Pegozafermin is an investigational drug designed to treat two metabolic conditions that currently have few effective pharmaceutical options: metabolic dysfunction-associated steatohepatitis (commonly called MASH, formerly NASH) and severe hypertriglyceridemia. It is a modified version of a naturally occurring hormone called fibroblast growth factor 21, engineered to last much longer in the body than the natural hormone does. Phase 2 trials have shown encouraging results on both liver scarring and dangerously elevated triglyceride levels, though the drug has not yet been approved and is still being tested in larger phase 3 studies.
How Pegozafermin Works
Your body naturally produces a hormone called FGF21 that helps regulate fat metabolism, blood sugar, and energy balance. The problem with using the natural hormone as a drug is that it breaks down in the bloodstream within hours, making it impractical as a treatment. Pegozafermin gets around this limitation through a chemical modification called glycoPEGylation, which essentially attaches sugar and polymer chains to the hormone molecule. This modification extends the drug’s half-life to roughly 55 to 100 hours, long enough to allow weekly or every-two-week injections instead of requiring daily dosing.1PubMed Central. Pegozafermin Is a Potential Master Therapeutic Regulator in Metabolic Disorders: A Review
The drug works by binding to the same receptors as natural FGF21, specifically fibroblast growth factor receptors and a co-receptor called β-klotho, which are found in both liver and fat tissue.2JCI Insight. Therapeutic horizons in metabolic dysfunction–associated steatohepatitis In laboratory cell-based testing, pegozafermin showed a receptor engagement profile similar to the natural hormone but with roughly eight times greater potency at one key receptor subtype (FGFR1c).3Journal of Pharmacology and Experimental Therapeutics. The Novel GlycoPEGylated FGF21 Analog Pegozafermin Activates Human FGF Receptors and Improves Metabolic and Liver Outcomes in Diabetic Monkeys and Healthy Human Volunteers Once the drug activates these receptors, the downstream effects include reduced liver fat accumulation, improved insulin sensitivity, and lower circulating triglycerides.
Results in Fatty Liver Disease
MASH is a progressive form of fatty liver disease in which excess fat triggers inflammation and eventually scarring (fibrosis) of the liver. It can advance to cirrhosis and liver failure. Until recently, there were no approved disease-modifying drugs for this condition, and treatment relied almost entirely on lifestyle changes like weight loss and exercise.4The Lancet Gastroenterology & Hepatology. A, B, and C safety, pharmacokinetics, and pharmacodynamics of pegozafermin, a glycoPEGylated FGF21 analogue, in participants with non-alcoholic steatohepatitis
Pegozafermin has been tested in two main liver-focused trials. In an earlier phase 1b/2a dose-finding study, 13 weeks of treatment significantly reduced liver fat content compared to placebo across all doses tested. The largest absolute reduction was seen at the 27 mg weekly dose, where liver fat dropped by about 15 percentage points more than it did with placebo. The drug also lowered ALT, a blood marker of liver cell damage, at several dose levels.4The Lancet Gastroenterology & Hepatology. A, B, and C safety, pharmacokinetics, and pharmacodynamics of pegozafermin, a glycoPEGylated FGF21 analogue, in participants with non-alcoholic steatohepatitis
The larger and more important trial was the phase 2b ENLIVEN study, which enrolled 222 patients with confirmed MASH and significant fibrosis (stage F2 or F3). Participants were randomized to different doses of pegozafermin or placebo, given as subcutaneous injections weekly or every two weeks, for 24 weeks. The two co-primary endpoints were fibrosis improvement (at least one stage of scar reduction without worsening of the underlying liver inflammation) and MASH resolution (clearance of the inflammatory disease without worsening of fibrosis).2JCI Insight. Therapeutic horizons in metabolic dysfunction–associated steatohepatitis
The results were striking. Fibrosis improved in about a quarter of patients on pegozafermin (ranging from 22% to 27% across dose groups), compared to just 7% of those on placebo. That three-to-four-fold difference was statistically significant for the 30 mg weekly and 44 mg every-two-week doses. MASH resolution told an even more dramatic story: between 23% and 37% of pegozafermin-treated patients met the criteria for disease resolution, compared to only 2% on placebo.5PubMed Central. Randomized, Controlled Trial of the FGF21 Analogue Pegozafermin in NASH For context, a 2% placebo rate in MASH resolution is typical of these trials, so seeing rates above 20% in treated groups represents a meaningful pharmacological effect.
Results in Severe Hypertriglyceridemia
Severe hypertriglyceridemia, defined as fasting triglyceride levels above 500 mg/dL, carries a real risk of acute pancreatitis and cardiovascular events. Existing treatments like fibrates and omega-3 fatty acids help but often fail to bring levels under control. Pegozafermin’s second major clinical target is this population.
The phase 2 ENTRIGUE trial tested four pegozafermin doses against placebo in patients with triglycerides between 500 and 2,000 mg/dL. After eight weeks of treatment, pooled pegozafermin data showed a placebo-corrected median triglyceride reduction of about 44%. Across individual dose groups, the placebo-corrected drops ranged from roughly 29% to 53%.6Nature Medicine. The FGF21 analog pegozafermin in severe hypertriglyceridemia: a randomized phase 2 trial
Those percentage changes translated to clinically meaningful thresholds. Eighty percent of all pegozafermin-treated patients dropped below 500 mg/dL, the level at which pancreatitis risk begins to climb sharply. At the highest dose tested (27 mg), three-quarters of patients achieved at least a 50% reduction in triglycerides, and about a third brought their levels all the way down to normal (below 150 mg/dL). The 27 mg dose also improved several other lipid markers, reducing non-HDL cholesterol and apolipoprotein B while raising HDL cholesterol and adiponectin. LDL cholesterol did not change significantly.7Journal of Clinical Lipidology. Pegozafermin for the Treatment of Severe Hypertriglyceridemia, a Randomized, Double-blind, Placebo-controlled Phase 2 Trial (ENTRIGUE STUDY)
Side Effects and Safety Profile
Across the trials conducted so far, pegozafermin has been generally well tolerated.4The Lancet Gastroenterology & Hepatology. A, B, and C safety, pharmacokinetics, and pharmacodynamics of pegozafermin, a glycoPEGylated FGF21 analogue, in participants with non-alcoholic steatohepatitis The most common side effects are gastrointestinal, particularly nausea and diarrhea, which tend to be mild to moderate in severity. A network meta-analysis comparing FGF21 analogs confirmed that while the odds of adverse events were higher with pegozafermin than with placebo, the excess was driven largely by these GI complaints rather than by serious or life-threatening problems.8The Journal of Pharmacology and Experimental Therapeutics. Efficacy and safety of fibroblast growth factor 21 analogs in metabolic dysfunction–associated steatotic liver disease and metabolic dysfunction–associated steatohepatitis: A systematic review and network meta-analysis
One concern with drugs that target metabolic hormones is unintended effects on bone health, cardiovascular parameters, or body composition. Data from the 48-week extension of the ENLIVEN trial found no clinically meaningful or statistically significant changes in bone mineral density, bone biomarkers, blood pressure, or heart rate compared to placebo. The same meta-analysis noted that pegozafermin did not produce significant changes in body weight, which may disappoint patients hoping for weight loss as a secondary benefit but is worth knowing for expectation-setting.
Injection-site reactions are another expected side effect of any subcutaneous therapy. In pegozafermin trials, these have generally been mild. Because all trial data so far comes from studies lasting at most a year, long-term safety information is still limited, and phase 3 trials are collecting more extensive data on this front.
How Pegozafermin Compares to Other Treatments
Pegozafermin is not the only new therapy being tested for MASH. Two broad categories of competing drugs have generated the most attention: other FGF21 analogs (such as efruxifermin) and drugs from entirely different classes, including the thyroid hormone receptor agonist resmetirom (the first drug actually approved for MASH in the United States) and GLP-1 receptor agonists, which are better known as the drugs behind semaglutide and tirzepatide.
A network meta-analysis comparing these classes found that FGF21 analogs as a group had the highest probability of being the most effective treatment for both MASH resolution and fibrosis improvement. Ranking scores placed FGF21 analogs ahead of resmetirom, which in turn ranked ahead of GLP-1 agonists, for both of those liver-specific endpoints.9PubMed Central. Comparative Analysis of Resmetirom vs. FGF21 Analogs vs. GLP-1 Agonists in MASLD and MASH: Network Meta-Analysis of Clinical Trials However, resmetirom scored highest for reducing liver fat content specifically, so the “best” drug depends on which outcome you prioritize.
Within the FGF21 analog class, a separate systematic review found that both pegozafermin and efruxifermin significantly improved liver fibrosis, while other FGF21-based drugs in development did not reach statistical significance on that endpoint. The two drugs had somewhat different profiles on liver enzyme improvements: efruxifermin was more effective at reducing one enzyme marker (GGT), while a third analog called efimosfermin α showed the largest reductions in ALT and AST.8The Journal of Pharmacology and Experimental Therapeutics. Efficacy and safety of fibroblast growth factor 21 analogs in metabolic dysfunction–associated steatotic liver disease and metabolic dysfunction–associated steatohepatitis: A systematic review and network meta-analysis
These comparisons come with a caveat: no head-to-head trial has directly pitted pegozafermin against efruxifermin or resmetirom. Network meta-analyses estimate relative effects by comparing each drug against shared placebo groups, which is useful but less reliable than a direct contest. The true competitive picture will become clearer as phase 3 data emerge for multiple drugs simultaneously.
Dosing and How It Is Given
Pegozafermin is administered as a subcutaneous injection, similar to insulin or the GLP-1 drugs many patients are already familiar with. The trials have tested both weekly and every-two-week dosing schedules, and pharmacokinetic modeling has shown that liver fat reduction correlates with average drug concentrations in the blood regardless of which schedule is used.10PubMed. Population Pharmacokinetics and Pharmacodynamics of Pegozafermin in Patients with Nonalcoholic Steatohepatitis In practical terms, this means the every-two-week option, which uses a higher per-injection dose, can produce similar results to weekly injections at a lower per-injection dose.
In the ENLIVEN trial for MASH, the tested regimens were 15 mg weekly, 30 mg weekly, and 44 mg every two weeks. The 30 mg weekly and 44 mg every-two-week groups performed similarly on both fibrosis and MASH resolution endpoints, supporting the idea that patients and physicians could choose based on convenience and tolerability.5PubMed Central. Randomized, Controlled Trial of the FGF21 Analogue Pegozafermin in NASH For severe hypertriglyceridemia, the ENTRIGUE trial tested weekly doses ranging from 9 mg to 27 mg, with the 27 mg dose showing the strongest triglyceride reductions.
The drug’s extended half-life is what makes less frequent dosing feasible. With a half-life in the range of 55 to 100 hours, drug levels stay therapeutic between injections even on a biweekly schedule.1PubMed Central. Pegozafermin Is a Potential Master Therapeutic Regulator in Metabolic Disorders: A Review Final dosing for commercial use has not been determined and will depend on the outcomes of the ongoing phase 3 programs.
Phase 3 Trials and the Road to Approval
Pegozafermin is currently in phase 3 testing for both of its target conditions. For severe hypertriglyceridemia, the ENTRUST trial is enrolling roughly 360 patients globally. Participants have baseline triglycerides between 500 and 2,000 mg/dL and are receiving standard lipid-lowering therapy in the background. They are randomized to weekly injections of 30 mg, 20 mg, or placebo over 52 weeks, with the primary endpoint being the percent change in fasting triglycerides at 26 weeks.11Journal of Clinical Lipidology. Study Design of a Phase 3 Randomized Controlled Trial Evaluating the Efficacy and Safety of Pegozafermin in Patients with Severe Hypertriglyceridemia The extended 52-week treatment period will also provide important safety and durability data that the shorter phase 2 trial could not.
For MASH, the company has launched phase 3 trials as well, following the strong phase 2b results. One question that early data is already helping to answer is whether pegozafermin works in patients who are simultaneously taking GLP-1 receptor agonists, since those drugs are increasingly prescribed for obesity and diabetes in the same patient population. Long-term data from the ENLIVEN extension showed that pegozafermin’s benefits were consistent in patients receiving background GLP-1 therapy, suggesting the two drug classes can be used together.12Gut. P5 Pegozafermin treatment demonstrates long-term benefit in subjects with metabolic dysfunction-associated steatohepatitis and fibrosis: results from the Phase 2b ENLIVEN clinical trial
Regulatory approval, if it comes, is probably several years away. Phase 3 trials for liver disease typically require large patient numbers, longer treatment durations (often 72 weeks or more for histological endpoints), and convincing evidence of clinical benefit. The competitive landscape is also evolving rapidly: resmetirom has already been approved with conditions, and efruxifermin is in its own phase 3 program. For patients, this growing pipeline is good news regardless of which specific drug ultimately proves best, because it signals that an era of effective pharmacotherapy for fatty liver disease is arriving.
Patient-Reported Outcomes and Quality of Life
One underexplored aspect of MASH drug development is how patients actually feel during treatment. A review of over 300 registered clinical trial protocols for MASH found that only about 5% included patient-reported outcomes as a measured endpoint.13Cell Metabolism. New and emerging treatments for metabolic dysfunction-associated steatohepatitis This is a meaningful gap because FDA approval is partly contingent on demonstrating that a drug improves how a patient feels, functions, or survives. Liver biopsy results showing less fibrosis matter, but they are invisible to the patient living with the disease day to day.
MASH itself causes symptoms that are easy to overlook in clinical trials focused on biopsies and blood tests. Fatigue, abdominal discomfort, and reduced physical capacity are common complaints, and the psychological burden of a progressive liver diagnosis compounds them. Two measurement tools, known as CLDQ-NASH and NASH-CHECK, have been developed specifically to capture these quality-of-life dimensions in MASH patients. Whether pegozafermin’s phase 3 trials will incorporate these instruments comprehensively remains to be seen, but the broader field is under increasing pressure to take these outcomes seriously. For patients weighing whether to enroll in a trial or eventually use a newly approved drug, knowing whether it makes you feel better and not just whether it improves a biopsy score is a practical question the current data cannot fully answer.