Preclinical Investigations of a Novel PEGylated Long-Acting Human Growth Hormone.

Abstract

Purpose: The daily administration of recombinant human growth hormone (rhGH) replacement therapies via subcutaneous (SC) injections can be burdensome for patients. Long-acting Growth hormone (GH) formulation could reduce injection frequency, and it will be expected to increase treatment adherence. ZHB111 is a PEGylated rhGH that requires sc injection every two weeks. This study aims to examine the pharmacokinetics (PK), pharmacodynamics (PD), safety, and tolerability of multiple sc doses of ZHB111.

Design and methods: In the PK study, naïve cynomolgus monkeys were divided into four groups with 3/sex/group. Each group received single subcutaneous administration at 0 (control article, Sodium chloride injection), 0.3, 1.0 and 3.0 mg/kg, respectively. To access safety and PD profile, cynomolgus monkeys were randomly assigned to 4 groups of 5/sex/group, and were dosed with ZHB111 once weekly for 4 times by subcutaneous injection at 0 (control article, Sodium chloride injection), 1, 5 or 20.6 mg/kg/dose. Tissue distribution was accessed by administering a single subcutaneous dose of ZHB111 to Sprague-Dawley Rats.

Results: ZHB111 exhibits a significant difference in serum half-life (in monkeys) across varying dosages, with a trend of decreasing half-life as the dosage increases, ranging from 110-30 h. No significant differences were observed between different genders at the same dosage level. After subcutaneous administration of 0.3mg/kg of ZHB111, the mean values of IGF-1 in male animals ranged among 594.93~1294.98ng/mL at various time points, while those in female animals were within the range of 394.15~770.01ng/mL.

Conclusion: The tolerability of ZHB111 was demonstrated in both rat and monkey models, with only minimal adverse effects observed. These findings support the continued clinical development of ZHB111 as a novel treatment for growth hormone deficiency (GHD) in both children and adult patients.