Lipoatrophy in GH deficient patients treated with a long-acting pegylated GH

Abstract

Objective: Changes observed during adult GH deficiency (GHD) are most often reversed with the administration of recombinant human GH (rhGH). To avoid daily injections, a long-acting GH molecule has been obtained by covalent binding of polyethylene glycol (PEG) with rhGH (PEG-GH), allowing weekly s.c. injections. This study was designed to assess its efficacy and safety, in adult GHD subjects. Design and methods: This was a randomized, double-blind, placebo-controlled, multiple-dose, parallel group study. Subjects were recruited from 34 centers. A total of 105 subjects with GHD were assigned a treatment. They received 6 weekly injections of either PEG-GH or placebo. Subjects were randomized into one out of four treatment groups (Groups A-D) or placebo (Group E). Groups A, B, and C received 1, 3, and 4 mg PEG-GH respectively, for the first 3 weeks followed by 2, 6, and 8 mg PEG-GH respectively, for the remaining 3 weeks. Group D received 4 mg PEG-GH for 6 weeks. Group E received placebo. The study was suspended because of the development of lipoatrophy in certain subjects and restarted with an injection rotation plan, before being terminated due to further subjects developing lipoatrophy. Results: A total of 13 cases of injection-site lipoatrophy were reported, of which ten were in females and three occurred after the first injection; all cases were independent of PEG-GH dose or IGF1 levels, either basal or under treatment. Conclusion: The unpredictable occurrence of injection-site lipoatrophy with weekly long-acting pegylated GH molecules may be a limiting factor for their development.

Status of long-acting-growth hormone preparations — 2015

“…However, 13 out of 105 adults with GHD who were treated with PEG-GH developed lipoatrophy at the injection site after the first injection and all further development was terminated in 2009 [35]. The local-site reactions were independent of either PEG-GH dose or IGF-I levels.…”

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 .…”

Immunogenicity, toxicology, pharmacokinetics and pharmacodynamics of growth hormone ligand–receptor fusions

“…Bruising and pain at the injection site is associated with other long-acting GH therapies, such as PEGylated GH (Pegvisomant) [22] and Nutropin Depot [23]; the latter is also associated with small erythematous nodules at the injection site [23,24]. Lipoatrophy has been of concern with long-acting GH molecules and has recently been reported with PEGylated GH [25].…”