Pegozafermin: FGF21 Pathways and Metabolic Effects

Pegozafermin is an experimental drug designed to mimic fibroblast growth factor 21 (FGF21), a hormone involved in regulating metabolism. As metabolic disorders like nonalcoholic steatohepatitis (NASH) and diabetes become more prevalent, interest in FGF21-based therapies has grown due to their potential benefits in improving lipid and glucose balance.

FGF21 Analogs In The Body

Fibroblast growth factor 21 (FGF21) is an endocrine hormone that influences lipid metabolism, glucose regulation, and thermogenesis. Synthetic FGF21 analogs like pegozafermin have been developed to enhance these effects while improving stability and bioavailability. Unlike native FGF21, which has a short half-life due to rapid degradation, engineered analogs extend circulation time and enhance receptor binding efficiency, ensuring sustained metabolic effects.

Pegozafermin exerts its effects by binding to FGF receptors (FGFRs) in conjunction with the co-receptor β-Klotho, which is primarily expressed in metabolic tissues such as the liver, adipose tissue, and pancreas. This targeted interaction enhances insulin sensitivity, reduces hepatic fat accumulation, and promotes lipid oxidation. Clinical trials have shown that pegozafermin significantly reduces liver fat content and improves markers of systemic inflammation, reinforcing its potential as a treatment for NASH.

A key challenge in developing FGF21 analogs is maintaining structural integrity while optimizing pharmacokinetics. Native FGF21 is susceptible to proteolytic cleavage, limiting its therapeutic utility. To address this, pegozafermin has been engineered with amino acid substitutions that enhance stability and resistance to enzymatic degradation. Additional modifications, such as pegylation, prolong half-life and reduce dosing frequency, improving drug efficacy and making long-term treatment more feasible for chronic metabolic conditions.

Unique Structural Aspects

Pegozafermin has been engineered for enhanced stability, bioavailability, and receptor-binding properties. Endogenous FGF21 degrades quickly due to proteolytic cleavage, limiting its therapeutic potential. Pegozafermin incorporates amino acid substitutions that improve resistance to enzymatic degradation, particularly by dipeptidyl peptidase-4 (DPP-4), ensuring prolonged metabolic effects with less frequent dosing.

Pegylation further extends pegozafermin’s half-life by attaching polyethylene glycol (PEG) chains, reducing renal clearance and shielding it from immune recognition. This modification allows for weekly or biweekly administration, easing the burden of frequent injections.

Another critical structural feature is its optimized binding affinity for FGFRs in conjunction with β-Klotho. While native FGF21 binds FGFR1c, FGFR2c, and FGFR3c with moderate affinity, pegozafermin enhances receptor engagement, ensuring efficient activation of metabolic pathways. This targeted interaction increases potency at lower doses, reinforcing its therapeutic potential for NASH and insulin resistance.

Mechanistic Pathways

Pegozafermin activates FGFRs in the presence of β-Klotho, restricting signaling to metabolic tissues. Binding to FGFR1c in adipose tissue triggers intracellular events that enhance insulin sensitivity and promote lipid oxidation. This includes phosphorylation of extracellular signal-regulated kinases (ERK1/2), which modulate transcription factors involved in metabolic regulation. As a result, circulating glucose and fatty acids are more efficiently stored or utilized, reducing systemic lipid accumulation.

In the liver, FGFR1c activation suppresses de novo lipogenesis by downregulating sterol regulatory element-binding protein 1c (SREBP-1c), a key factor in fatty acid synthesis. This reduces triglyceride accumulation, particularly relevant for NASH. Additionally, pegozafermin enhances fatty acid oxidation via peroxisome proliferator-activated receptor alpha (PPARα), promoting lipid breakdown and improving lipid profiles.

Pegozafermin also influences glucose homeostasis by suppressing hepatic gluconeogenesis. It downregulates phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase), lowering fasting blood glucose levels. Simultaneously, it enhances glycogen synthesis, facilitating glucose storage rather than excessive release into circulation. These combined effects improve glycemic control and reduce pancreatic beta-cell stress.

Metabolic Processes Involving Lipids

Pegozafermin modulates lipid metabolism by regulating synthesis, breakdown, and transport, addressing dyslipidemia common in metabolic disorders. It reduces hepatic triglyceride accumulation by downregulating SREBP-1c, limiting the conversion of carbohydrates into fatty acids and preventing hepatic steatosis.

In addition to reducing lipid production, pegozafermin enhances fatty acid oxidation by activating PPARα, promoting lipid breakdown and reducing circulating triglycerides. It also increases lipoprotein lipase (LPL) expression, facilitating triglyceride clearance from the bloodstream and improving overall lipid profiles.

Metabolic Processes Involving Glucose

Pegozafermin enhances insulin sensitivity and glucose uptake, particularly in adipose tissue and skeletal muscle. By activating FGFR1c, it increases glucose transporter type 1 (GLUT1) expression, facilitating cellular glucose absorption and reducing hyperglycemia.

In the liver, pegozafermin inhibits gluconeogenesis by suppressing PEPCK and G6Pase, reducing endogenous glucose production. It also promotes glycogen synthesis, enhancing glucose storage and improving glycemic control. These effects reduce pancreatic beta-cell stress and support long-term metabolic stability.

Tissue-Level Interactions

Pegozafermin’s effects extend beyond isolated pathways, creating a coordinated systemic response. In adipose tissue, FGFR1c activation enhances lipolysis and thermogenesis, increasing lipid mobilization for energy production. This shift, partly mediated by uncoupling protein 1 (UCP1) in brown adipose tissue, promotes energy expenditure and reduces fat accumulation.

In the pancreas, pegozafermin supports beta-cell function by lowering circulating glucose and lipid levels, reducing glucotoxicity and lipotoxicity. This preserves insulin secretion and may directly enhance pancreatic cell survival, benefiting individuals with impaired insulin production.