Pegylated Long-Acting Human Growth Hormone Is Well-Tolerated in Healthy Subjects and Possesses a Potential Once-Weekly Pharmacokinetic and Pharmacodynamic Treatment Profile

Abstract

After a single sc administration of NNC126-0083 in healthy male volunteers, a sustained dose-dependent pharmacodynamic response was induced. These results indicate that NNC126-0083 has the potential for an efficacious, well-tolerated, once-weekly rhGH compound in the treatment of GH deficiency in adults.

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

“…Diurnal variations in the PK profiles were observed in all cohorts. Similar variations were also observed in the previous trials with NNC126-0083 in healthy volunteers and adult GHD (6)(7)(8), and the reason for these fluctuations remains to be elucidated. As discussed in recent publications (6)(7)(8), it may be related to the diurnal variation of lymphatic drainage in the subcutaneous tissue, but this has yet to be verified.…”

“…Similar variations were also observed in the previous trials with NNC126-0083 in healthy volunteers and adult GHD (6)(7)(8), and the reason for these fluctuations remains to be elucidated. As discussed in recent publications (6)(7)(8), it may be related to the diurnal variation of lymphatic drainage in the subcutaneous tissue, but this has yet to be verified. The typically observed PK profile for NNC126-0083 with its diurnal variations and the PK profile for daily GH injection with its characteristic peak and through GH levels over 24 h (15) are both very different from the general profile of the normal physiological pulsatile GH secretion (16).…”

“…At 0.06 mg protein/kg, the resulting IGF1 response began subsiding at w3 days post-dose. Furthermore, in previous studies, a satisfactory IGF1 profile was achieved with higher doses of NNC126-0083 in adults (6)(7)(8). Thus, higher dose levels than those investigated in this study may potentially have achieved an IGF1 profile suitable for once-weekly dosing in GHD children but such higher dose levels would also need to be explored with regard to safety.…”

“…The pegylation of a protein generally results in prolongation of the in vivo mean residence time, mainly through reduced clearance by filtration in the kidneys (prolonged elimination phase) and a slower absorption. The safety, pharmacokinetic (PK) and pharmacodynamic (PD) profiles of NNC126-0083 obtained in recent single-and multiple-dose clinical trials have shown that NNC126-0083 is well tolerated by both healthy adults and adults with GHD and that the compound possesses a potential once-weekly treatment profile (6)(7)(8). We report here the first data on once-weekly administration of NNC126-0083 to children with GHD and how the generated profiles on safety, PK and PD compared to profiles obtained in children after seven once-daily doses of GH.…”

Optimized clinical performance of growth hormone with an expanded genetic code

“…Importantly, this technology allows one to rapidly optimize the physical, biological, and pharmacological properties of a protein conjugate through recombinant-based protein chemistry that is unrestricted in site of conjugation. This constitutes a significant advance relative to conventional conjugation methods that are restricted by the native 20 amino acids (16)(17)(18). For example, the modification of lysines by electrophiles that is widely used in research settings results in mixtures of positional isomers even when the stoichiometry is controlled to provide one PEG per protein.…”