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

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.

The growth hormone–insulin-like growth factor-I axis in the diagnosis and treatment of growth disorders

“…A number of long-acting GH preparations are currently in various phases of clinical studies ( 3 , 4 ). Several different techniques have been used in their development, such as modification of the GH molecule by protein enlargement or albumin binding, which results in GH analogues with longer half-lives.…”

Treatment with Growth Hormone for Adults with Growth Hormone Deficiency Syndrome: Benefits and Risks

“…There are ongoing preparations of prolonged-release GH, which would reduce the frequency of injections [ 111 , 112 ]. Nowadays, there are long-acting GH preparations in various stages of development, including depot, pegylated, and prodrug formulations, as well as non-covalent albumin-binding GH and GH-fusion protein compounds [ 113 , 114 , 115 , 116 ].…”

Engineering a Long Lasting Tethered, Multimeric Human Growth Hormone Protein to Improve Pharmacokinetic Half-Life and Potency

“…More recently, second generation, long lasting growth hormone products have entered clinical trials [5,6]. These forms of hGH impart improved pharmacokinetics by including PEGylation, addition of lipid or protein linkers, or other modifications to improve half-life [7][8][9][10]. The premise of these next generation protein therapeutics is to increase the size or bulk of growth hormone via a permanent modification to decrease renal clearance.…”

“…The premise of these next generation protein therapeutics is to increase the size or bulk of growth hormone via a permanent modification to decrease renal clearance. The addition of a linker that associates the hGH protein with circulating serum albumin or otherwise protects the protein from clearance or degradation have also been employed [7]. These protein engineering strategies attempt to balance the need for increased circulating half-life while maintaining receptor binding and also to avoid immunogenicity or other adverse response to the engineered therapeutic.…”

“…These protein engineering strategies attempt to balance the need for increased circulating half-life while maintaining receptor binding and also to avoid immunogenicity or other adverse response to the engineered therapeutic. These experimental therapeutics include ACP-001, MOD-4023, VRS-317, and NNC0195-0092, to name a few examples [7]. The market for growth hormone is greater than $3 Billion USD worldwide and has attracted many novel follow on therapeutics.…”