P5 Pegozafermin treatment demonstrates long-term benefit in subjects with metabolic dysfunction-associated steatohepatitis and fibrosis: results from the Phase 2b ENLIVEN clinical trial

<h3>Introduction</h3> Pegozafermin (PGZ), a long-acting fibroblast growth factor 21 (FGF21) analog, was evaluated for efficacy and safety in the Phase 2b ENLIVEN trial in metabolic dysfunction-associated steatohepatitis (MASH) patients with biopsy-proven F2/F3 fibrosis. Co-morbidities such as obesity and T2DM are common in patients with MASH and may be treated with glucagon-like peptide-1 receptor agonists (GLP-1 therapy). Primary histology endpoints and non-invasive tests (NITs) were assessed at week 24, followed by additional NIT evaluation at the end of a 24-week blinded extension for a total of 48 weeks. <h3>Methods</h3> Patients were randomized to PGZ 15mg QW, 30mg QW, or 44mg Q2W or placebo for 24 weeks (histology-based primary endpoints). During the 24-week extension, most patients continued their assigned treatment except for a subset of placebo patients who were re-randomized to receive PGZ 30mg QW. The full analysis set includes patients who were F2-F3 and NAS ≥4 at baseline (n=192 of which 163 continued into the extension phase). The GLP-1 therapy population included 36 patients who received a GLP-1 during the study with the majority having baseline utilization of ≥ 6 months. Twenty-six received PGZ (30 mg QW or 44 mg Q2W) and 10 received placebo. Changes in liver steatosis, fibrosis and inflammation, metabolic effects, as well as safety, and tolerability were assessed at 48 weeks. <h3>Results</h3> At 24-weeks, PGZ 30mg QW or 44mg Q2W led to statistically significant improvement in both primary histological endpoints compared to placebo. Non-invasive testing at weeks 24 and 48 demonstrated that PGZ treatment was associated with robust and sustained reductions in liver fat content (MRI-PDFF), biomarkers of fibrosis (VCTE, ELF, PRO-C3) and liver injury (ALT, AST). PGZ also improved metabolic parameters such as lipids and HbA1c at both 24 and 48 weeks. These results remained consistent in patients on background GLP-1 therapy. PGZ was generally safe and well tolerated with the most common treatment emergent adverse events (TEAEs) being mild/moderate nausea and diarrhea. <h3>Conclusion</h3> PGZ treatment in MASH patients with F2/F3 fibrosis led to significant fibrosis regression and MASH resolution, corroborated by improvement across a variety of non-invasive tests including liver fat, inflammation, fibrosis, and metabolic markers. Benefits on NITs were sustained across the full 48-weeks of the study, while maintaining a favorable safety and tolerability. Phase 3 studies in non-cirrhotic and cirrhotic patients are currently underway to confirm these results.