Current treatment options - an update

Growth hormone deficiency can be congenital, acquired, or idiopathic. The clinical course depends on age and severity of growth hormone deficiency. Treatment of growth hormone deficiency is by substitution of endogenous growth hormone. Conventional recombinant somatropin is injected subcutaneously once daily. A long-acting somatropin analogue to be administered only once a week was approved in Switzerland last year.

In children, growth hormone deficiency typically results in growth retardation, usually associated with short stature with normal proportions, this can manifest during the first year of life [1–3]. Children with growth hormone deficiency often have midface hypoplasia, hypotonia, high-pitched voice, thin hair, slow nail growth, and truncal obesity [2]. Depending on the severity of growth hormone deficiency, neuropsychiatric and cognitive complications may also occur [4]. Congenital growth hormone deficiency is caused by autosomal inherited gene mutations or morphological malformations of the brain. In the case of acquired growth hormone deficiency, injuries to the pituitary gland and/or hypothalamus, for example due to traumatic effects, infections or tumors, are possible causes.

Therapy with recombinant somatropin

Treatment with recombinant somatropin injected subcutaneously once daily produces catch-up growth over several years in children with severe growth hormone deficiency [3,5]:

The current Pediatric Endocrine Society guideline recommends an initial daily dose of 0.022-0.035 mg/kg body weight in pediatric patients, with subsequent individualization of the daily dose [6]. Treatment should be continued until closure of the epiphyseal joints [5]. This guideline recommends that plasma levels of insulin-like growth factor 1 (IGF-1) be measured to monitor therapy during treatment with recombinant somatropin and that the dose be reduced if plasma levels of IGF-1 exceed the normal range [6].
The current American Association of Clinical Endocrinologists/American College of Endocrinology guideline recommends an initial daily dose of 0.3-0.4 mg in non-diabetic younger (<30 years) patients [7]. The dose should subsequently be individualized based on clinical response, IGF-1 levels, and tolerability [7]. This guideline also recommends monitoring plasma levels of IGF-1 to monitor therapy [7]. The average SDS (standard deviation score) of IGF-1 should be within the age-specific normal range of -2 to +2 [7].

Overall, the benefit-risk ratio of somatropin treatment of pediatric patients with growth hormone deficiency is considered favorable [3]. Whereas somatropin can lead to hyperglycemia due to increased insulin resistance and decreased glucose uptake into skeletal muscle, especially with long-term therapy (box) . To minimize the risks associated with therapy, appropriate clinical and laboratory monitoring of patients is advisable.

Somatrogon as a new therapeutic option: long-acting growth hormone

Somatrogon (^Ngenla®), a somatropin analogue for once-weekly use, was approved in Switzerland in June 2022 [8]. Somatrogone can be used for proven growth hormone deficiency in children and adolescents aged 3 years and older [8]. With this drug, the number of necessary injections can be reduced with a similar therapeutic effect as with recombinant somatropin for daily use [3]. This can bring an improvement in quality of life and a gain in flexibility for patients for whom daily injections create distress.

Somatrogone can be detected in the circulation for approximately six days after the last administration [9]. There is no accumulation of somatrogone after once-weekly administration [9]. During somatrogone treatment, serum concentrations of IGF-1 increase in a dose-dependent manner [9]. Compared to daily use, the IGF profile of somatrogone differs. Serum concentrations of IGF-1 are maximal about two days after subcutaneous administration of somatrogon, and average IGF-1 levels are reached about four days later [9]. Somatrogon is currently available as an injection solution in a pre-filled pen in two different strengths (24 mg and 60 mg) [9]. The main study comparing the safety and efficacy of somatrogone with somatropin for daily use was a randomized, unblinded, controlled clinical trial [9,10]. In this study, a total of 228 pediatric patients with growth hormone deficiency were randomized 1:1 to receive somatrogone (0.66 mg/kg/week) or somatropin for once-daily use (0.24 mg/kg/week) for a period of twelve months [10]. During the study, 224 patients received at least one dose of study treatment [10]. The primary clinical endpoint was annualized size growth after 12 months of treatment [10]. Somatrogone was noninferior to somatropin for daily use at 12 months with respect to the primary clinical end point (Table 1) [9,10]. After 12 months of treatment, the mean IGF-1 SDS in the somatrogone group was 0.65, and the mean IGF-1 SDS in the somatropin group was near 0 [9,10]. In total, 29 study participants had an IGF-1 SDS greater than +2 (somatrogone: n=26; somatropin: n=3) at least one time point during the study [10].

Literature:

Second revision of the guideline Diagnosis of growth hormone deficiency in childhood and adolescence (as of 03/14/2022). Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften e.V. (AWMF).
Dattani MT, et al: A review of growth hormone deficiency. Paediatr Child Health 2019; 29(7): 285-292.
Frizler M, Paesler J: Long-acting growth hormone analogues for substi tution of endogenous growth hormone in children and adults with growth hormone deficiency: once-weekly administration. Drug Safety Bulletin. Information from BfArM and PEI, Paul Ehrlich Institute 2022; Issue 4, pp. 9-23.
Feldt-Rasmussen U: Adult Growth Hormone Deficiency – Clinical Management; www.ncbi.nlm.nih.gov/ books/NBK425701 (accessed www.ncbi.nlm.nih.gov/ books/NBK425701 ).
Bruno A, et al: Praktische Endokrinologie. Elsevier GmbH, Urban & Fischer Verlag. 2nd edition 2010; p. 105.
Grimberg A, et al: Drug and Therapeutics Committee and Ethics Committee of the Pediatric Endocrine Society. Guidelines for Growth Hor mone and Insulin-Like Growth Factor-I Treatment in Children and Adolescents: Growth Hormone Deficiency, Idiopathic Short Stature, and Primary Insulin-Like Growth Factor-I Deficiency. Horm Res Paediatr 2016; 86(6): 361-397.
Yuen KCJ et al: American Association of Clinical EndocrinoLogists and American College of Endocrinology Guidelines for Management of Growth Hormone Deficiency in Adults and Patients transitioning from pediatric to adult care. Endocr Pract 2019; 25(11): 1191-1232.
Drug Information, www.swissmedicinfo.ch,(last accessed Feb. 08, 2023).
Product information Ngenla; www.ema.europa.eu/en/medicines/ human/EPAR, (last accessed Feb. 08, 2023).
Deal CL et al: Efficacy and Safety of Weekly Somatrogon vs Daily Somatropin in Children With Growth Hormone Deficiency: A Phase 3 Study. J Clin Endocrinol Metab. 2022; 107(7): e2717-e2728.
Child CJ et al: Safety Outcomes During Pediatric GH Therapy: Final Results From the Prospective GeNeSIS Observational Program. J Clin Endocrinol Metab 2019; 104(2): 379-389.
Kim SH et al: Effects of growth hormone on glucose metabolism and insulin resistance in humans. Ann Pediatr Endocrinol Metab. 2017;22(3): 145-152.