Pegozafermin is a novel therapeutic agent developed by 89bio. This medication addresses underlying metabolic dysfunctions that contribute to specific metabolic and liver diseases.
How Pegozafermin Works
Pegozafermin is a specialized version of fibroblast growth factor 21 (FGF21), a naturally occurring hormone. FGF21 plays a significant role in regulating the body’s energy expenditure, glucose levels, and lipid metabolism. The natural hormone has a very short half-life, but pegozafermin is designed with glycopegylation technology to significantly extend its presence in the body, ranging from 55 to 100 hours.
This extended action allows pegozafermin to continuously activate the FGF21 receptor complex. Activating these receptors triggers intracellular signaling pathways that lead to beneficial metabolic effects. Pegozafermin enhances insulin sensitivity, promotes fat breakdown, and reduces inflammation. It also decreases new fat production in the liver and increases adiponectin levels, a hormone known for its anti-inflammatory and anti-fibrotic properties. Through these actions, pegozafermin aims to restore metabolic balance, reduce fat accumulation in the liver, and reduce inflammation and injury.
Conditions Pegozafermin Addresses
Pegozafermin is primarily under development for metabolic dysfunction-associated steatohepatitis (MASH), previously known as non-alcoholic steatohepatitis (NASH). MASH is a progressive liver disease characterized by fat accumulation, inflammation, and liver scarring, known as fibrosis. Pegozafermin’s mechanism directly targets the metabolic imbalances that drive MASH, including improved insulin sensitivity and lipid metabolism.
The medication is also being investigated for severe hypertriglyceridemia (SHTG), a condition marked by high levels of triglycerides in the blood. Its ability to reduce liver fat and improve lipid profiles makes it a potential option for managing this disorder. Beyond these primary targets, pegozafermin’s broad metabolic effects suggest potential benefits for other related conditions, such as insulin resistance and obesity.
Clinical Findings and Patient Experience
In the Phase 2b ENLIVEN trial for MASH, pegozafermin demonstrated improvements in liver fibrosis and resolution of MASH without worsening fibrosis. Fibrosis improvement (a reduction by at least one stage) was observed in 26% of patients receiving 30 mg weekly and 27% of those receiving 44 mg biweekly, compared to 7% in the placebo group. MASH resolution without worsening fibrosis occurred in 23% and 26% of the respective treatment groups, versus 2% with placebo. The trial also showed significant reductions in liver fat content, liver enzyme levels, and improvements in non-invasive markers of fibrosis. These benefits were sustained over 48 weeks in an extension study.
For severe hypertriglyceridemia, a Phase 2 trial showed significant reductions in triglycerides, with a 57.3% decrease for pooled pegozafermin doses compared to an 11.9% reduction for placebo. The drug also led to reductions in other harmful lipids and a significant decrease in liver fat.
Pegozafermin has been generally well-tolerated in studies. The most commonly reported side effects were mild to moderate gastrointestinal issues, such as nausea and diarrhea. While one instance of acute pancreatitis was considered possibly related, other trials reported no serious adverse events or discontinuations due to side effects. Some patients also experienced increased appetite, though this was not linked to weight gain in one study.
Development and Availability
Pegozafermin is currently in Phase 3 clinical trials, representing the final stage of testing before potential regulatory submission. The development program includes the ENLIGHTEN trials for MASH, with separate studies for patients with moderate to severe fibrosis (F2-F3) and those with compensated cirrhosis (F4). A Phase 3 trial, ENTRUST, is also underway for severe hypertriglyceridemia.
The U.S. Food and Drug Administration (FDA) has granted pegozafermin Breakthrough Therapy Designation, and the European Medicines Agency (EMA) has given it Priority Medicines (PRIME) status for MASH with fibrosis. These designations indicate that the drug addresses a serious condition and may offer substantial advantages over existing therapies, potentially accelerating its review and approval process. Regulatory filings in the U.S. and Europe are planned, aiming for accelerated or conditional approval. There are currently no FDA-approved pharmacological treatments for MASH, highlighting the significant unmet need pegozafermin aims to address.