Once-Monthly Efimosfermin Alfa for Up to 48 Weeks in MASH With F2/F3 Fibrosis: Results From a Phase 2, Open-Label Extension Study

Efimosfermin is a novel engineered fibroblast growth factor 21 analog that was designed to have an extended half-life to allow for once-monthly dosing.¹ Clinical trials are evaluating efimosfermina alfa in patients with MASH. The randomized, double-blind, placebo-controlled, phase 2 trial of patients with MASH with biopsy-confirmed F2/F3 fibrosis reported that, among 65 evaluable patients, efimosfermin alfa 300 mg every 4 weeks was significantly more effective than placebo after 24 weeks of treatment.² This was assessed by the proportion of patients attaining a fibrosis improvement of 1 stage or higher without worsening of MASH (45% vs 21%; P=.038) and the proportion of patients attaining MASH resolution without worsening of fibrosis (68% vs 29%; P=.002). In the prior safety analysis, the most frequent treatment-emergent AEs were gastrointestinal (GI), including nausea (33% vs 13% with placebo), diarrhea (23% vs 8%), and vomiting (16% vs 3%), and were mostly mild to moderate. The rate of discontinuations owing to AEs in the efimosfermin alfa arm was 4.7%.

Noureddin and colleagues presented additional findings from the trial, including efficacy and safety outcomes through the 24-week OLE in 15 patients originally assigned to efimosfermin alfa and in 18 patients crossing over from the placebo arm.³ Results were reported for the full analysis set, which included patients who received at least 1 dose of study treatment in the OLE, and the biopsy analysis set, which included 11 patients initially assigned to efimosfermin alfa and 17 patients initially assigned to placebo.

Among patients initially assigned to efimosfermin alfa, who had received up to 48 weeks of treatment, 5 of 11 patients (45.5%) had fibrosis improvement of 1 stage or more without worsening of MASH, including 2 patients (18.2%) with new fibrosis improvement. MASH resolution without worsening of fibrosis occurred in 7 patients (63.6%) and was new in 2 patients (18.2%), and 5 patients (45.5%) had fibrosis improvement of 1 stage or more and MASH resolution (Figure 2). Improvements in noninvasive markers of fibrosis included a mean change from baseline in PRO-C3 of -20.1% (n=13), in Enhanced Liver Fibrosis (ELF) score of -0.7 (n=13), and in VCTE LSM of -12.8 kPa. The mean change from baseline in alanine amino-transferase (ALT) was -31.1U/L, and in aspartate aminotransferase (AST) was -29.2 U/L.

Figure 2.

Proportion of patients with sustained or new response during up to 48 weeks of continued treatment with efimosfermin alfa 300 mg every 4 weeks in a phase 2, open-label extension study.

^aImprovement in liver fibrosis ≥1 stage and no worsening of steatohepatitis (defined as no increase in NAS for ballooning, inflammation, or steatosis).

^bNAS score of 0 for ballooning and 0-1 for inflammation.

MASH, metabolic dysfunction-associated steatohepatitis; NAS, nonalcoholic fatty liver disease activity score.

Adapted from Noureddin M, et al. AASLD abstract 5011. Presented at: The Liver Meeting; November 7-11, 2025; Washington, DC.³

There were sustained reductions in liver fat over 48 weeks as assessed by hepatic fat fraction, with a mean change of -50.0% at the end of study (relative reductions of ≥30% and ≥50% were attained by 53.8% and 46.2% of patients, respectively). Nearly 40% of patients (38.5%) attained liver fat normalization (≤5%). Improvements in cardiometabolic profile with efimosfermin alfa at 48 weeks included a mean change from baseline in the following levels: triglycerides, -0.3 mmol/L; high-density lipoprotein cholesterol, 0.1 mmol/L; low-density lipoprotein (LDL-C), 0.1 mmol/L; total cholesterol, 0.1 mmol/L; adiponectin, 79.2% change; and glycated hemoglobin (A1c), -0.5% units in all patients (n=13) and -0.6% units in patients with type 2 diabetes mellitus (T2DM, n=11). Treatment responses in patients initially assigned to placebo who crossed over to efimosfermin alfa were consistent with those observed in patients originally assigned to the study drug.

With this small study, results must be interpreted carefully; however, having another class of agents in late-stage development is encouraging. This once-a-month therapy shows not only sustained improvement in MASH and fibrosis, but also favorable cardiometabolic effects, which is important in this population enriched in cardiometabolic risk factors. Notably, during the period of treatment disruption, there was a slip in that improvement, which was regained when treatment resumed. This emphasizes that the improvement is an agent effect, not just natural history.

—Nancy S. Reau, MD

In the safety analysis, the only serious AE was a case of appendicitis in the OLE that was considered not treatment-related. No patients discontinued treatment during the OLE period owing to AEs, and no antidrug antibodies were detected. Most GI AEs occurred in the first 24 weeks of treatment. Nausea was reported in 20% of patients in the original efimosfermin alfa group and 22% of patients in the crossover group; diarrhea occurred in 13% and 22% of patients, respectively, and vomiting occurred in 13% and 17% of patients, respectively. Two cases of hepatic calcification in the crossover group were considered not treatment-related.

Investigators concluded that once-monthly efimosfermin alfa was associated with fibrosis improvement and MASH resolution after up to 48 weeks in patients with F2/F3 MASH and improvements in noninvasive markers of fibrosis, liver injury, and liver fat through the end of the OLE. The ongoing phase 3 ZENITH-1 (NCT07221227) and ZENITH-2 (NCT07221188) trials are evaluating efimosfermin alfa in patients with biopsy-confirmed F2/F3 MASH.