136: Population Pharmacokinetics & Pharmacodynamics of Pegozafermin, a Novel GlycoPEGylated FGF21, in a Phase 2 Study in Severe Hypertriglyceridemia

Statement of Purpose, Innovation or Hypothesis: Pegozafermin is a specifically engineered, long-acting glycoPEGylated analog of fibroblast growth factor 21 (FGF21) under development for the treatment of metabolic dysfunction associated steatohepatitis (MASH) and severe hypertriglyceridemia (SHTG). In a randomized Phase 2 trial (ENTRIGUE) in SHTG (triglycerides [TG] ≥ 500 mg dl^-1), pegozafermin-treated patients showed a significant reduction in median TG levels versus placebo (57.3% for pooled pegozafermin versus 11.9% for placebo, with placebo-corrected difference of −43.7%, 95% confidence interval (CI): −57.1%, −30.3%; P < 0.001) (Reference 1). Pharmacokinetics (PK) and pharmacodynamics (PD) data from this study were analyzed using a population modeling approach to support dose selection for Phase 3 studies.

Description of Methods & Materials: Subjects in this analysis include pegozafermin treatment groups at 9 mg (n=12), 18 mg (n=21), 27 mg (n=18) once-weekly (QW) and at 36 mg (n=16) once-every-two-weeks (Q2W). PK and TG data were characterized based on a population nonlinear mixed-effects modelling approach using NONMEM 7.4.2. Tested covariates include sex, age, weight, ethnicity, race and immunogenicity for PK and additional parameters (ALT, AST, HbA1c) added for PD.

Data & Results: Pegozafermin exposure was adequately described by a one compartment PK model with one additional transit absorption compartment, consistent with the previous model in MASH (Reference 2). The model predicts a 6% increase in drug elimination (i.e., clearance) for each 10 kg increase in body weight.  An indirect response model was used to describe the longitudinal effect on TG. No significant covariates were identified. Pop PK/PD modeling data is shown in Figure 1 with 27 mg QW being the most efficacious as demonstrated by more pronounced reductions in TG as compared to the other doses.

Interpretation, Conclusion or Significance: Population PK/PD modeling provides rationale to support dose selection for the recently initiated Phase 3 ENTRUST study in SHTG. Pegozafermin 30 mg QW was selected to maximize efficacy and 20 mg QW was selected not only for its efficacious effect, but also to allow the sponsor to further explore the efficacy and tolerability profiles between two doses.

Disclosures:

Citations/References: 1. Nat Med. 2023; 29(7): 1782–1792.
2. Clin Pharmacol Ther 2023 Dec;114(6):1323-1331.

Additional Information/Authors: Phase 3 SHTG trial (ENTRUST): NCT05852431