Pegozafermin: A Literature Course

This course summarises the published literature on pegozafermin, an investigational analogue of fibroblast growth factor 21 (FGF21). Each module describes what researchers designed, measured and reported, and each module closes with the limits of that evidence. This page is for educational purposes only and is not medical advice; consult a licensed physician about any health decision or medical question. Nothing here describes how any compound should be used.

Module 1: What Pegozafermin Is and How It Has Been Studied

Pegozafermin has been characterised in the literature as a glycoPEGylated analogue of human FGF21, engineered so that a polyethylene glycol chain is attached at a glycosylation site, and a 2023 pharmacology paper reported that this molecule activated human FGF receptors and improved metabolic and liver measures in diabetic monkeys and produced pharmacodynamic changes in healthy human volunteers (PMID 37562970). A narrative review published in Cardiology in Review placed pegozafermin within the broader class of FGF21-based candidates being investigated across metabolic disorders and summarised the trial programme reported to that point (PMID 37889055).

The published human studies have all used subcutaneous administration. A randomised, double-blind, placebo-controlled phase 1b/2a multiple-ascending-dose study evaluated safety, pharmacokinetics and pharmacodynamics in patients with non-alcoholic steatohepatitis using weekly and every-two-week subcutaneous regimens (PMID 36521501). A separate analysis of that programme reported effects on the liver and on metabolic comorbidities in participants with biopsy-confirmed non-alcoholic steatohepatitis (PMID 37718721). Two mid-stage randomised trials followed: a phase 2b trial in NASH with fibrosis published in the New England Journal of Medicine (PMID 37356033) and a phase 2 trial in severe hypertriglyceridemia published in Nature Medicine (PMID 37355760).

Limits of the evidence in Module 1

The literature describes pegozafermin only as an investigational agent studied in controlled trials and preclinical models. Descriptions of the molecule's structure and class come from a small number of publications, and no paper in this set describes marketed formulations, long-term human use, or use outside of a clinical-trial or laboratory setting.

Module 2: Mechanism as Described in the Literature

FGF21 is described in this literature as an endocrine hormone acting on receptor complexes that require the co-receptor β-klotho. The 2023 pharmacology paper reported that pegozafermin activated human FGF receptors and, in diabetic monkeys, was associated with improvements in metabolic and liver outcomes, while in healthy human volunteers the study reported pharmacodynamic changes consistent with FGF21-pathway engagement (PMID 37562970). The stated rationale for glycoPEGylation in that paper was to extend exposure relative to native FGF21, which has a short circulating half-life (PMID 37562970).

The Cardiology in Review analysis framed the FGF21 pathway as acting across several tissues — liver, adipose tissue and central regulatory sites — and discussed pegozafermin as a candidate studied for simultaneous effects on hepatic fat, fibrosis biomarkers and circulating lipids in metabolic disease (PMID 37889055). Consistent with that framing, the phase 1b/2a study measured pharmacodynamic markers alongside safety and pharmacokinetics in patients with non-alcoholic steatohepatitis (PMID 36521501), and the biopsy-confirmed NASH analysis reported changes in both hepatic and metabolic comorbidity measures within the same programme (PMID 37718721).

Limits of the evidence in Module 2

Receptor activation demonstrated in cell systems and effects reported in monkeys do not establish which mechanisms drive any given human endpoint. Mechanistic statements in reviews are interpretive summaries rather than experimental results, and no paper in this verified set traced a complete causal chain from receptor binding to histological change in humans.

Module 3: Reported Outcomes by Study

Phase 1b/2a multiple-ascending-dose study in NASH

The randomised, double-blind, placebo-controlled phase 1b/2a multiple-ascending-dose study in patients with non-alcoholic steatohepatitis was designed with safety as its focus and also assessed pharmacokinetics and pharmacodynamic markers across subcutaneous weekly and every-two-week regimens (PMID 36521501). A companion clinical-trial report described effects on the liver and on metabolic comorbidities in subjects with biopsy-confirmed non-alcoholic steatohepatitis enrolled in that programme (PMID 37718721).

Phase 2b trial in NASH with fibrosis (ENLIVEN)

The phase 2b randomised, controlled trial reported in the New England Journal of Medicine assigned patients with biopsy-confirmed NASH and fibrosis to subcutaneous pegozafermin 15 mg weekly, 30 mg weekly, 44 mg every two weeks, or placebo for 24 weeks (PMID 37356033). The study's histological endpoints were improvement in fibrosis of at least one stage without worsening of steatohepatitis and resolution of steatohepatitis without worsening of fibrosis, and researchers reported that higher proportions of patients in pegozafermin weekly groups met the fibrosis-improvement endpoint than in the placebo group at 24 weeks (PMID 37356033).

Phase 2 trial in severe hypertriglyceridemia (ENTRIGUE)

The phase 2 trial in severe hypertriglyceridemia randomised participants to subcutaneous pegozafermin at several dose levels given weekly or every two weeks, or placebo, over eight weeks, with percent change in fasting triglycerides as the primary endpoint (PMID 37355760). Researchers reported greater reductions in triglycerides with pegozafermin than with placebo at week 8, along with changes in other lipid and metabolic parameters assessed as secondary measures (PMID 37355760).

Preclinical and healthy-volunteer work

The pharmacology paper reported metabolic and liver improvements in diabetic monkeys and pharmacodynamic effects in healthy human volunteers after administration of the glycoPEGylated FGF21 analogue (PMID 37562970).

Limits of the evidence in Module 3

The human trials described here were phase 1b/2a and phase 2 in size and duration — eight weeks in severe hypertriglyceridemia (PMID 37355760) and 24 weeks in the phase 2b NASH trial (PMID 37356033). Surrogate and histological endpoints measured over months are not the same as clinical outcomes such as progression to cirrhosis, hospitalisation, cardiovascular events or survival, none of which these studies were designed to measure. Results in monkeys do not transfer directly to humans, and findings in selected trial populations may not generalise to other groups.

Module 4: Pegozafermin Side Effects: What Studies Report

Adverse events in this literature are reported as trial safety data, not as a complete profile. In the phase 2b NASH trial, researchers reported that the most frequent adverse events were gastrointestinal, with nausea and diarrhoea described among the commonly reported events across pegozafermin groups over 24 weeks (PMID 37356033). In the phase 2 severe hypertriglyceridemia trial, the study reported that adverse events were predominantly mild or moderate in severity, with gastrointestinal events such as nausea and diarrhoea among the most frequently reported (PMID 37355760).

The phase 1b/2a multiple-ascending-dose study was designed primarily to characterise safety in patients with non-alcoholic steatohepatitis and reported adverse events across the tested subcutaneous regimens, including events related to the injection site and gastrointestinal symptoms (PMID 36521501). The clinical-trial report from that same programme in biopsy-confirmed non-alcoholic steatohepatitis also described tolerability alongside its liver and metabolic findings (PMID 37718721). The narrative review summarised the safety observations reported across these trials as generally mild-to-moderate events concentrated in gastrointestinal and injection-site categories (PMID 37889055).

• Gastrointestinal events — nausea and diarrhoea were among the most frequently reported adverse events in the phase 2b NASH trial (PMID 37356033) and in the phase 2 hypertriglyceridemia trial (PMID 37355760).
• Injection-site events — reported among adverse events in the placebo-controlled phase 1b/2a study of subcutaneous dosing (PMID 36521501).
• Severity grading — the phase 2 trial in severe hypertriglyceridemia reported that most adverse events were mild to moderate (PMID 37355760).

Limits of the evidence in Module 4

Safety data from trials of this size and length cannot detect rare events, delayed events, or effects emerging after years of exposure. Trial participants were screened and monitored, so event rates reported in these papers may not reflect what occurs in unmonitored settings. Immunogenicity, drug–drug interactions and effects in populations excluded from enrolment are not resolved by the publications above.

Module 5: Pharmacokinetics Where Data Exist

Pharmacokinetic data for pegozafermin come from a small number of publications. The phase 1b/2a multiple-ascending-dose study in patients with non-alcoholic steatohepatitis assessed pharmacokinetics alongside safety and pharmacodynamics for subcutaneous weekly and every-two-week regimens (PMID 36521501). A dedicated population pharmacokinetic and pharmacodynamic analysis in patients with non-alcoholic steatohepatitis developed a model describing pegozafermin exposure and its relationship to pharmacodynamic measures, supporting the weekly and every-two-week schedules evaluated in the clinical programme (PMID 37696614).

The pharmacology paper reported that glycoPEGylation was associated with extended exposure relative to native FGF21 and described pharmacokinetic and pharmacodynamic observations in healthy human volunteers (PMID 37562970). The narrative review summarised these exposure characteristics as the basis for the infrequent subcutaneous dosing intervals used in the trials (PMID 37889055).

Limits of the evidence in Module 5

Population models are descriptions fitted to trial data and depend on the sampling schedule, the doses studied and the characteristics of enrolled participants (PMID 37696614). These analyses do not describe exposure in children, in pregnancy, in advanced organ impairment beyond the enrolled range, or with co-administered medications not represented in the trials.

Module 6: Regulatory Status, Stated Factually

Across the publications in this course, pegozafermin is described as an investigational agent evaluated in randomised clinical trials rather than as an approved medicine: the phase 1b/2a study, the phase 2 trial in severe hypertriglyceridemia and the phase 2b NASH trial were all conducted as controlled clinical investigations (PMID 36521501, PMID 37355760, PMID 37356033). The 2025 review likewise discussed pegozafermin as a candidate under development in metabolic disorders rather than as a marketed product (PMID 37889055).

Some general regulatory facts apply to any investigational biologic in this situation. Investigational agents are supplied for use in authorised clinical trials under regulatory oversight, and material sold with a research-use-only label is designated for laboratory research and is not intended for human administration. Pharmacy compounding in the United States is governed by specific statutory pathways and applicable substance lists, and investigational biologics are not automatically eligible for compounding simply because they appear in published research. Regulatory status also differs between jurisdictions and can change over time, so the facts summarised here reflect how these papers described the agent at publication. This section is general information and is not legal advice.

Limits of the evidence in Module 6

The verified papers in this course report trial results; they are not regulatory documents and do not state approval decisions, labelling text or prescribing conditions. Anyone seeking current status information would need to consult the relevant regulatory agency directly.

What the Studies Did Not Test

Reading these publications together, several gaps are explicit:

1. Long-term clinical outcomes. The phase 2b NASH trial measured histological endpoints at 24 weeks, not progression to cirrhosis, liver-related events or mortality (PMID 37356033).
2. Cardiovascular event reduction. The severe hypertriglyceridemia trial measured lipid changes over eight weeks and was not designed to test whether those changes altered clinical events (PMID 37355760).
3. Use in healthy people for non-disease purposes. Healthy volunteers appeared only in early pharmacology work focused on receptor activation and pharmacodynamics (PMID 37562970).
4. Special populations. Pregnancy, paediatric populations and many comorbid conditions were outside the enrolled populations described in the phase 1b/2a and phase 2 reports (PMID 36521501, PMID 37718721).
5. Head-to-head comparisons. These trials compared pegozafermin with placebo, not with other metabolic or hepatology agents (PMID 37356033).
6. Alternative routes and unstudied regimens. Published human data describe subcutaneous administration on the schedules modelled in the population pharmacokinetic analysis (PMID 37696614).

This course summarises published findings only. It does not recommend, endorse or describe use of any compound, and questions about individual health should go to a licensed physician.

References

• Randomized, Controlled Trial of the FGF21 Analogue Pegozafermin in NASH (The New England Journal of Medicine, 2023)
• The FGF21 analog pegozafermin in severe hypertriglyceridemia: a randomized phase 2 trial (Nature Medicine, 2023)
• Safety, pharmacokinetics, and pharmacodynamics of pegozafermin in patients with non-alcoholic steatohepatitis: a randomised, double-blind, placebo-controlled, phase 1b/2a multiple-ascending-dose study (The Lancet Gastroenterology & Hepatology, 2023)
• Pegozafermin Is a Potential Master Therapeutic Regulator in Metabolic Disorders: A Review (Cardiology in Review, 2025)
• Clinical trial: Effects of pegozafermin on the liver and on metabolic comorbidities in subjects with biopsy-confirmed nonalcoholic steatohepatitis (Alimentary Pharmacology & Therapeutics, 2023)
• Population Pharmacokinetics and Pharmacodynamics of Pegozafermin in Patients with Nonalcoholic Steatohepatitis (Clinical Pharmacology and Therapeutics, 2023)
• The Novel GlycoPEGylated FGF21 Analog Pegozafermin Activates Human FGF Receptors and Improves Metabolic and Liver Outcomes in Diabetic Monkeys and Healthy Human Volunteers (The Journal of Pharmacology and Experimental Therapeutics, 2023)