Phase 1 study and population PK/PD modeling of long-acting growth hormone, GB08, to guide pediatric dosing.

Objective: Growth hormone deficiency (GHD) requires long-term treatment, but daily injections and adverse effects of current therapies often pose adherence challenges in children. GB08, a novel Fc-GH, leverages the extended half-life of Fc-fusion proteins to reduce injection frequency with potential for improved safety. This study evaluates the safety, immunogenicity, pharmacokinetics, and pharmacodynamics profiles of GB08 in healthy adults. The findings, along with population PK/PD modeling, will guide dosing strategies for a Phase 2 trial in pediatric GHD patients.

Design: The study consisted of 2 parts: a randomized, double-blind, placebo-controlled single ascending dose trial and a randomized, open-label, parallel-group positive control trial.

Methods: Subjects received a single dose of GB08 (0.16-2.4 mg/kg), 0.2 mg/kg of Jintrolong, or 7 daily doses of Norditropin (0.035 mg/kg/day). Evaluations included adverse events (AEs), immunogenicity, pharmacokinetics, and pharmacodynamics.

Results: GB08 demonstrated a favorable safety profile with low immunogenicity, no serious AEs reported, and all AEs were mild to moderate. Pharmacokinetics and pharmacodynamics revealed dose-dependent increases, with GB08's half-life ranging from 81.7 to 110.0 h, supporting its potential for once-weekly injection. PK/PD modeling identified an optimal adult dose of 0.7 mg/kg. Further allometric scaling of adult PK data to develop a pediatric PK model suggested optimal pediatric dose of 0.8 mg/kg, balancing efficacy and safety profiles.

Conclusion: GB08 provides notable advantages over traditional therapies, like short-acting GH, by enhancing treatment adherence and offering a potentially safer alternative. The findings from this study will guide dosing strategies for Phase 2 trial in children with GHD.