Long-acting pegylated human GH in children with GH deficiency: a single-dose, dose-escalation trial investigating safety, tolerability, pharmacokinetics and pharmacodynamics

Abstract

Objective: GH replacement therapy currently requires daily injections, which may be inconvenient and distressing for young patients. This study determined the safety, tolerability, pharmacokinetics and pharmacodynamics of escalating single doses of a pegylated GH (NNC126-0083) developed for onceweekly administration, in children with GH deficiency (GHD). Design and methods: Thirty children (age R6 and %12 years, weight R16 kg) were randomised to NNC126-0083 or daily GH treatment. The subjects discontinued their daily GH treatment 7-9 days before receiving NNC126-0083 at 0.01, 0.02, 0.04 or 0.06 mg protein/kg (nZ22) or seven once-daily doses of GH at 0.035 mg protein/kg (nZ8). Results: NNC126-0083 was well tolerated, and no short-term safety or local tolerability issues were identified. After NNC126-0083 treatment, dose-dependent IGF1 increases were evident for maximum concentration (C max ), but not area under the curve (AUC 0-168 h ). Mean values for IGF1 AUC 0-168 h /168 h and C max were higher for GH than for NNC126-0083, although the difference was not statistically significant for cohort's 0.06 mg protein/kg. At 0.06 mg protein/kg, the resulting IGF1 response began subsiding at w3 days post-dose. Conclusion: Single doses of long-acting NNC126-0083 were safe and well tolerated in children with GHD. Increased IGF1 levels were observed in all NNC126-0083 dose groups; however, a satisfactory once-weekly IGF1 profile was not reached within the NNC126-0083 dose levels administered.

Status of long-acting-growth hormone preparations — 2015

“…NNC126-0083 was well tolerated, and no lipoatrophy was observed [37]. In 30 children with GHD randomized to a single dose of NNC126-0083 vs daily GH, a rise in IGF-I levels was observed in all NNC126-0083 dose groups; however, a satisfactory once-weekly IGF-I profile was not reached within the NNC126-0083 dose levels administered [38], and further development was stopped.…”

“…No lipoatrophy was noted and there were no neutralizing antibodies. In a 6 month phase 2 study of 43 young adults with childhood onset GHD ARX201 was shown to be well-tolerated and improved body composition, lipid profile and quality of life [38]. A dose dependent increase in IGF-I was observed [39].…”

In Vitro and in Vivo Characterization of MOD-4023, a Long-Acting Carboxy-Terminal Peptide (CTP)-Modified Human Growth Hormone

“…Conjugation of GH to albumin decreased renal clearance and increased half-life; however, this formulation did not exhibit an improved bioavailability in comparison to rhGH 6 . PEGylated GH demonstrated local injection site lipoatrophy in adults and children, thus raising a safety concern 7 ; an additional study with PEGylated GH demonstrated an inadequate IGF-1 response 8 . Another approach involved the fusion of an unstructured amino acid sequence (XTEN) to hGH in order to reduce its renal clearance (VRS-317) 9 .…”

Developments in human growth hormone preparations: sustained-release, prolonged half-life, novel injection devices, and alternative delivery routes

“…37 De Schepper et al developed another PEGylated rhGH called NNC126-0083 to attain a onceweekly preparation. 37 Lipoatrophy was not observed in 30 children, but further research was required to ensure its safety by testing it in adults and more subjects. However, the IGF-1 profile was not satisfactory, since the response began subsiding 3 days after injection, rather than lasting for 1 week as planned.…”