Study Design of a Phase 3 Randomized Controlled Trial Evaluating the Efficacy and Safety of Pegozafermin in Patients with Severe Hypertriglyceridemia

Abstract

Study Funding

89bio, Inc.

Background/Synopsis

Severe hypertriglyceridemia (SHTG; defined as greater than or equal to 500 mg/dL) increases the risk of acute pancreatitis, non-alcoholic fatty liver disease and cardiovascular disease. Currently available medications often do not reduce triglycerides to desired levels, highlighting the need for new therapeutic options. Fibroblast growth factor 21 (FGF21) is an endogenous hormone, mainly secreted by the liver, which functions as a master metabolic regulator of lipid and glucose metabolism, as well as energy expenditure. Pegozafermin (PGZ), a long acting FGF21 analog, is in development for the treatment of SHTG and non-alcoholic steatohepatitis. Previous Phase 2 data demonstrated PGZ significantly reduced TGs and hepatic steatosis and improved atherogenic lipoprotein particles and glycemic control, with a good safety and tolerability profile. These promising results led to the design of the first Phase 3 trial of PGZ for the treatment of SHTG.

Objective/Purpose

To determine the effect of Pegozafermin on fasting serum triglyceride levels in subjects with Severe Hypertriglyceridemia (TG greater than or equal to 500 to less than or equal to 2000 mg/dL) after 26 weeks of treatment.

Methods

ENTRUST is a global 52-week Phase 3, randomized, double-blind, placebo-controlled study designed to evaluate the efficacy and safety of pegozafermin in patients with SHTG. Approximately 360 patients aged 22 years old or older, with baseline triglycerides between 500 and 2000 mg/dL and receiving background standard-of-care lipid-modifying therapy will be randomized in a 3:3:2 ratio to weekly subcutaneous injections of PGZ 30 mg, PGZ 20 mg, or placebo. Exclusion criteria include uncontrolled or newly diagnosed T2DM, T1DM, symptomatic gallstone/biliary disease, uncontrolled hypertension, or an acute pancreatitis event within 6 months. The primary endpoint will be percent change in fasting serum TGs from baseline after 26 weeks of PGZ/placebo treatment. Key secondary endpoints include changes in serum lipids, lipoproteins, glycemic control, liver steatosis and safety. Final efficacy analysis will be based on 52 weeks of treatment.

Results

The study was initiated in June 2023 and has an estimated primary completion date of August 2025. NCT05852431.

Conclusions

ENTRUST is a pivotal Phase 3 clinical trial designed to confirm the efficacy and safety of PGZ in the treatment of SHTG. Expected clinical benefits include significant reductions of triglycerides and hepatic steatosis, as well as other metabolic improvements.