Pegozafermin

GlycoPEGylated fibroblast growth factor 21 analog, a long-acting protein developed by 89bio, in phase 3 trials for MASH with fibrosis or compensated cirrhosis after positive phase 2 histology and triglyceride results.

Also referenced as: BIO89-100

Also appears in: Cardiovascular

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What is Pegozafermin?

Pegozafermin, developed by 89bio as BIO89-100, is a long-acting analog of human fibroblast growth factor 21 (FGF21), a stress-inducible hormone secreted mainly by the liver that coordinates lipid and glucose metabolism across the liver, adipose tissue, pancreas and brain. It is a protein, not a peptide: the molecule is a recombinant FGF21 analog to which a polyethylene glycol chain has been attached by glycoPEGylation, a process that uses site-specific glycosyltransferases to install a glycan at a defined position and couples the PEG through that sugar. The modification extends the short plasma half-life of native FGF21 to about 55 to 100 hours across the clinically relevant dose range, which is what allows weekly or every-other-week subcutaneous injection (Rosenstock et al., Journal of Pharmacology and Experimental Therapeutics, 2023;387(2):204–213; Loomba et al., New England Journal of Medicine, 2023;389(11):998–1008).

FGF21 analogs have produced histologic regression of liver fibrosis in metabolic dysfunction-associated steatohepatitis (MASH, formerly NASH) within 24 weeks in phase 2 trials, and pegozafermin is one of the analogs in phase 3, together with efruxifermin. Hoffmann-La Roche, which now owns 89bio, is the listed sponsor of the two ENLIGHTEN phase 3 trials. Pegozafermin has no approval anywhere.

How it works

• Agonist at the FGFR1c–beta-Klotho receptor complex. FGF21 cannot signal through fibroblast growth factor receptors alone: beta-Klotho acts as the primary high-affinity receptor, binding the hormone’s C-terminal tail, while FGFR1c serves as the catalytic subunit that drives intracellular signaling (Kuzina et al., Proceedings of the National Academy of Sciences, 2019;116(16):7819–7824). In cell-based assays pegozafermin reproduced the receptor-engagement profile of recombinant FGF21 with roughly eightfold higher potency at FGFR1c (Rosenstock et al., Journal of Pharmacology and Experimental Therapeutics, 2023;387(2):204–213).
• Metabolic effects in primates and healthy volunteers. In diabetic monkeys, weekly and every-2-weeks subcutaneous pegozafermin lowered triglycerides, cholesterol, fasting glucose, glycated hemoglobin, alanine aminotransferase, food intake and body weight and raised adiponectin; in healthy adults, single ascending doses significantly improved triglycerides, LDL and HDL cholesterol and adiponectin, an insulin-sensitizing adipokine (Rosenstock et al., Journal of Pharmacology and Experimental Therapeutics, 2023;387(2):204–213).
• Liver fat reduction with exposure-dependent response. Across six regimens in the phase 1b/2a study, 12 weeks of pegozafermin cut hepatic fat fraction by 8.9 to 14.9 absolute percentage points more than placebo, with falls in aminotransferases, triglycerides, non-HDL cholesterol and the collagen marker PRO-C3 (Loomba et al., Lancet Gastroenterology & Hepatology, 2023;8(2):120–132). Population pharmacokinetic modeling showed that liver fat response tracked average drug concentration regardless of dosing interval and that 30 mg weekly approximated the full pharmacodynamic effect, the basis for the phase 2b dose selection (Tseng et al., Clinical Pharmacology and Therapeutics, 2023;114(6):1323–1331).
• Antifibrotic action beyond weight loss. FGF21 analogs suppress hepatic de novo lipogenesis, dampen hepatocellular stress and innate immune activation, inhibit hepatic stellate cell activation and remodel adipose tissue through the FGF21–adiponectin axis, with additional central effects on energy expenditure; they produce fibrosis regression despite only modest weight loss (Holleboom and Schattenberg, JHEP Reports, 2026;8(11):101957).

Research status

Phase 1b/2a (NCT04048135). A double-blind, placebo-controlled multiple-ascending-dose study at 12 US centers randomized 81 adults with biopsy-confirmed or phenotypic NASH to six pegozafermin regimens (3 to 27 mg weekly or 18 to 36 mg every 2 weeks) or placebo for 12 weeks. The most common treatment-related adverse event was mild increased appetite (16% versus none on placebo) without weight gain, no treatment-related serious adverse events occurred, anti-drug antibodies were detected in 41 of 63 (65%) treated participants, and every regimen reduced liver fat significantly versus placebo by week 13 (Loomba et al., Lancet Gastroenterology & Hepatology, 2023;8(2):120–132). In an open-label part 2 at 16 US centers, 20 adults with biopsy-confirmed NASH and F2 or F3 fibrosis received 27 mg weekly for 20 weeks; 12 of 19 completers (63%) met the primary endpoint of a 2-point or greater improvement in NAFLD activity score without worsening of fibrosis, 26% improved fibrosis, 32% had NASH resolution and liver fat fell 64.7% from baseline (Alkhouri et al., Alimentary Pharmacology & Therapeutics, 2023;58(10):1005–1015).

ENTRIGUE phase 2 in severe hypertriglyceridemia (NCT04541186). A double-blind, five-arm trial randomized 85 adults with fasting triglycerides of 500 to 2,000 mg/dL to one of four pegozafermin regimens (67 patients) or placebo (18) for 8 weeks. Median triglycerides fell 57.3% with pooled pegozafermin versus 11.9% with placebo (difference −43.7%, 95% CI −57.1 to −30.3; p<0.001), with reductions of 36.4 to 63.4% across arms; apolipoprotein B fell 10.5% and non-HDL cholesterol 18.3%, and in an MRI substudy liver fat fell 42.2% versus 8.3%. Nausea (13.4%), diarrhea (10.4%) and injection-site reactions (9%) were the main adverse events, none were grade 3 or higher, and no serious adverse event was attributed to the drug (Bhatt et al., Nature Medicine, 2023;29(7):1782–1792).

ENLIVEN phase 2b in MASH (NCT04929483). The phase 2b trial randomized 222 adults with biopsy-confirmed NASH and F2 or F3 fibrosis to pegozafermin 15 mg or 30 mg weekly, 44 mg every 2 weeks, or placebo for 24 weeks; 219 received treatment and 192 formed the full analysis population after a three-pathologist consensus re-read excluded 27 patients who no longer met histologic entry criteria. Fibrosis improvement of at least one stage without worsening of NASH occurred in 7% on placebo versus 22% on 15 mg (difference 14 points, 95% CI −9 to 38), 26% on 30 mg (difference 19 points, 95% CI 5 to 32; p=0.009) and 27% on 44 mg (difference 20 points, 95% CI 5 to 35; p=0.008). NASH resolution without worsening of fibrosis occurred in 2% on placebo versus 37%, 23% and 26% in the three active arms. Nausea, diarrhea and injection-site erythema were the most frequent adverse events, grade 3 events ran 4 to 10% across pegozafermin arms against 9% on placebo, the one serious adverse event judged drug-related was uncomplicated acute pancreatitis in a patient with gallbladder sludge after a single 44 mg dose, and drug-related discontinuations ran 2 to 6% across active arms with none on placebo (Loomba et al., New England Journal of Medicine, 2023;389(11):998–1008). In the blinded 24-week extension, 89bio reported on November 27, 2023 that liver fat at week 48 had fallen 60% on 30 mg weekly and 47% on 44 mg every 2 weeks versus 11% on placebo in F2 to F3 patients, that the most common adverse events were grade 1 or 2 gastrointestinal events, and that bone mineral density, bone biomarkers and blood pressure showed no clinically meaningful change relative to placebo. A secondary analysis of 163 ENLIVEN participants showed that a 50% or greater decline in MRI-PDFF, reached by 57.8% of treated versus 11.1% of placebo patients, independently predicted fibrosis regression (Loomba et al., Clinical Gastroenterology and Hepatology, 2026;24(10):2707–2714). A network meta-analysis of nine FGF21-analog trials found pegozafermin and efruxifermin to be the only analogs with significant effects on fibrosis, with more gastrointestinal adverse events (Abdeljawad et al., Journal of Pharmacology and Experimental Therapeutics, 2026;393(1):103786).

Regulatory designations. The FDA granted Breakthrough Therapy Designation for NASH with fibrosis on September 21, 2023, and the European Medicines Agency granted PRIME status for MASH with fibrosis and compensated cirrhosis on March 27, 2024, both on the strength of ENLIVEN. Drugs@FDA lists no pegozafermin application, DailyMed carries no label, and no approval exists in any jurisdiction as of November 2026.

ENTRUST phase 3 in severe hypertriglyceridemia (NCT05852431). A global, double-blind trial at 177 sites randomized 369 adults with fasting triglycerides of 500 to 2,000 mg/dL to pegozafermin 30 mg, 20 mg or placebo weekly for 52 weeks, with the primary endpoint of % change in fasting triglycerides at week 26. The trial began on June 15, 2023, reached primary completion on July 7, 2025 and study completion on April 9, 2026, and is listed as completed with no results posted and no peer-reviewed publication as of November 2026.

ENLIGHTEN-Fibrosis phase 3 (NCT06318169). A placebo-controlled trial of pegozafermin in an estimated 1,350 adults with biopsy-confirmed MASH and F2 or F3 fibrosis at 370 sites, started on March 13, 2024 and recruiting as of its October 23, 2026 update. The primary endpoints are the two ENLIVEN histologic endpoints at week 52 plus time to first disease-progression event over up to five years; primary completion is estimated for February 2029.

ENLIGHTEN-Cirrhosis phase 3 (NCT06419374). A placebo-controlled trial in an estimated 1,800 adults with compensated cirrhosis due to MASH at 330 sites, started on May 24, 2024 and recruiting as of its October 23, 2026 update. The primary endpoints are fibrosis regression at the month 24 biopsy and time to a composite of clinical events over up to five years; primary completion is estimated for June 30, 2028 and study completion for August 31, 2031.

Common dosage forms

• Investigational subcutaneous injection. Pegozafermin is supplied only to clinical-trial sites as a solution for subcutaneous injection; a liquid formulation was also characterized in a single-dose study (NCT05022693).
• No approved product. No marketed, compounded or oral presentation exists anywhere.

Key considerations

• Regulatory status. The Investigational status reflects the active registered phase 3 program and the FDA Breakthrough Therapy Designation granted on September 21, 2023 for NASH with fibrosis. No pegozafermin application is on record at Drugs@FDA and no approval exists anywhere as of November 2026; ENLIGHTEN-Fibrosis and ENLIGHTEN-Cirrhosis are recruiting under Hoffmann-La Roche sponsorship, and ENTRUST has completed without published results.
• A protein therapeutic, not a peptide. Pegozafermin is a glycoPEGylated recombinant FGF21 analog injected under the skin. It is not a synthetic peptide and has no research-market form.
• Fibrosis evidence is phase 2 and biopsy-based. The case rests on ENLIVEN, where 26 to 27% of patients on 30 mg weekly or 44 mg every 2 weeks improved fibrosis by one stage at 24 weeks against 7% on placebo. Whether that translates into fewer liver-related clinical events awaits the five-year ENLIGHTEN endpoints, and no peer-reviewed histology exists yet in compensated cirrhosis.
• Tolerability and immunogenicity. Nausea, diarrhea and injection-site reactions are the characteristic adverse events, and one drug-attributed case of acute pancreatitis occurred in ENLIVEN. Anti-drug antibodies developed in 65% of treated participants in the phase 1b/2a study, and bone density and blood pressure, monitored because of class-level concerns, showed no clinically meaningful change in 48-week sponsor-reported data, with longer follow-up still pending.
• Naming and class. BIO89-100 and pegozafermin are the same molecule. Efruxifermin, efimosfermin and pegbelfermin are distinct FGF21 analogs from other developers, not aliases, and results from one cannot be assumed to apply to another.