Abstract:Context: TransCon Growth Hormone (GH) (Ascendis Pharma) is a long-acting recombinant sustained-release human GH prodrug in development for children with GH deficiency (GHD).Objective: To compare the pharmacokinetics, pharmacodynamics, safety, and efficacy of weekly TransCon GH to that of daily GH in prepubertal children with GHD.
Design:Randomized, open-label, active-controlled study of three doses of weekly TransCon GH versus daily Genotropin (Pfizer).Setting: Thirty-eight centers in 14 European countries and… Show more
“…In a multicentre, phase 2, open-label, randomised, controlled study, safety, tolerability, efficacy, pharmacokinetics and pharmacodynamics of three different once-weekly doses of MOD-4023were compared to once-daily recombinant human GH (r-hGH) in prepubertal children with GHD for 12 months of treatment, revealing the better efficacy of 0.66 mg/kg/week dose along with a good tolerability and safety [61]. In a randomised, open-label, active-controlled study of 3 doses of once-weekly TransCon GH, a long-acting sustained-release r-hGH prodrug, compared to once-daily Genotropin; both drugs were comparable in the context of safety and efficacy [62]. Finally, in a phase 2 and 3, open-label, multicentre, randomised studies with a long-acting PEGylated r-hGH (0.2 mg/kg/week), when compared to once-daily rhGH (0.25 mg/kg/week) for 25 weeks in children with GHD, the former was shown to be effective and safe for GHD treatment [63] (Table 3).…”
Hypopituitarism includes all clinical conditions that result in partial or complete failure of the anterior and posterior lobe of the pituitary gland’s ability to secrete hormones. The aim of management is usually to replace the target-hormone of hypothalamo-pituitary-endocrine gland axis with the exceptions of secondary hypogonadism when fertility is required, and growth hormone deficiency (GHD), and to safely minimise both symptoms and clinical signs. Adrenocorticotropic hormone deficiency replacement is best performed with the immediate-release oral glucocorticoid hydrocortisone (HC) in 2–3 divided doses. However, novel once-daily modified-release HC targets a more physiological exposure of glucocorticoids. GHD is treated currently with daily subcutaneous GH, but current research is focusing on the development of once-weekly administration of recombinant GH. Hypogonadism is targeted with testosterone replacement in men and on estrogen replacement therapy in women; when fertility is wanted, replacement targets secondary or tertiary levels of hormonal settings. Thyroid-stimulating hormone replacement therapy follows the rules of primary thyroid gland failure with L-thyroxine replacement. Central diabetes insipidus is nowadays replaced by desmopressin. Certain clinical scenarios may have to be promptly managed to avoid short-term or long-term sequelae such as pregnancy in patients with hypopituitarism, pituitary apoplexy, adrenal crisis, and pituitary metastases.
“…In a multicentre, phase 2, open-label, randomised, controlled study, safety, tolerability, efficacy, pharmacokinetics and pharmacodynamics of three different once-weekly doses of MOD-4023were compared to once-daily recombinant human GH (r-hGH) in prepubertal children with GHD for 12 months of treatment, revealing the better efficacy of 0.66 mg/kg/week dose along with a good tolerability and safety [61]. In a randomised, open-label, active-controlled study of 3 doses of once-weekly TransCon GH, a long-acting sustained-release r-hGH prodrug, compared to once-daily Genotropin; both drugs were comparable in the context of safety and efficacy [62]. Finally, in a phase 2 and 3, open-label, multicentre, randomised studies with a long-acting PEGylated r-hGH (0.2 mg/kg/week), when compared to once-daily rhGH (0.25 mg/kg/week) for 25 weeks in children with GHD, the former was shown to be effective and safe for GHD treatment [63] (Table 3).…”
Hypopituitarism includes all clinical conditions that result in partial or complete failure of the anterior and posterior lobe of the pituitary gland’s ability to secrete hormones. The aim of management is usually to replace the target-hormone of hypothalamo-pituitary-endocrine gland axis with the exceptions of secondary hypogonadism when fertility is required, and growth hormone deficiency (GHD), and to safely minimise both symptoms and clinical signs. Adrenocorticotropic hormone deficiency replacement is best performed with the immediate-release oral glucocorticoid hydrocortisone (HC) in 2–3 divided doses. However, novel once-daily modified-release HC targets a more physiological exposure of glucocorticoids. GHD is treated currently with daily subcutaneous GH, but current research is focusing on the development of once-weekly administration of recombinant GH. Hypogonadism is targeted with testosterone replacement in men and on estrogen replacement therapy in women; when fertility is wanted, replacement targets secondary or tertiary levels of hormonal settings. Thyroid-stimulating hormone replacement therapy follows the rules of primary thyroid gland failure with L-thyroxine replacement. Central diabetes insipidus is nowadays replaced by desmopressin. Certain clinical scenarios may have to be promptly managed to avoid short-term or long-term sequelae such as pregnancy in patients with hypopituitarism, pituitary apoplexy, adrenal crisis, and pituitary metastases.
“…One TransCon GH subject developed a low-titer, non-neutralizing antibody response; no neutralizing anti-GH binding antibodies were detected. Similar to daily GH, the mean body mass index SDS was stable across three TransCon GH cohorts ( 69 ).…”
Section: Transcon Ghmentioning
confidence: 95%
“…Mean annualized HV ranged from 11.9 cm to 13.9 cm/year at a dose range of 0.14–0.30 mg GH/kg/week and compared favorably to 11.6 cm/year for 0.21 mg GH/kg/week of daily GH ( Fig. 2 ) ( 69 ). Figure 2 Annualized height velocity (mean + s.d. )…”
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.
“…TransCon Growith Hormone was well tolerated with no binding antibody formation and comparable measures of serum growth hormone and IGF-1 (25). Phase 2 trials among 37 adults with growth hormone deficiency and 53 previously untreated prepubertal children with growth hormone deficiency revealed similar safety and efficacy of weekly TransCon Growth Hormone and daily growth hormone (26,27). The results of the Phase 3 heiGHt trial (NCT02781727) were presented at ENDO 2019 in New Orleans (28).…”
Growth hormone therapy with daily injections of recombinant human growth hormone has been available since 1985, and is shown to be safe and effective treatment for short stature in children and for adult growth hormone deficiency. In an effort to produce a product that would improve patient adherence, there has been a strong effort from industry to create a long acting form of growth hormone to ease the burden of use. Technologies used to increase half-life include depot formulations, PEGylated formulations, pro-drug formulations, non-covalent albumin binding growth hormone and growth hormone fusion proteins. At present, two long acting formulations are on the market in China and South Korea, and several more promising agents are under clinical investigation at various stages of development throughout the world.
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