The rationale and design of TransCon Growth Hormone for the treatment of growth hormone deficiency.

Kennett Sprogøe,Jonathan A Leff,Eva Mortensen,David B Karpf

doi:10.1530/ec-17-0203

Abstract

The fundamental challenge of developing a long-acting growth hormone (LAGH) is to create a more convenient growth hormone (GH) dosing profile while retaining the excellent safety, efficacy and tolerability of daily GH. With GH receptors on virtually all cells, replacement therapy should achieve the same tissue distribution and effects of daily (and endogenous) GH while maintaining levels of GH and resulting IGF-1 within the physiologic range. To date, only two LAGHs have gained the approval of either the Food and Drug Administration (FDA) or the European Medicines Agency (EMA); both released unmodified GH, thus presumably replicating distribution and pharmacological actions of daily GH. Other technologies have been applied to create LAGHs, including modifying GH (for example, protein enlargement or albumin binding) such that the resulting analogues possess a longer half-life. Based on these approaches, nearly 20 LAGHs have reached various stages of clinical development. Although most have failed, lessons learned have guided the development of a novel LAGH. TransCon GH is a LAGH prodrug in which GH is transiently bound to an inert methoxy polyethylene glycol (mPEG) carrier. It was designed to achieve the same safety, efficacy and tolerability as daily GH but with more convenient weekly dosing. In phase 2 trials of children and adults with growth hormone deficiency (GHD), similar safety, efficacy and tolerability to daily GH was shown as well as GH and IGF-1 levels within the physiologic range. These promising results support further development of TransCon GH.

Highlights

Following secretion from the anterior pituitary, human growth hormone (GH) is transported throughout the body, exerting its effects via GH receptors on virtually every cell of the body
Lessons learned from past development attempts have shown that the optimal long-acting growth hormone (LAGH) must mimic all aspects of daily GH in terms of safety, efficacy and tolerability
Integrating the experiences of previous developments in the LAGH space, TransCon GH was developed as a sustained-release GH prodrug

Summary

Introduction

Following secretion from the anterior pituitary, human growth hormone (GH) is transported throughout the body, exerting its effects via GH receptors on virtually every cell of the body. Like unmodified GH, protein-enlarged GH molecules do readily access hepatic GH receptors via fenestrated (open) hepatic sinusoidal endothelium, stimulating hepatic IGF-1 production Such imbalances within peripheral tissue vs organ distribution have been described for another protein-enlarged hormone, namely permanently PEGylated insulin, in which increased molecular size favored the liver over peripheral tissue [57]. Lessons learned from past development attempts have shown that the optimal LAGH must mimic all aspects of daily GH in terms of safety, efficacy and tolerability These include increased bone growth and mineral deposition, muscle mass gain with improved exercise tolerance and enhanced lipolysis with body composition optimization, and yet, without increased immunogenicity, metabolic complications, injection site reactions, lipoatrophy or pain. Given GH receptor distribution throughout the body and the pleiotropic actions of GH, a viable LAGH would likely have to maintain the same organ and tissue distribution as native GH, e.g., a candidate based on unmodified GH

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