Phase II · Frontiers in Endocrinology 2022

PK, PD, and 12-week growth outcomes

This page summarizes a peer-reviewed Phase II report of the Y‑shape branched PEGylated rhGH later developed as Pegpesen (inpegsomatropin). The trial characterized pharmacokinetics (PK), pharmacodynamics (PD) via IGF‑1, and short-term height velocity versus daily somatropin. It is the scientific precursor to the Phase III program described under Trials.

Download PDF (local copy) Publisher (DOI) Phase III summary

Publication details

• Title: The pharmacokinetic and pharmacodynamic properties and short-term outcome of a novel once-weekly PEGylated recombinant human growth hormone for children with growth hormone deficiency
• Journal: Frontiers in Endocrinology, 11 August 2022; 13:922304
• DOI: 10.3389/fendo.2022.922304
• Authors: Liang Y, Zhang C, Wei H, Du H, Zhang G, Yang Y, Zhang H, Gong H, Li P, Song F, Xu Z, He R, Zhou W, Zheng H, Sun L, Luo X (multicenter investigators and Amoytop; see paper for full affiliations)
• Trial registry: ClinicalTrials.gov NCT04513171

Study design (overview)

• Design: Randomized, multicenter, active-controlled, double-blind with respect to the three once-weekly doses of YPEG‑rhGH.
• Arms: Once-weekly YPEG‑rhGH at 0.10, 0.12, and 0.14 mg/kg/week vs Norditropin (Novo Nordisk) 0.035 mg/kg/day subcutaneously.
• Period: Enrollment March 2019 – January 2020; assessments at baseline, week 4, and week 12.
• Primary endpoint: Area under the curve of the change in IGF‑1 (IGF‑1 response over time).
• Secondary endpoint: Height velocity (HV) increment at week 12 (annualized).

Population PK/PD modeling

The manuscript integrates sparse PK and IGF‑1 data with a population approach (NONMEM 7.2, PsN, R) using 751 PK and 818 IGF‑1 observations from 67 YPEG‑exposed subjects (including Phase 1 healthy adults plus Phase 2 pediatric participants) after exclusions.

PK highlights (model-derived)

• Dose-dependent C_max and AUC_0–168h across the three weekly dose levels.
• Median T_max ≈ 24 h after dosing (first and last dose), with modest concentration increases from first to last weekly dose (ratios reported ~1.09–1.11 for C_max and ~1.22–1.26 for AUC_0–168h), interpreted as limited accumulation.
• Steady-state PK profile approximated by week 12 of weekly dosing.

PD / IGF‑1

• IGF‑1 fold-change (FC) versus baseline modeled with indirect response; pcVPC supported model fit.
• Dose-dependent AUEC of IGF‑1 FC; median T_max for IGF‑1 FC ≈ 48 h vs ~24 h for drug—lag consistent with IGF‑1 biology.
• Model-derived mean IGF‑1 SDS remained largely within −2 to +2 over 12 weeks for all weekly doses; authors note occasional predicted upper 95% intervals above +2 at 0.12 and 0.14 mg/kg/week, suggesting monitoring.
• Geometric mean AUEC of IGF‑1 FC for weekly therapy intersected the daily comparator around a lower weekly dose; authors infer weekly exposures near 0.11–0.12 mg/kg/week as PK/PD‑similar to 0.035 mg/kg/day Norditropin for IGF‑1 exposure, while 0.12–0.14 mg/kg/week best matched observed HV vs daily therapy (see conclusions in paper).

Clinical height velocity at week 12

Observed annualized height velocity at week 12 (reported means):

Baseline characteristics were comparable across arms (authors note slightly younger/shorter profile in the highest weekly dose group but comparable HV and GH peaks).

Safety and adherence

Adherence and overall safety resembled daily rhGH experience in this short window. No related serious adverse events attributed to YPEG‑rhGH were reported. One patient in the daily arm discontinued for rash with recovery.

Authors’ conclusions

How this links to later development

• The same registry ID NCT04513171 continued into the combined Phase II/III program summarized on Trials (52-week primary analysis at 0.14 mg/kg/week).
• Long-horizon dose-strategy simulations appear in PK/PD modeling (separate publication).
• Molecular background: Molecule & formulation.