Paediatric growth hormone deficiency (GHD) is an orphan disease characterised by abnormally short stature, increased and abnormal fat distribution and metabolic abnormalities, and can be congenital or acquired. In GHD, the pituitary gland does not produce sufficient growth hormone, which is important not only for height but also for optimal bone, heart, muscle and brain development.1 In addition to the physical manifestations, GHD has psychosocial and behavioural impacts, including poor sleep, reduced performance in physical activities and experiencing teasing or bullying.2
Treatment of paediatric GHD with human growth hormone (hGH) began in the 1950s,3 when growth hormone was obtained from human cadavers but, in 1985, cadaver-derived pituitary growth hormone was implicated in several cases of Creutzfeldt-Jakob disease, causing the US Food and Drug Administration (FDA) to cease distribution of cadaver-derived growth hormone.4 Since then, recombinant DNA-produced hGH (somatropin) has ensured a safe and unlimited supply for uninterrupted therapy at doses sufficient to restore normal growth. Increased awareness of paediatric GHD has resulted in a substantial increase in the demand for hGH and this has become a growing market.5
Currently approved hGH for the long-term treatment of children with GHD include GenotropinÒ (Pfizer, New York, New York, USA), HumatropeÒ (Eli Lilly, Indianapolis, Indiana, USA), NorditropinÒ (Novo Nordisk, Bagsværd, Denmark), NutropinÒ (Genentech, South San Francisco, California, USA), and SaizenÒ (EMD Serono, Rockland, Massachusetts, USA). Daily subcutaneous administration is the preferred administration route of hGH as it leads to the significant rise in growth rates and low incidence of antibody development.6 However, daily hGH injections impose substantial burdens upon patients and their caregivers. Among older children and adolescents, noncompliance is common, resulting in impaired growth.7 Caregivers of younger children have to deal with resistance and hesitation, and experience emotional effects from administering an uncomfortable or painful treatment.8 There is, therefore, a need for longer-acting formulations of hGH. The use of a depot hGH preparation in children with GHD was first reported in 1979.9 Since then, many companies have attempted to develop a long-acting hGH, either using depot formulations of unmodified hGH or by increasing the molecular size of hGH through permanent protein modification, but most have been discontinued or are approved only in limited geographic areas.10
The development of TransConÒ hGH (Ascendis Pharma, Hellerup, Denmark), a once-weekly therapy for children with GHD, has attracted a great deal of attention. TransCon hGH has been designed to provide sustained release of unmodified hGH at a predictable rate over 1 week, in order to allow the same tissue distribution and receptor activation as endogenous hGH. Recombinant hGH is transiently bound to a carrier, methoxy PEG (mPEG), via a proprietary TransCon linker that is autohydrolysed under physiologic pH and temperature. The release of hGH liberates the inactive mPEG carrier, allowing elimination from the body, primarily by renal filtration and to a minor extent by hepatobiliary excrettion.10 In a phase II study, the formulation was found to be safe and well-tolerated, and was comparable to daily Genotropin in terms of pharmacokinetics, with no occurrence of neutralising antibodies.11
Data from the phase III heiGHt study (ClinicalTrials.gov Identifier: NCT02781727) were presented at the Annual Meeting of the Endocrine Society (ENDO) 23–26 March 2019 in New Orleans, Louisiana. In this study, 161 treatment-naïve prepubertal children with GHD were randomly assigned (2:1) to receive either once-weekly TransCon hGH (0.24 mg/kg/week subcutaneously) or daily Genotropin (34 µg/kg/day or 0.24 mg/kg/week subcutaneously) for 52 weeks. The mean age of study participants, of whom 82% were male, was 8.5 years, and inclusion criteria included bone age at least 6 months behind chronological age. Two subjects, one from each arm, withdrew from the trial prior to the final visit.
Treatment with TransCon hGH over 52 weeks resulted in an annualised height velocity (AHV) of 11.2 cm/year compared to 10.3 cm/year for daily Genotropin (95% confidence interval [CI] 0.22–1.50 cm/year; p=0.0088). The AHV was greater for TransCon hGH than for daily hGH at each visit, with the treatment difference reaching statistical significance from and including week 26 onwards. Height standard deviation score (SDS) at 52 weeks increased from baseline by 1.05 for TransCon hGH and by 0.94 for daily hGH, and the treatment difference in height SDS increased at each visit over 52 weeks. In addition, the incidence of poor responders (AHV <8.0 cm/year) was lower in the TransCon hGH group compared with the daily hGH group (11% versus 45%). No neutralising antibodies were detected, and a low level (<10%) of low-titre non-neutralising antibodies was similar between the two arms. Body mass index and mean glycated haemoglobin values were stable over the course of the study.12
No serious adverse events related to the study drug and no treatment-emergent adverse events leading to discontinuation of study drug occurred in either treatment arm. Adverse events leading to dose reduction were reported twice in the TransCon hGH arm (1.9%) and once in the daily hGH arm (1.8%). Two subjects in each treatment arm experienced mild injection site reactions.12
TransCon hGH is being further evaluated in children in two other phase III studies. The fliGHt Trial (ClinicalTrials.gov Identifier: NCT03305016) is evaluating TransCon hGH over 26 weeks in subjects who switch from daily hGH; results are expected in the second quarter of 2019. The enliGHten Trial (ClinicalTrials.gov Identifier: NCT03344458) is a long-term extension study that allows subjects from the heiGHt and fliGHt Trials to continue once-weekly TransCon hGH treatment, and will complete in December 2021. Ascendis Pharma is expected to submit a Biologics License Application to the FDA in the first half of 2020. Ascendis is also developing an auto-injector to administer TransCon hGH, and the formulation is being evaluated in adult HGD.13
In a press statement, Mary Andrews, Chief Executive Officer and co-founder of the MAGIC Foundation, the global leader in endocrine health, advocacy, education, and support, commented: “Children have a short time to grow and a lifetime to live, which is why it is so important to help those with GHD have the best chance possible of growing up to achieve normal adult height and experience both good physical and mental health given the substantial psychosocial impact of the disease. Children with GHD and their families have waited years for a long-acting growth hormone therapy that could ultimately reduce the number of injections needed to help these children thrive.”14
This study has shown that TransCon hGH has the potential to optimise adherence to GH replacement therapy, improving treatment outcomes in real-world situations.
- National Organisation for Rare Disorders (NORD). Growth Hormone Deficiency. 2016. Available at: https://rarediseases.org/rare-diseases/growth-hormone-deficiency/ (accessed 30 April 2019).
- Brod M, Alolga SL, Beck JF, et al. Understanding burden of illness for child growth hormone deficiency. Qual Life Res. 2017;26:1673–86.
- Raben MS. Treatment of a pituitary dwarf with human growth hormone. J Clin Endocrinol Metab. 1958;18:901–3.
- Appleby BS, Lu M, Bizzi A, et al. Iatrogenic Creutzfeldt-Jakob disease from commercial cadaveric human growth hormone. Emerg Infect Dis. 2013;19:682–4.
- Reuters. Human Growth Hormone Market 2019 Trends, Size, Share, Growth Insight, New Development And Global Forecast To 2023. 2019. Available at: https://www.reuters.com/brandfeatures/venture-capital/article?id=94110 (accessed 30 April 2019).
- Takano K, Shizume K, Hibi I. A comparison of subcutaneous and intramuscular administration of human growth hormone (hGH) and increased growth rate by daily injection of hGH in GH deficient children. Endocrinol Jpn. 1988;35:477–84.
- Cutfield WS, Derraik JG, Gunn AJ, et al. Non-compliance with growth hormone treatment in children is common and impairs linear growth. PLoS One. 2011;6:e16223.
- Loftus J, Lamoureux RE, Yaworsky A, et al. Caregiver burden in daily human growth hormone injections for children. Value in Health. 2017;20:A758.
- Lippe B, Frasier SD, Kaplan SA. Use of growth hormone-gel. Arch Dis Child. 1979;54:609–13.
- Sprogoe K, Mortensen E, Karpf DB, et al. The rationale and design of TransCon Growth Hormone for the treatment of growth hormone deficiency. Endocr Connect. 2017;6:R171–81.
- Chatelain P, Malievskiy O, Radziuk K, et al. A randomized phase 2 study of long-acting TransCon GH vs daily GH in childhood GH deficiency. J Clin Endocrinol Metab. 2017;102:1673–82.
- Thornton P, Hofman P, Maniatis AK, et al. OR17-4. Transcon Growth Hormone In The Treatment Of Pediatric Growth Hormone Deficiency: Results Of The Phase 3 Height Trial. Presented at the Annual Meeting of the Endocrine Society (ENDO) 23–26 March 2019, New Orleans, Louisiana, USA.
- Hoybye C, Pfeiffer AF, Ferone D, et al. A phase 2 trial of long-acting TransCon growth hormone in adult GH deficiency. Endocr Connect. 2017;6:129–38.
- Ascendis Pharma. Ascendis Pharma Announces Phase 3 heiGHt Trial Demonstrated Superior Efficacy and Comparable Safety and Tolerability of TransCon™ hGH to a Daily Growth Hormone. 2019. Available at: www.globenewswire.com/news-release/2019/03/24/1759837/0/en/Ascendis-Pharma-Announces-Phase-3-heiGHt-Trial-Demonstrated-Superior-Efficacy-and-Comparable-Safety-and-Tolerability-of-TransCon-hGH-to-a-Daily-Growth-Hormone.html (accessed 30 April 2019).