Pegozafermin

Pegozafermin (BIO89-100) is a glycoPEGylated recombinant analog of human fibroblast growth factor 21 (FGF21), a hepatokine central to the regulation of lipid metabolism, glucose homeostasis, and energy expenditure. The compound was engineered using site-specific glycosylation and PEGylation to extend the circulating half-life from approximately 0.5 to 2 hours (native FGF21) to 55 to 100 hours, enabling once-weekly or once-every-two-week subcutaneous administration while preserving the receptor binding profile of the native hormone. Pegozafermin signals through the FGF receptor 1c (FGFR1c) and FGF receptor 3c in complex with the obligate coreceptor beta-klotho (KLB), activating the extracellular signal-regulated kinase 1/2 (ERK1/2) cascade and downstream transcription factors that govern hepatic de novo lipogenesis, adipose tissue adiponectin secretion, fatty acid oxidation, and insulin sensitivity. The compound was originally developed by Teva Pharmaceutical Industries and subsequently licensed to 89bio, Inc. in 2019 for global development (excluding Israel).

In the Phase 2b ENLIVEN trial (Loomba et al., 2023, New England Journal of Medicine), 222 patients with biopsy-confirmed nonalcoholic steatohepatitis (NASH) and stage F2 or F3 fibrosis were randomized to pegozafermin 15 mg weekly, 30 mg weekly, 44 mg every two weeks, or placebo for 24 weeks. The co-primary histological endpoints were met at both the 30 mg weekly and 44 mg every-two-week doses: fibrosis improvement of at least one stage without worsening of steatohepatitis was achieved in 26 percent and 27 percent of treated patients, respectively, compared with 7 percent on placebo. NASH resolution without fibrosis worsening was achieved in 23 percent and 26 percent, respectively, compared with 2 percent on placebo. Hepatic fat fraction measured by magnetic resonance imaging proton density fat fraction (MRI-PDFF) decreased by 48.2 percent (30 mg weekly) and 41.9 percent (44 mg every two weeks) versus 5.0 percent on placebo. Alanine aminotransferase levels normalized in 59 to 65 percent of treated patients versus 24 percent on placebo, and the fibrosis biomarker PRO-C3 decreased by 17 to 18 percent versus a 6.4 percent increase on placebo.

In the Phase 2 ENTRIGUE trial in severe hypertriglyceridemia (Bhatt et al., 2023, Nature Medicine), pegozafermin at doses of 9 to 27 mg weekly or 36 mg every two weeks produced a pooled median triglyceride reduction of 57.3 percent versus 11.9 percent on placebo, with 79.7 percent of treated patients achieving triglycerides below 500 mg/dL compared with 29.4 percent on placebo. Secondary lipid endpoints included reductions in non-HDL cholesterol (18.3 percent), apolipoprotein B (10.5 percent), apolipoprotein C3 (41.9 percent), and increases in HDL cholesterol of up to 44.5 percent at the 27 mg weekly dose.

Safety across both trials was characterized by mild-to-moderate gastrointestinal adverse events (nausea, diarrhea) and injection site reactions. No hepatotoxicity, drug-induced liver injury, or clinically significant bone density changes were observed. One treatment-related serious adverse event (acute pancreatitis in a patient with gallbladder sludge) was reported in the ENLIVEN trial.

Pegozafermin received Breakthrough Therapy designation from the United States Food and Drug Administration and Priority Medicines (PRIME) designation from the European Medicines Agency for the treatment of MASH with fibrosis in September 2023. The compound is currently in Phase 3 development in the ENLIGHTEN program (MASH with fibrosis and compensated cirrhosis) and the ENTRUST program (severe hypertriglyceridemia). This monograph reviews the compound identification, discovery and development history, molecular pharmacology of the FGF21 signaling axis, pharmacokinetics, preclinical pharmacology, clinical evidence base, sourcing and quality verification, reconstitution and handling, stack interactions and combinations, adverse events and safety signal, and a comparative assessment of five alternative metabolic liver disease candidates against pegozafermin on five competency standards.