1RAs playing a beneficial role. According to the study authors, GLP-1RAs indirectly enhance liver health by decreasing calorie intake and redirecting energy away from the liver through increased peripheral uptake of dietary energy. Fibroblast growth factor 21 (FGF21) also shows promise due to its capacity to regulate lipid and glucose metabolism and reduce cellular stress. Efruxifermin (EFX), an Fc-FGF21 analog, has demonstrated the ability to address steatosis, liver fibrosis, hepatocyte injury, fibrogenesis, and insulin resistance in MASH (search) treatment. This led researchers to hypothesize that EFX could augment the pharmacologic impact of GLP-1RAs.
Study Design and Patient Population
The multicenter study, conducted between May and December 2022, involved 31 patients (29 completing the study) from 24 clinics across the US. The 12-week treatment period included a 4-week follow-up. Eligible patients had MASH (search) and T2D and were on stable GLP-1RA doses for at least 90 days before screening. Patients with fibrosis stage 4 (F4), HCC (search) history, liver transplant, or decompensated liver disease were excluded.
Participants were randomized 2:1 to receive either 50 mg of EFX (n = 21) or a placebo (n = 10) weekly, in addition to their GLP-1RA therapy. Tolerability and safety were assessed through adverse event reports, electrocardiograms, clinical laboratory tests, and immunogenicity assessments. Outcomes related to HFF, fibrosis, insulin sensitivity, weight changes, and liver markers were also evaluated. The average age of patients was 57.4 years, with an average weight of just over 99 kg. The GLP-1RAs used included liraglutide, semaglutide, and dulaglutide.
Key Findings
The most common treatment-emergent adverse event was nausea (33% in the treatment group vs 10% in the placebo group). Other reported events included increased appetite (24% vs 0%), diarrhea (19% vs 30%), and decreased appetite (14% vs 20%). No serious drug-related adverse events occurred, although two participants withdrew. The treatment group had significantly higher baseline heart rates (6 beats/min vs 4 beats/min; P = .0042), but no significant differences in systolic or diastolic blood pressure were observed by week 12. No significant clinical differences were noted in other laboratory tests or safety measures.
After 12 weeks, patients receiving EFX showed significantly lower liver fat levels, with 88% achieving normal HFF levels (≤ 5%) compared to 10% in the placebo group (P = .002). The treatment group's HFF decreased by 65% from baseline, versus 10% in the placebo group (P < .0001). Furthermore, 88% of the treatment group experienced at least a 50% reduction in HFF, compared to 0% in the placebo group (P < .0001).
EFX was associated with improvements in fibrosis, lipid metabolism, glucose levels, and noninvasive liver injury markers, while patients maintained weight loss from their GLP-1RA therapy.
Conclusion
The authors concluded that combining EFX with GLP-1RAs shows preliminary indications of accelerating MASH (search) resolution and fibrosis regression.