PEGOZAFERMIN DEMONSTRATED ROBUST HISTOLOGIC IMPROVEMENT AND BENEFIT IN HEPATIC AND METABOLIC BIOMARKERS IN A 48-WEEK MULTI-CENTER, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED PHASE 2B TRIAL (ENLIVEN)

Therapeutic Area

Pharmacologic Therapy

Background

Metabolic dysfunction-associated steatohepatitis (MASH) is often associated with metabolic disorders such as obesity, metabolic syndrome, and/or diabetes. FGF21 analogs such as pegozafermin (PGZ) have direct effects on liver fibrosis as well as additional hepatic and extrahepatic benefits in patients with MASH. The Phase 2b ENLIVEN trial evaluated the efficacy and safety of PGZ given weekly (QW) or every two-weeks (Q2W) versus placebo in MASH patients with biopsy-proven F2/F3 fibrosis. The primary histology endpoints were assessed at week 24, followed by a 24-week blinded extension for a total of 48 weeks.

Methods

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, 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 F2/F3 patients with NAFLD activity score (NAS) ≥4 at baseline (n=192).

Results

Both primary histological endpoints considered as reasonably likely surrogates of clinical outcome benefit - at least one stage of fibrosis improvement without worsening of MASH and MASH resolution without worsening of fibrosis - were achieved by a significantly higher proportion of patients treated with PGZ 30mg QW or 44 mg Q2W than placebo. PGZ treatment also improved liver fat content (MRI-PDFF), biomarkers of fibrosis (VCTE, ELF, PRO-C3) and liver injury (ALT, AST) as well as lipids and HgA1c at both 24 weeks and week 48. PGZ was generally safe and well tolerated with the most common treatment emergent adverse events (TEAEs) being mild/moderate nausea and diarrhea. No deaths occurred; six early terminations for TEAEs including one drug-related serious AE occurred.

Conclusions

Treatment with PGZ in MASH patients with F2/F3 fibrosis led to highly significant fibrosis regression and MASH resolution and to robust and sustained improvements in non-invasive biomarkers of liver fat and inflammation, fibrosis, and metabolic markers, with a favorable safety and tolerability profile. PGZ is the first therapy to achieve fibrosis regression and MASH resolution with a Q2W dosing regimen. The confirmatory Phase 3 program in MASH was recently initiated.

Please note that ENLIVEN 28-week data were presented at EASL 2023 and ENLIVEN 48-week data are accepted as an oral presentation for EASL 2024. This is the first abstract to include both data sets.