† Pegozafermin for the Treatment of Severe Hypertriglyceridemia, a Randomized, Double-blind, Placebo-controlled Phase 2 Trial (ENTRIGUE STUDY)

Background/Synopsis FGF21, an endogenous stress hormone, regulates glucose and lipid metabolism and energy expenditure. Pegozafermin (PGZ) is a long-acting glycopegylated recombinant analog of human fibroblast growth factor 21 (FGF21) being developed for severe hypertriglyceridemia (SHTG) and non-alcoholic steatohepatitis (NASH). Objective/Purpose PGZ has previously demonstrated efficacy on serum lipids, insulin resistance, HbA1c, body weight, and liver fat in a NASH population. The ENTRIGUE trial was designed to investigate PGZ as a novel therapeutic agent for the treatment of SHTG. Methods ENTRIGUE is a Phase 2 double-blind, randomized 5-arm trial of pegozafermin at 4 different doses administered either once weekly or once every two weeks versus matching placebo for 8 weeks in subjects with triglycerides (TGs) ≥500 mg/dL and ≤2,000 mg/dL. Subjects could be on background lipid-modifying therapy (LMT), including statins, prescription fish oil, and/or fibrates. The primary endpoint was percent change in TGs from baseline. Prespecified secondary endpoints included additional lipids, liver fat fraction assessed by MRI-PDFF (n=24), and markers of insulin sensitization. Results Eighty-five subjects were randomized and treated; baseline characteristics were balanced across dose groups with mean TG of 733 mg/dL, 51% with T2D, and 55% on background LMT. PGZ significantly reduced median TGs for the pooled pegozafermin doses versus placebo (57.3% versus 11.9%). Placebo-corrected reductions in TGs ranged from 29% to 53% across the four PGZ doses independent of LMT background status or T2D status. Eighty percent of all PGZ treated subjects achieved a target TG level of <500 mg/dL. For the 27 mg dose, 75% of subjects achieved ≥ 50% reduction in TGs from baseline (p<0.001) and 31% normalized their TG levels to <150 mg/dL (p<0.01) at week 8. Additionally at the 27 mg dose, significant decreases were seen in non-HDL-C and ApoB, along with concurrent increases in HDL-C and adiponectin and no change in LDL-C compared to placebo. In an MRI-PDFF sub-study (n=23 with follow-up assessment), liver fat was significantly reduced for the pooled arms (placebo-corrected 35%, p=0.012) with 88% of PGZ subjects achieving ≥ 30% relative reduction from baseline. At week 8, improvements in HbA1c, fasting insulin, and plasma glucose were also observed in PGZ-treated subjects. The most common treatment-related AEs (all mild-to- moderate) were nausea, diarrhea, and injection site reactions. There were no serious adverse events related to study drug. Conclusions Pegozafermin significantly reduced triglycerides, non-HDL cholesterol, ApoB, and liver fat in subjects with SHTG, with the potential to positively impact other aspects of metabolic dysregulation. External Funding Yes Funding Sources 89bio sponsored clinical trial. FGF21, an endogenous stress hormone, regulates glucose and lipid metabolism and energy expenditure. Pegozafermin (PGZ) is a long-acting glycopegylated recombinant analog of human fibroblast growth factor 21 (FGF21) being developed for severe hypertriglyceridemia (SHTG) and non-alcoholic steatohepatitis (NASH). PGZ has previously demonstrated efficacy on serum lipids, insulin resistance, HbA1c, body weight, and liver fat in a NASH population. The ENTRIGUE trial was designed to investigate PGZ as a novel therapeutic agent for the treatment of SHTG. ENTRIGUE is a Phase 2 double-blind, randomized 5-arm trial of pegozafermin at 4 different doses administered either once weekly or once every two weeks versus matching placebo for 8 weeks in subjects with triglycerides (TGs) ≥500 mg/dL and ≤2,000 mg/dL. Subjects could be on background lipid-modifying therapy (LMT), including statins, prescription fish oil, and/or fibrates. The primary endpoint was percent change in TGs from baseline. Prespecified secondary endpoints included additional lipids, liver fat fraction assessed by MRI-PDFF (n=24), and markers of insulin sensitization. Eighty-five subjects were randomized and treated; baseline characteristics were balanced across dose groups with mean TG of 733 mg/dL, 51% with T2D, and 55% on background LMT. PGZ significantly reduced median TGs for the pooled pegozafermin doses versus placebo (57.3% versus 11.9%). Placebo-corrected reductions in TGs ranged from 29% to 53% across the four PGZ doses independent of LMT background status or T2D status. Eighty percent of all PGZ treated subjects achieved a target TG level of <500 mg/dL. For the 27 mg dose, 75% of subjects achieved ≥ 50% reduction in TGs from baseline (p<0.001) and 31% normalized their TG levels to <150 mg/dL (p<0.01) at week 8. Additionally at the 27 mg dose, significant decreases were seen in non-HDL-C and ApoB, along with concurrent increases in HDL-C and adiponectin and no change in LDL-C compared to placebo. In an MRI-PDFF sub-study (n=23 with follow-up assessment), liver fat was significantly reduced for the pooled arms (placebo-corrected 35%, p=0.012) with 88% of PGZ subjects achieving ≥ 30% relative reduction from baseline. At week 8, improvements in HbA1c, fasting insulin, and plasma glucose were also observed in PGZ-treated subjects. The most common treatment-related AEs (all mild-to- moderate) were nausea, diarrhea, and injection site reactions. There were no serious adverse events related to study drug. Pegozafermin significantly reduced triglycerides, non-HDL cholesterol, ApoB, and liver fat in subjects with SHTG, with the potential to positively impact other aspects of metabolic dysregulation.