Evaluation of Pegozafermin Efficacy and Safety in Severe Hypertriglyceridemia: A Phase 3 Randomized, Double-Blind, Placebo-Controlled Trial

The primary objective of this study is to determine the effect of **pegozafermin** on fasting serum triglyceride levels in subjects with Severe Hypertriglyceridemia after 26 weeks of treatment. This is clinically relevant as elevated triglyceride levels are associated with an increased risk of cardiovascular diseases and pancreatitis, and effective management can significantly reduce these risks.

Secondary objectives include:

• To determine the effect of pegozafermin on selected serum lipids, lipoproteins, measures of glycemic control, and liver steatosis after 26 weeks of treatment, and on serum triglycerides after 52 weeks of treatment.
• To evaluate the safety and tolerability of pegozafermin when used in subjects with Severe Hypertriglyceridemia.

The clinical trial investigating the effects of pegozafermin on fasting serum triglyceride levels in individuals with **Severe Hypertriglyceridemia** includes a total of 247 participants. The study population comprises both male and female subjects aged 22 years and older. Participants are required to maintain stable medication, dietary, and exercise habits throughout the study duration. All subjects are on a stable background of Lipid Modifying Therapy to manage atherosclerotic cardiovascular disease (ASCVD) for at least four weeks prior to the initial qualifying triglyceride measurement. The trial includes a vulnerable population, ensuring a comprehensive assessment of the treatment's efficacy across diverse demographic groups.

The clinical trial is a **Phase 3**, randomized, double-blind, placebo-controlled study designed to evaluate the efficacy and safety of **pegozafermin** in subjects with **severe hypertriglyceridemia**. The primary objective is to determine the effect of pegozafermin on fasting serum triglyceride levels after 26 weeks of treatment. The trial will include a total duration of 52 weeks, with the estimated end date set for April 6, 2026. Participants will be randomly assigned to receive either pegozafermin, administered as a solution for injection via subcutaneous use, or a placebo. Additionally, participants may continue their standard of care lipid-modifying therapy, such as **simvastatin**, which is administered orally as a film-coated tablet.

The study will commence with an inclusion (screening) visit, where eligibility criteria will be assessed. Key inclusion criteria include an age of 22 years or older, willingness to maintain stable medication, diet, and exercise habits, and being on stable lipid-modifying therapy for at least four weeks prior to the first qualifying triglyceride measurement. Following the screening, eligible participants will enter the treatment phase, which includes regular follow-up visits to monitor safety and efficacy outcomes. The primary endpoint is the percent change from baseline in fasting triglycerides at Week 26, with secondary endpoints including changes in various cholesterol levels and liver fat content.

Participants are expected to be involved in the study for the entire 52-week duration unless conditions arise that necessitate early termination. Such conditions may include adverse events, non-compliance with study protocols, or withdrawal of consent. The study will conclude with an end-of-study visit, where final assessments will be conducted to evaluate the long-term effects of the treatment. The trial is structured to ensure rigorous data collection and analysis, adhering to the highest standards of clinical research methodology.

The clinical trial involves the administration of **Pegozafermin**, an experimental medication formulated as a **solution for injection**. The active substance, BIO89-100, is a protein of other origin, developed by 89BIO INC. Pegozafermin is administered via **subcutaneous use** using a pre-filled syringe. The maximum daily dose is 30 mg, with a total maximum dose of 1560 mg over a treatment period of 52 weeks. The administration schedule is designed to ensure optimal efficacy and safety, with participant compliance monitored throughout the study.

A **placebo** is utilized in this study as a comparator to Pegozafermin. The placebo is administered using a combined integral administration device, specifically a pre-filled syringe, to maintain blinding and ensure consistency in the administration process. The placebo is designed to mimic the administration form of Pegozafermin, ensuring that any observed effects can be attributed to the active treatment.

Additionally, **Simvastatin**, a standard-of-care therapy, is included as an auxiliary treatment. Simvastatin is provided in the form of a **film-coated tablet** and is administered orally. The maximum daily dose is 10 mg, with a total maximum dose of 5180 mg over a treatment period of 74 weeks. Simvastatin serves as a lipid-modifying agent, and its use is consistent with standard treatment protocols for managing severe hypertriglyceridemia. Compliance with Simvastatin administration is monitored to ensure adherence to the study protocol.

The efficacy of the investigational product, **Pegozafermin**, will be assessed in a Phase 3, randomized, double-blind, placebo-controlled clinical trial involving subjects with Severe Hypertriglyceridemia (SHTG). The primary endpoint for evaluating efficacy is the percent change from baseline in fasting triglyceride (TG) levels at Week 26. Secondary endpoints include percent changes from baseline in non-high-density lipoprotein cholesterol (non-HDL-C), high-density lipoprotein cholesterol (HDL-C), very low-density lipoprotein cholesterol (VLDL-C), and total cholesterol (TC) at Week 26. Additionally, the study will assess the percent change from baseline in fasting TG at Week 52, change from baseline in liver fat by magnetic resonance imaging - whole liver proton density fat fraction (MRI-PDFF) at Week 26, percent change from baseline in apolipoprotein B (apo-B) at Week 26, and change in HbA1c at Week 26 for those with baseline levels of 7.0% or higher.

Measurements will be collected at specified timepoints, including Week 26 and Week 52, using validated laboratory tests and imaging techniques. The data will be analyzed to determine the efficacy of Pegozafermin in reducing fasting serum triglyceride levels and other lipid parameters. The trial is designed to ensure rigorous assessment of the investigational product's impact on lipid profiles and related biomarkers in the target population.