Introduction

Metabolic dysfunction-associated steatohepatitis (MASH) is often associated with metabolic disorders such as obesity, metabolic syndrome, and/or diabetes. FGF21 analogs are promising therapies for MASH due to their direct anti-fibrotic effects as well as additional hepatic and extrahepatic benefits. Pegozafermin (PGZ), an FGF21 analog, was evaluated for safety and efficacy in a Phase 2b trial (ENLIVEN) with either weekly (QW) or every two-week (Q2W) dosing versus matching placebo in MASH patients with biopsy-proven F2/F3 fibrosis. 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.

Aims & 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, most patients continued their assigned treatment with the exception of 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

At 24-weeks, PGZ 30mg QW or 44mg Q2W led to statistically significant and clinical meaningful improvement in both primary histological endpoints (one stage of fibrosis improvement without worsening of MASH and MASH resolution without worsening of fibrosis) 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. 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.

Conclusion

At 24 weeks, treatment with PGZ in MASH patients with F2/F3 fibrosis led to significant fibrosis regression and MASH resolution, which was corroborated by improvement across a variety of non-invasive tests including liver fat, inflammation, fibrosis, and metabolic markers. Benefits on NITs were sustained over the full 48-weeks of the study, with favorable safety and tolerability. PGZ is the first therapy to achieve fibrosis regression and MASH resolution with a Q2W dosing regimen. Phase 3 studies in noncirrhotic (ENLIGHTEN-Fibrosis) and cirrhotic (ENLIGHTEN-cirrhosis) patients are currently underway to confirm these results.

Disclosure

Jörn Schattenberg: Consultant: Akero, Alentis Therapeutics, Astra Zeneca, 89Bio, Boehringer Ingelheim, GSK, Ipsen, Inventiva Pharma, Madrigal, MSD, Northsea Therapeutics, Novartis, Novo Nordisk, Pfizer, Roche, Sanofi, Siemens Healthineers; Speaker: Gilead Sciences, Advanz, Echosens, MedPublico GmbH; Grants: Boehringer Ingelheim, Siemens Healthcare GmbH; Stock Options: AGED diagnostics, Hepta Bio
Arun J Sanyal: Consulting: Genefit, Gilead, Malinckrodt, Pfizer, Salix, Boehringer Ingelheim, Novartis, Bristol Meyers Squibb, Merck, Hemoshear, Lilly, Novo Nordisk, Terns, Albireo, Jannsen, Poxel, 89bio, Siemens, AstraZeneca, NGM Bio, Amgen, Regeneron, Genentech, Alnylam, Roche, Madrigal, Inventiva, Covance, Prosciento, HistoIndex, PathAI; Grants: Gilead, Malinckrodt, Boehringer Ingelheim, Novartis, Bristol Meyers Squibb, Merck, Lilly, Novo Nordisk, Fractyl, Madrigal, Inventiva; Stock holder: Exhalenz, GenFit, Hemoshear, Durect, Indalo, NorthSea, Tiziana, Rivus
Naim Alkhouri: Research funding: 89Bio, AbbVie/Allergan, Akero, Better Therapeutics, Boehringer Ingelheim, Bristol-Myers Squibb, Corcept, DSM, Galectin, Genentech, Genfit, Gilead, Hepagene, Healio, Intercept, Inventiva, Ionis, Madrigal, Merck, NGM, Noom, NorthSea, Novo Nordisk, Perspectum, Pfizer, Poxel, Viking, and Zydus; Speaker bureau: AbbVie/Allergan, Alexion, Echosens, Eisai, Exelixis, Gilead, Intercept, Perspectum, Salix, and Theratechnologies; Consultant: 89Bio, AbbVie/Allergan, Echosens, Fibronostics, Gilead, Intercept, Madrigal, Novo Nordisk, Perspectum, Pfizer, and Zydus.
Rohit Loomba: Consultant: Aardvark Therapeutics, Altimmune, Anylam/Regeneron, Amgen, Arrowhead Pharmaceuticals, AstraZeneca, Boston Pharmaceuticals, Bristol-Meyers Squibb, CohBar, Eli Lilly, Galmed, Gilead, Glympse Bio, Hightide, Inipharma, Intercept, Inventiva, Ionis, Janssen Inc., Madrigal, Metacrine, Inc., NGM Biopharmaceuticals, Novartis, Novo Nordisk, Merck, Pfizer, Sagimet, Theratechnologies, 89bio, Terns Pharmaceuticals and Viking Therapeutics; Grants: Arrowhead Pharmacetuicals, AstraZeneca, Boegringer-Ingelheim, Bristol-Meyers Squibb, Eli Lilly, Galectin Therapeutics, Galmeed Pharmaceuticals, Gilead, Hanmi, Intercept, Inventiva, Ionis, Janssen, Madrigal Pharmaceuticals, Merck, NGM Biopharmaceuticals, Novo Nordisk, Pfizer, Sonic Incytes and Terns Pharmaceuticals; Stockholder: Co-founder LipoNexus, Inc
Mildred D Gottwald, Shibao Feng, Germaine D Agollah, Cynthia L Hartsfield, Hank Mansbach, Maya Margalit: 89bio employee and stock holder