ENGLISH
Take-home message
Based on phase 3 clinical trials, three long-acting growth hormone (LAGH) formulations – lonapegsomatropin, somapacitan, and somatrogon – have recently been approved for the treatment of paediatric growth hormone deficiency (GHD). These agents are indicated for use in children from the age of 3 years (from 30 months for somapacitan) until attainment of bone age > 14 years in girls and > 16 years in boys, corresponding to the approved indications for daily recombinant human growth hormone (rhGH).
Available evidence does not demonstrate clinically relevant superiority of any of the approved LAGH preparations over the others with respect to efficacy or safety. Based on current data, LAGH therapy may be considered for most children with GHD; however, long-term real-world studies are required to confirm sustained safety and effectiveness.
Importantly, selected patient groups may particularly benefit from once-weekly administration due to improved treatment adherence. Dosing of LAGH should be guided by serum IGF-1 concentrations, optimally assessed on day 4 after injection. Initial doses recommended by the manufacturer may be adjusted by the treating physician based on individual clinical response.
Clinical trials evaluating the use of LAGH in children with short stature of causes other than GHD – including idiopathic short stature, small for gestational age, Noonan syndrome, Turner syndrome, achondroplasia, and SHOX gene mutations – are currently ongoing. Results from these studies are awaited.
Introduction
Recombinant human growth hormone (rhGH) was approved for the treatment of paediatric growth hormone deficiency (GHD) in Europe, the United States, and Japan in 1985. Subsequently, rhGH gained approvals for additional indications, including adult GHD (1996) and short stature associated with Turner syndrome (1996), Prader–Willi syndrome (2000), and small for gestational age (SGA) birth (2001) across Europe, the United States, and Japan. In the United States, rhGH was additionally approved for idiopathic short stature (ISS) in 2003 and for Noonan syndrome in 2007 [1]. Long-term studies have confirmed the efficacy and safety of rhGH administered as daily subcutaneous injections [2, 3]. However, the burden of long-term daily therapy for children and caregivers and the growing problem of suboptimal adherence have been recognised as major limitations that may compromise treatment effectiveness [4, 5].
In response, development of long-acting growth hormone (LAGH) formulations began as early as 1999. The aim was to reduce injection frequency while maintaining comparable or superior efficacy and an acceptable safety profile. Long-acting growth hormone implementation in paediatric practice was also expected to improve quality of life and the cost-effectiveness of therapy [6]. A series of clinical trials have therefore evaluated the efficacy and safety of LAGH preparations.
Results regarding efficacy and safety during phase 3 clinical trials for currently approved long-acting growth hormone products for the treatment of paediatric growth hormone deficiency
At present, three different products classified as LAGH are available on European markets; following completion of phase 3 clinical trials, they have been approved for the treatment of GHD in children:
Each of the above products acts on the growth hormone receptor (GHR) in a manner analogous to native GH, resulting in activation of the intracellular signalling cascade (JAK2/STAT) and stimulation of IGF-1 secretion. However, the method used to extend the serum half-life of the GH molecule differs for each product. Regardless of the approach employed, in each case it was possible to administer these drugs every 7 days as subcutaneous injections.
Recently, in addition to publications of the clinical-trial results of individual LAGH products (i.e. comparisons between the efficacy and safety of a daily preparation, used as the comparator, and each of the above LAGH products, used as the investigational drug), the first publications have appeared on the efficacy and safety of individual products in real-world settings, i.e. clinical observations made after completion of phase 3 trials. Moreover, initial attempts have been presented to compare the estimated costs of treatment between long- and short-acting preparations. Treatment effects have also been compared based on collated available clinical-trial results for all LAGH products. In addition, an expert position statement has been prepared regarding the use of LAGH in children with GHD.
Lonapegsomatropin (Skytrofa®)
Lonapegsomatropin was the first LAGH approved for the treatment of children with GHD, as mentioned above, in 2021.
Mechanism of action: Lonapegsomatropin is a pegylated preparation. This means that the somatropin (rhGH) molecule is conjugated to a methoxy polyethylene glycol (mPEG) carrier via a linker (referred to as TransCon). The linker binds somatropin to the carrier, and auto-cleavage of somatropin from the carrier occurs in a predictable manner, resulting in somatropin being present in the bloodstream at therapeutic (although not constant) concentrations over one week after injection. The molecular mass is therefore the same as native somatropin, i.e. 22 kDa, and the half-life is 25 hours. PEGylation has been used in biotechnology for over 20 years; examples include Pegasys (pegylated interferon α-2a), used to treat chronic hepatitis B and C, and Pelgraz, used to prevent complications associated with neutropenia.
Phase 3 trial results: The phase 3 trial conducted for this product had registration number NCT02781727. It commenced on 13 December 2016 and was completed on 17 January 2019. For the purposes of the trial, 161 prepubertal children from 15 countries were recruited, aged 3 to 12 years inclusive (boys) and up to 12 years inclusive (girls). GHD was dia- gnosed based on the following test results: max GH ≤ 10 ng/ml in two different stimulation tests, IGF-1 ≤ −1.0 SD, bone age (BA) at least 6 months younger than chronological age (CA), and height SDS (HSDS) ≤ −2.0. Eligible children could not have been previously treated with rhGH. Children were randomised 2:1 to receive the investigational product (lonapegsomatropin once weekly) or the comparator (Genotropin® once daily). The investigational dose was established in phase 2 as 0.24 mg hGH/kg/week [10], while the comparator was administered at the standard dose, i.e. 0.24 mg hGH/kg/week (0.034 mg/kg/day).
The primary endpoint was annualised height velocity (HV) after 52 weeks compared with the control group. After 52 weeks of treatment, mean HV was 11.2 cm/year in the lonapegsomatropin group and 10.3 cm/year in the control group receiving Genotropin®. Secondary endpoints, including comparable improvement (relative to daily somatropin) in HSDS and IGF-1, as well as the absence of clinically relevant adverse events and anti-drug antibodies, were also met [11].
The trial subsequently entered an open-label extension (OLE) phase, which continued until 21 February 2023. Initially, results from two additional years of the OLE phase were published [12]. These data demonstrated efficacy and safety of the new drug both in children who had participated in the main phase (all of whom were now receiving lonapegsomatropin) and in an additionally recruited cohort. This cohort included children with GHD aged ≥ 1 to 17 years (with body weight not below 11.5 kg); these children could have been previously treated with daily rhGH injections (except those younger than 3 years). In total, 307 children received the investigational drug in this phase. Further improvement in HSDS and continued improvement in HV were observed; no unfavourable changes were found in BMI or advancement of BA. The drug was well tolerated with a high compliance rate (98%) [12].
In 2025, results were published covering up to 6 years of lonapegsomatropin use in this clinical-trial programme [13]. Lonapegsomatropin demonstrated sustained efficacy over the analysed period. At the end of year 4 of therapy, 298 children remained on treatment, and mean HSDS was −0.39, indicating that their height approached the population mean for healthy children (HSDS = 0, i.e. the 50th percentile). It should be recalled that at entry into the main phase of the clinical trial, mean HSDS was −2.93 ±0.87.
At the time of this summary, 81 participants had completed treatment due to attainment of final height. Height exceeding the mean target HSDS calculated from parental height was achieved by 48 children (59.3%).
Across the treated cohort, mean weekly IGF-1 values remained within the range of 0 to +2.0 SD throughout the trial. However, it should be considered that, according to the protocol, target IGF-1 SDS values were intended to remain between 0 and +2.0; if this criterion was not met, the lonapegsomatropin dose was increased or decreased by 20%. Ultimately, the dose remained relatively stable over this stage of the trial.
Height velocity was also presented by pubertal stage and was found to be stable across stages (stage I: 7.28; II: 7.82; III: 9.23; IV: 9.08; V: 8.3 cm/year). There was no evidence of accelerated skeletal maturation that could prematurely terminate growth and reduce efficacy. At the end of follow-up, the BA/CA ratio remained at 0.9, indicating that BA advanced more slowly than CA (at baseline, BA/CA was 0.69 ±0.15). Adverse events were mostly mild or moderate and comparable to those reported with daily GH. No negative safety signals related to anti-drug antibodies were identified [13].
Somapacitan (Sogroya®)
Somapacitan was approved for the treatment of paediatric GHD in 2023. It is the only LAGH also approved for the treatment of GHD in patients after completion of linear growth (in 2020); however, this approval applies to individuals aged 18 years or older.
Mechanism of action: Somapacitan is a preparation in which a small non-covalent albumin-binding moiety is attached to hGH. This facilitates reversible binding to endogenous albumin, delaying elimination from circulation and thereby extending the duration of action. The molecular mass is slightly higher than native somatropin (23 kDa), and the half-life is approximately 34 hours. Similar techniques of conjugating a peptide drug with an albumin-binding moiety to extend half-life have been used for insulin detemir and for glucagon-like peptide-1 receptor agonists liraglutide and once-weekly semaglutide.
Phase 3 trial results: The phase 3 trial for this product had registration number NCT03811535. It commenced on 20 May 2019 and was completed on 30 September 2025. For the purposes of the trial, 200 prepubertal children from 21 countries were recruited, aged 30 months (2 years and 26 weeks) to 11 years inclusive (boys) and up to 10 years inclusive (girls). Growth hormone deficiency was diagnosed based on the following: max GH ≤ 10 ng/ml in two different stimulation tests, IGF-1 < −1.0 SD, HSDS < −2.0, and HV < 25th percentile. Eligible children could not have been previously treated with rhGH or rhIGF-1. Children were randomised 2:1 to receive the investigational product (somapacitan once weekly) or the comparator (Norditropin® once daily). The investigational dose was established in phase 2 as 0.16 mg/kg/week [14], while the comparator was administered at the standard dose, i.e. 0.24 mg hGH/kg/week (0.034 mg/kg/day). The main phase lasted 52 weeks. The primary endpoint was HV during the first treatment year. Based on results from the main phase published in 2022 [15], mean HV after one year was 11.2 and 11.7 cm/year for somapacitan and daily GH (Norditropin®), respectively, confirming non-inferiority. Secondary endpoints, including comparable improvement (vs. daily somatropin) in HSDS, HSDS gain, BA/CA progression, IGF-1 SDS values, and the absence of clinically relevant adverse events and anti-drug antibodies were also met. Safety in the somapacitan group was comparable to the control group and consistent with well-established daily GH therapy. Injection-site reactions were infrequent: 5.3% for somapacitan and 5.9% for Norditropin®.
In this trial, questionnaire assessments were also conducted at baseline and after 52 weeks. The Growth Hormone Deficiency–Child Impact Measure (GHD-CIM) evaluated the impact of GHD on physical functioning and social/emotional well-being. Two additional questionnaires assessed treatment burden: the Growth Hormone Deficiency–Child Treatment Burden (GHD-CTB), measuring physical burden and emotional/disruption aspects for children, and the Growth Hormone Deficiency–Parent Treatment Burden (GHD-PTB), measuring emotional burden and disruption in daily activities for parents/caregivers; these were completed after one year. All questionnaires were developed in accordance with US FDA guidance. Changes in GHD-CIM scores from baseline to week 52 showed substantial similarity between treatment groups in reduced disease burden [16]. Treatment burden (GHD-CTB and GHD-PTB) assessed after one year favoured somapacitan across domains, with a statistically significant difference for GHD-PTB. Results from the Growth Hormone Device Assessment Tool indicated that an equally high proportion of respondents (96%) considered both somapacitan and Norditropin® (FlexPro family devices) easy or very easy to use and handle [16].
The trial entered an extension phase lasting 3 years, in which all children received the investigational product. In 2023, results summarising the 2-year treatment period after all children had switched to somapacitan were published [17]. In 2025, an analysis of efficacy and safety over the entire 3-year period (52-week main phase plus 2-year extension) was presented [18].
It was found that after 3 years of treatment in children with GHD, there were no differences in ongoing HV between children switched from daily GH and those treated with somapacitan from the outset. After a further 2 years of therapy, HV remained very good in both groups: 7.4 cm/year in those receiving somapacitan from the beginning and 7.8 cm/year in those receiving Norditropin® during the first year and somapacitan during the last 2 years. A further favourable and comparable HSDS gain was observed in both groups: 2.04 ±0.85 and 2.38 ±1.14; HV SDS gain: 4.07 ±2.5 and 4.57 ±2.75; and IGF-1 SDS gain: 1.79 ±1.12 and 1.96 ±1.02, respectively. BA/CA progression was comparable between groups: 3.88 ±1.39 and 3.81 ±1.17 over 3 years [17].
Target height based on parental height was established at baseline. At the time of this summary, children’s current height was similar in percentile position to target height (indicating catch-up toward the expected growth channel). Analysis of adverse events and anti-drug antibody effects supported the safety of treatment.
The 2025 publication [17] also presented results of the GH: patient preference questionnaire (GH-PPQ), completed by children who switched from daily to weekly therapy at 4 weeks after the change. Results indicated that 90% of respondents strongly or very strongly recommended once-weekly therapy and believed that they would be more adherent to once-weekly somapacitan compared with the daily GH regimen. The clinical programme was also continued in a substantially smaller group of children who had participated in an earlier phase 2 study; in this cohort, data regarding up to 4 years of therapy were collected by 2023 [14] and were evaluated positively.
It is also worth noting that, in addition to IGF-1 SDS and IGFBP-3 SDS changes, endpoints such as the IGF-1/IGFBP-3 molar ratio and bioactive IGF-1 were analysed. Bioactive IGF-1 was measured at baseline and at weeks 13, 26, 78, and 104 using an in-house IGF-1 receptor kinase activation assay. Finally, in addition to total IGF-1 analyses, the novel IGF-1/IGFBP-3 molar ratio and bioactive IGF-1 data presented here suggest similar IGF-1 response between somapacitan and daily GH treatments at both the level of total IGF-1 and the bioactive fraction of IGF-1 [17].
Somatrogon (Ngenla®)
Somatrogon was approved for the treatment of GHD in children in 2023. It is the only LAGH that has been included in Poland as an alternative therapy (alongside rhGH for daily use) in the Ministry of Health’s B19 therapeutic program “Treatment of short children with GHD” (alongside rhGH for daily use) since October 1, 2024, and currently in Poland many children with GHD use Ngenla as a fully reimbursed drug.
Mechanism of action: Somatrogon was engineered by attaching, via glycosylation, three copies of the C-terminal peptide (CTP) derived from the beta subunit of human chorionic gonadotropin. One copy was attached at the N-terminus and two copies (in tandem) at the C-terminus. The molecular mass is substantially higher than native somatropin (40 kDa), and the half-life is 37.7 hours. This technology was introduced to the market over 10 years ago, when CTP was attached to FSH (ELONVA), and the safety and efficacy of the technology were confirmed. The prolonged half-life of somatrogon is therefore attributable to CTP glycosylation, enabling once-weekly dosing. As noted, somatrogon also binds the GH receptor, initiates a signalling cascade (JAK2/STAT), and induces IGF-1 synthesis.
Phase 3 trial results: The phase 3 trial for this product had registration number NCT02968004. It began in December 2016 and ended in May 2024. For trial purposes, 224 prepubertal children from 21 countries were recruited, aged 3 to 12 years inclusive (boys) and up to 11 years inclusive (girls). Growth hormone deficiency was diagnosed based on the following: max GH ≤ 10 ng/ml in two different stimulation tests, IGF-1 ≤ −1.0 SD, and HV < −0.7 SD. Notably, short stature < –2.0 SD was not required in this trial. Eligible children could not have been previously treated with rhGH or rhIGF-1. Children were randomised 1:1 to receive the investigational product (somatrogon once weekly) or the comparator (Genotropin® once daily). The investigational dose was established in phase 2 as 0.66 mg/kg/week [19], while the comparator was administered at the standard dose of 0.24 mg hGH/kg/week (0.034 mg/kg/day). The main phase lasted 52 weeks. The primary endpoint was HV in the first year of therapy. Based on results from the main phase published in 2022 [20] and in 2024 as plain-language [21], mean HV after one year was 10.1 and 9.78 cm/year for somatrogon and daily GH (Genotropin®), respectively, confirming non-inferiority. Secondary endpoints, including comparable improvement (vs. daily somatropin) in HSDS gain, BA/CA progression, IGF-1 SDS values, and the absence of clinically meaningful adverse events, were also met. Safety was comparable to the control group and consistent with well-established daily rhGH therapy. A substantially higher rate (than for somapacitan) of injection-site reactions, mainly injection-site pain, was reported: 39% for somatrogon and 25% for Genotropin®. During the main trial phase (between February 2019 and August 2020) an additional clinical study (NCT03831880) was conducted; its results were published on the clinical trials website [22]. The study involved 12-week treatment with one of two randomly assigned preparations (daily or weekly) in 87 children with GHD aged 3 to < 18 years, followed by switching to the other preparation for another 12 weeks. At the end of the study, preference data were collected regarding the two regimens, taking into account multiple aspects related to the device, family burden, and injection-related pain. The vast majority of patients preferred once-weekly injections [22].
During the main trial, questionnaire assessments of health-related quality of life (HRQoL) were also performed. The Quality of Life in Short Stature Youth (QoLISSY) questionnaire was administered at baseline and after 12 months of treatment in 117 patients (half treated daily and half once weekly). The QoLISSY-Parent questionnaire was completed by parents/caregivers of children aged < 7 years and by some parents/caregivers of children aged ≥ 7 years; children aged ≥ 7 years completed the QoLISSY-Child questionnaire. Among children aged < 7 years, total and subscale QoLISSY-Parent scores showed similar HRQoL improvement after 12 months in both treatment groups compared with baseline. In children aged ≥ 7 years, self-reported QoLISSY-Child total and subscale scores indicated HRQoL improvement after 12 months that was numerically greater with somatrogon than with somatropin (similar results were observed for QoLISSY-Parent in this age group). At both time points, children reported better HRQoL than perceived by their parents/caregivers [23].
After completion of the main phase, the trial entered a 4-year open label extension (OLE) phase in which all children received the investigational product. Initially, data covering the main phase and two years after switching children to somatrogon were presented as conference reports; a publication from this period is currently under review [24]. Subsequently, a final analysis of the full 5-year treatment period was prepared; it has also been presented as conference reports and will be published soon [25]. Based on these data, treatment effects after 3 and 5 years can be examined.
It was found that after an additional 3 years of somatrogon treatment in children with GHD, there were no differences in ongoing HV and HSDS improvement between the group switched from daily therapy and the group treated with somatrogon from the outset: after a further 2 years of therapy, HV remained very good in both groups and was 7.78 cm/year in those receiving somatrogon from the beginning and 8.05 cm/year in those receiving Genotropin® in the first year and somatrogon during the last 2 years. HSDS continued to improve during OLE. In the group receiving somatrogon (OLE Y2) from the outset, HSDS was −1.49 at the end of the first year of OLE, i.e. OLE Y1 and −1.08 in the group receiving Genotropin® in the first year and somatrogon during the last 2 years. In the group receiving somatrogon from the outset, mean HSDS after 2 years of treatment was −1.08, while in the group initially receiving Genotropin® it was −0.81.
Mean IGF-1 SDS at baseline was −1.98 and −1.74 in patients originally randomised to somatrogon and somatropin, respectively. At the start of OLE, mean (SD) IGF-1 SDS was +0.64 (1.34) and −0.70 (1.07) in patients originally randomised to somatrogon and somatropin, respectively, indicating a substantially greater improvement after one year in the somatrogon group. For all patients combined, IGF-1 SDS increased during OLE, with a mean (SD) of 1.21 (1.23) at the end of OLE Y1 and 1.25 (1.24) at the end of OLE Y2. The change in IGF-1 SDS remained positive throughout OLE, with a mean (SD) of 2.96 (1.20) at the end of OLE Y1 and 2.97 (1.2) at the end of OLE Y2. Mean IGF-1 SDS and change in IGF-I SDS were similar when patients were stratified by main-phase treatment assignment.
The frequency of injection-site pain decreased compared with the first treatment year. Injection-site pain was reported by 55 patients (25.9%) by the end of OLE Y1 and 35 patients (19.8%) by the end of OLE Y2.
Regarding the summary of results up to 5 years after switching children (i.e. when all children were receiving somatrogon) [25], HV remained very good and was 8.11, 7.91, 7.02, and 6.56 cm/year in OLE Y1, Y2, Y3, and Y4, respectively, while mean HSDS systematically improved until reaching 0 SD (the 50th percentile on growth charts). Mean IGF-1 SDS increased and remained within the normal range throughout the trial; however, dose reductions were required in approximately 20% of patients due to IGF-1 SDS > 2.0. AE incidence ranged from 53.8% to 72.3%, typically mild or moderate; the frequency of serious AEs in individual years was low (0–4.7%), and investigators did not attribute them to the investigational drug. The most common AEs remained injection-site pain and erythema. Although anti-drug antibodies were relatively frequent, they did not affect efficacy or safety.
Summary of clinical-trial results
Based on the obtained results, the three LAGH products described above have been approved for the treatment of paediatric GHD from age 3 years (from 30 months for somapacitan) until attainment of bone age > 14 years in girls and > 16 years in boys (i.e. the same as for daily rhGH preparations). Indications differ by product: lonapegsomatropin and somatrogon are approved for paediatric GHD in children aged 3 to < 18 years, whereas somapacitan is approved for both children and adults with GHD, which in some cases allows continuity of therapy without switching products during transition to adult care. Table I provides an overview of the highlights from the Phase 3 clinical trials of the currently approved LAGH products for the treatment of paediatric GHD.
Table I
Overview of key information from phase 3 clinical trials of currently approved LAGH products for the treatment of paediatric GHD
Results of meta-analysis comparing first-year outcomes across all three long-acting growth hormone products available in Europe and the United States for paediatric growth hormone deficiency
In 2025, a meta-analysis was published evaluating the efficacy and safety of LAGH during the one-year main phase of the individual phase 3 paediatric GHD trials discussed above [26]. As emphasised earlier, individual LAGH products are molecularly distinct; the additional moieties or mechanisms extending LAGH action confer unique pharmacodynamic/pharmacokinetic properties that may influence efficacy and safety.
Four publications concerning three LAGH products (lonapegsomatropin, somapacitan, and somatrogon administered once weekly) were included in this network meta-analysis [11, 15, 20, 27], as well as one study concerning Eutropin Plus (LB03002) [28], a once-weekly LAGH used in South Korea. For sensitivity analysis, results from an additional data source were added, namely a somatrogon trial conducted in Japan [27], because the daily somatropin comparator dose in that trial was markedly lower than in other studies (0.025 mg/kg/day).
Based on this meta-analysis, treatment with lonapegsomatropin was associated with significantly higher annual HV and HSDS improvement at week 52 compared with daily somatropin and somapacitan. Improvement in IGF-1 SDS at week 52 was significantly higher for somatrogon compared with all other treatments, and for lonapegsomatropin compared with daily somatropin and somapacitan (with IGF-1 SDS remaining within the normal range in all trials). No significant differences were observed in BA/CA progression or in the frequency of serious adverse events (SAEs) [26]. It should be emphasized, however, that these data are only from the first year of treatment with individual LAGH preparations. Conclusions based on meta-analyses regarding longer treatment periods are unfortunately pending.
Expert recommendations for long-acting growth hormone use based on currently available clinical-trial evidence
Patient groups in whom long-acting growth hormone is particularly recommended or discouraged
Given the possibility of treating paediatric GHD with any of the discussed LAGH products, a 2024 expert Consensus Statement [29] objectively described the advantages and benefits of these LAGH preparations and the precautions to consider when planning treatment in this population. First and foremost, the position was presented that these drugs may be used in any child with GHD, in accordance with the summary of product characteristics regarding diagnosis, age, body weight, and bone age. However, it appears that particular groups of patients who may benefit most from LAGH include the following:
children at increased risk of poor adherence to daily rhGH (e.g. adolescents, or children treated long term with injection fatigue);
children receiving multiple medications;
children with neurodiversity (including autism and ADHD);
children (or parents/caregivers) with injection anxiety;
children who travel frequently and those from split households;
children whose families are in an unfavourable socio-economic situation and for whom GH treatment constitutes an additional burden.
When selecting a treatment approach, caution should be exercised when using LAGH in the following patient groups:
children with GHD after cancer and intracranial tumours – further studies of LAGH use in these patients are needed;
children with GHD and concomitant Prader–Willi syndrome – they may be predisposed to sleep apnoea and metabolic abnormalities;
children under 3 years old with GHD – there may be an increased risk of hypoglycaemia 1–2 days before the next LAGH injection (when GH concentrations are lowest);
children with short stature not related to GHD (i.e. due to SGA, ISS, Turner syndrome, Noonan syndrome, SHOX variants, or chronic kidney disease). Although phase II and III studies evaluating LAGH in many of these conditions are ongoing, at the time of publication the results were still unknown (their scope and status are presented in a separate chapter). It should be recalled that these conditions often require higher GH doses and higher IGF-1 levels and are associated with condition-specific genetic risk factors.
Recommendations for insulin-like growth factor-1 monitoring and long-acting growth hormone dose adjustment
The Consensus Statement [29] also extensively discussed recommendations for interpreting IGF-1 results used to adjust dosing. A key aspect of treating children with GHD using LAGH is the lack of stable IGF-1 concentrations between injections (which is noted with well-adhered daily injections). During LAGH therapy, IGF-1 fluctuations are observed: from a maximum level typically reached on day 2 after dosing, to an average level on day 4 after injection (optionally −1 day for somatrogon and somapacitan or +1 day for lonapegsomatropin), down to the lowest values on the day preceding the next injection.
For this reason, treatment monitoring is recommended using IGF-1 concentrations measured optimally 4 days (96 hours) after the previous dose (optionally −1 day for somatrogon and somapacitan or +1 day for lonapegsomatropin). If IGF-1 measurement was performed on another day (patients should be asked to note the date and time of dosing), correction tables (provided in the Consensus) should be used. IGF-1 should remain between −2.0 SD and +2.0 SD, ideally close to 0 SD. If IGF-1 SDS exceeds +2.0, a dose reduction of 15–20% per kg/week is recommended [29].
Although the initial LAGH dose is calculated based on body weight, clinicians may adjust doses according to experience and depending on IGF-1 levels, BMI, severity of GH deficiency, height velocity, pubertal stage, concomitant oestrogen replacement, and bone-age advancement. In children with obesity and GHD, a lower initial dose may be considered and calculated based on ideal rather than actual body weight to minimise the risk of transient hyperglycaemia. A lower initial dose may also be needed in patients at increased risk of intracranial hypertension, severe GHD, genetic abnormalities, or renal failure [29].
Review of available real-world evidence on long-acting growth hormone use
Physicians’ preferences regarding patient selection for long-acting growth hormone and long-acting growth hormone dosing
The first studies published after LAGH treatment of children with GHD began globally (real-world) confirmed physicians’ concerns outlined in the Consensus [29]. In 2025, results of a survey study characterising attitudes and barriers among paediatric endocrinologists toward somatrogon in the treatment of paediatric GHD in Israel were presented [30]. A 19-item questionnaire addressing frequency of LAGH use, patient selection, dosing strategies, monitoring practices, and physicians’ concerns was sent to 102 paediatric endocrinologists. Responses were obtained from 65 physicians (63.7%), who reported use of somatrogon in a total of 874 patients. More than half of the respondents (53.2%) reported switching more than half of their patients from daily GH to LAGH. However, the vast majority (91.9%) were reluctant to prescribe somatrogon to patients with an oncological history or genetic syndromes (66.1%); the main barrier was concern about the lack of long-term safety data. Regarding dosing, only 54.8% recommended a somatrogon starting dose consistent with the summary of product characteristics (0.66 mg/kg/week), while the remaining physicians used lower initial doses. Notably, 59.7% reported at least one case in which a decision was made to switch back to daily therapy. The most commonly reported adverse events were injection-site reactions (62.9%); in one case, marked injection-site lipoatrophy was reported after repeated injections into the same area [30].
The lipoatrophy case was described in a separate report [31] and is, in my view, worth brief discussion. It concerned a 5.5-year-old girl with GHD who initiated somatrogon at the standard dose of 0.66 mg/kg/week. Within 11 weeks, localised lipoatrophy developed in the right arm (right arm circumference 14 cm vs. 16 cm in the left arm); importantly, injections had been performed consistently in the same area of the right arm without recommended site rotation. After identification, therapy was modified to daily rhGH and strict injection-site rotation was requested. Despite these recommendations, the parents continued administering somatrogon injections, this time into the left arm, resulting in recurrence of lipoatrophy within 8 weeks [31]. This case illustrates the real challenges associated with injections observed in patients’ homes, the fear and reluctance of children to receive injections, and the frequent failure to follow medical recommendations for this reason in practice, and the best intentions of both parties.
Patient preferences regarding treatment choice
As noted above, each product uses a different pen device and has specific handling and storage requirements. The main issues regarding individual LAGH pens, dosage and use principles, and drug storage are presented in Table II. As the availability of these therapies expands across countries, it is likely that patient-level preferences for a given product will emerge. Notably, relevant analyses were reported in 2023 [32] and 2025 [33].
Table II
Dosing recommendations for individual LAGH products in children with GHD
First, patient and caregiver preferences for somapacitan versus somatrogon were compared [32]. In a randomised crossover study conducted in 2023, a total of 33 children with growth disorders and 37 caregivers were recruited at six sites in the United States. Each participant received structured training (provided by a certified nurse using the official instructions for use for each device) on both devices and subsequently performed a simulated injection. Training time, preparation and injection time, and successful completion of the injection were recorded; video recordings were used to document training and task duration for each device. Participants also completed the Device Handling and Preference Questionnaire (DHPAQ) to report device preference and perceived ease of use. After the standard visit, 10 children and 10 caregivers were randomly selected for a substudy evaluating the DHPAQ for validity, comprehensiveness, and interpretability. Most participants (84.3%) preferred the somapacitan device over the somatrogon device. Nearly all participants (98.6%) rated the somapacitan device as easy or very easy to use; the corresponding proportion for somatrogon was 74.3%. Mean training and injection time was shorter with the somapacitan device than with the somatrogon device [32].
A similar crossover study comparing somapacitan and lonapegsomatropin was conducted in 2025 [33] among 75 children aged 10–17 years with various growth disorders, and their caregivers. Participants were randomly assigned to receive training on one device followed by the other, and outcomes were analysed analogously to the earlier study. The majority of participants (78.6%) preferred somapacitan over lonapegsomatropin, whereas 7.1% reported no preference. Most participants considered somapacitan easy to use (97.1%) and easy to learn (95.7%); the respective values for lonapegsomatropin were 57.1% and 54.3%. Mean training time and mean preparation/injection time were shorter for somapacitan than for lonapegsomatropin (5.9 vs. 24.0 minutes and 0.9 vs. 10.6 minutes, respectively) [33].
Long-acting growth hormone dosage considerations
Beyond differences in usability and learnability, product-specific characteristics also affect drug utilisation. In some cases, two injections may be required for a single weekly dose, namely when the weight-based dose exceeds the maximum deliverable volume per injection.
For multi-dose pens (e.g. somapacitan and somatrogon), patients should be clearly instructed on correct pen use and discard rules to minimise drug loss due to expiry of the in-use pen. Dosing tables are currently available for Ngenla® to facilitate calculations for parents and patients. In contrast, lonapegsomatropin is administered as a single full dose at each dosing occasion (with the caveat of higher body weight, i.e. above 65 kg) (Table II).
In real-world practice, both patients and clinicians may prefer starting doses other than those recommended, for practical reasons (improved drug utilisation), economic reasons (reducing treatment costs), or to reduce the frequency of two-injection dosing occasions caused by limited remaining pen volume.
In 2025, a German study was published in the context of national availability of all three LAGH products (lonapegsomatropin, somapacitan, and somatrogon) [34]. The study aimed to provide early real-world data on their use and to characterise patient selection and clinician preferences outside clinical trials [34]. The cohort comprised the first 100 patients receiving LAGH in Germany, including 70 children with GHD from 15 centres and 31 adults from six centres. Among paediatric patients, 76% were boys, and the mean age at LAGH initiation was 9.2 years. Approximately half of the children (54%) were switched from daily GH therapy. Notably, 82% of patients received an initial LAGH dose below the manufacturer-recommended dose, with a median of 92% of the recommended dose. Among adult patients, all were switched from daily to once-weekly therapy, and 41% were prescribed a lower-than-recommended dose (it should be emphasised that somapacitan dosing recommendations in adults differ for treatment-naïve individuals versus those switching from daily GH therapy, see Table III) [34].
Table III
Starting doses of somapacitan in adult patients with GHD
| Age or additional factors | Treatment-naïve patient | Patient switching from prior therapy |
|---|---|---|
| 18–60 years | 1.5 mg/week | 2 mg/week |
| Woman receiving oestrogens | 2 mg/week | 4 mg/week |
| > 60 years | 1 mg/week | 1.5 mg/week |
Another 2025 report summarised IGF-1 concentrations after switching 14 children with GHD at a single US centre from daily GH to once-weekly lonapegsomatropin at manufacturer-recommended doses [35]. Five children required rapid dose reduction due to IGF-1 > 2.3 SDS, and in four cases further reductions were needed [35]. This finding supports the concept that treatment sensitivity, as with daily GH, varies across individuals; therefore, careful monitoring of both auxological outcomes and laboratory parameters is necessary to optimise therapy.
In clinical trials, LAGH dose reductions were also common. In the somatrogon programme, dose reductions during main phase due to IGF-1 SDS > 2.0 occurred in 10.1% of children; in subsequent years, the respective rates were 23.1% (OLE Y1), 19.3% (OLE Y2), and 17.6% (OLE Y3) [25]. Dose reductions were markedly less frequent in children treated with somapacitan. The numbers of participants with IGF-1 > +2.5 SDS during year 3 were 14 (11.1%) and three (4.6%) in the soma/soma and switch groups, respectively; those exceeding +3.0 SDS were four (3.2%) and one (1.5%), respectively [18]. In the lonapegsomatropin programme, dose reduction due to elevated IGF-1 SDS was required in 42% of children over the full treatment period [13]. Across the clinical programmes discussed, no trend was observed in the number or type of adverse events among participants with IGF-1 levels > +2.0 SDS.
Economic analyses of long-acting growth hormone use in children with growth hormone deficiency
Dose reductions applied when switching children from daily GH are economically important. To date, two economic analyses have been published comparing projected costs of LAGH versus daily injections. In the first analysis [6], somatrogon was projected to provide clinically meaningful benefits (higher final height and improved quality of life) together with lower total treatment costs and lower cost per centimetre gained compared with daily GH therapy in children with GHD. The authors concluded that somatrogon was cost-effective versus daily GH, with consistent results across sensitivity analyses.
In 2025, a cost analysis of lonapegsomatropin was reported [36]. Total expenditures were estimated for two scenarios (daily GH vs. lonapegsomatropin) over five years, using a US payer model covering one million lives. It turned out that introduction of lonapegsomatropin was associated with cumulative savings of USD 959,629 over five years, with annual savings increasing from USD 40,314 in year 1 to USD 373,258 in year 5. The main drivers of cost reduction were lower acquisition costs and elimination of drug wastage with LAGH. The authors concluded that adding lonapegsomatropin to a US health plan formulary may meaningfully reduce the total cost of paediatric GHD treatment [36].
Detectability of long-acting growth hormone in athletes
An additional relevant issue is the detectability of LAGH as potential doping agents. In 2025, a real-world report described detection of somatrogon in urine samples collected in doping controls using liquid chromatography coupled with high-resolution tandem mass spectrometry (LC–HRMS/MS). The method detected somatrogon in urine with sufficient sensitivity for anti-doping applications, and it was reported to be repeatable and stable. This represents the first fully validated method enabling identification of somatrogon in urine [37].
Review of clinical trials on long-acting growth hormone for growth hormone deficiency after completion of growth
As noted above, only one of the currently available LAGH products has been approved for adult GHD after completion of linear growth: somapacitan (approved in 2020). The pivotal phase 3 trial was NCT02229851. Patients were randomised 2:2:1 to once-weekly somapacitan, daily GH, or once-weekly placebo for 34 weeks (main period); during a 52-week extension, patients continued somapacitan or daily GH. The study was conducted in 17 countries, and participants with adult GHD were GH-naïve at baseline. In total, 301 patients were enrolled, and 257 completed the study. In adults, the primary endpoint was improvement in body composition, specifically reduction in percentage trunk fat at week 34, measured by dual-energy X-ray absorptiometry (DXA). At week 34, somapacitan significantly reduced the percentage trunk fat versus placebo, and it improved additional body composition measures (including visceral fat and lean body mass) as well as IGF-1 SDS. At week 86, improvements were maintained in both the somapacitan and daily GH arms. Somapacitan was well tolerated, and adverse events (including injection-site reactions) were comparable to daily GH [38]. These reports are also important in the context of children treated for GHD. Accordingly, if a patient treated during childhood with GH (daily or LAGH) discontinues growth-promoting therapy and retesting confirms severe persistent GHD requiring ongoing replacement, continuation with daily rhGH preparations or somapacitan can currently be considered. This also applies to individuals diagnosed de novo at this stage of life. It should be emphasised, however, that somapacitan approval applies to individuals aged ≥ 18 years.
The other LAGH products (somatrogon and lonapegsomatropin) have completed phase 3 trials in adults; however, at the time of manuscript submission they had not yet received approval.
It should also be reiterated that treatment of adults with severe GHD after completion of growth aims to improve lean body mass and optimise bone mineralisation. Dosing differs from that used in growing children (as is also the case with daily GH). Moreover, recommended starting doses of somapacitan differ between treatment-naïve adults and those switching from paediatric GH therapy, as shown in Table III.
Because the final dose is individualised, gradual titration by 0.5 mg to 1.5 mg/week at 2–4-week intervals is recommended depending on clinical response and IGF-1 monitoring; target levels are typically achieved after approximately 8 weeks of dose adjustment [8].
Overview of clinical trials assessing the potential use of long-acting growth hormone in other (non-growth hormone deficiency) causes of growth failure in children
Phase 3 clinical trials are currently ongoing to evaluate the use of the three aforementioned LAGH preparations in indications other than paediatric GHD, i.e. in short-stature girls with Turner syndrome, children with Noonan syndrome, children born small for gestational age (SGA), children with idiopathic short stature (ISS), children with SHOX gene mutations, and children with achondroplasia. It should be emphasised that, to date, none of these clinical trials has resulted in the registration of any of the discussed LAGH preparations for these diagnoses.
Lonapegsomatropin (Skytrofa®)
With regard to lonapegsomatropin, a phase 2 clinical trial (NCT05690386) is ongoing in girls aged 1–10 years with Turner syndrome, in which the investigational drug is administered at three different doses (0.24, 0.30, or 0.36 mg hGH/kg/week), while the control group consists of girls with Turner syndrome receiving Genotropin® at 0.05 mg/kg/day. A phase 2 trial (NCT06433557) is also ongoing with lonapegsomatropin in children aged 2–11 years with achondroplasia. This study involves concomitant administration of lonapegsomatropin at 0.30 mg hGH/kg/week and navepegritide at 100 µg C-type natriuretic peptide (CNP)/kg/week, given as two separate weekly injections. It should be emphasized that navepegritide is also an investigational drug, a prodrug of CNP, which allows once-weekly administration. This study will last 3 years, until September 2027.
In November 2025, a phase 3 clinical trial (ID: NCT07221851) was initiated to evaluate lonapegsomatropin in children with short stature independent of GH deficiency. This is also a basket trial, planned to include 186 prepubertal short-stature children with SHOX gene mutations, SGA, ISS, or girls with Turner syndrome, aged 2–18 years. The study is planned for 2 years.
Somapacitan (Sogroya®)
With regard to somapacitan, phase 3 of two basket trials is currently ongoing, conducted in parallel in children with ISS, growth failure secondary to SGA, short-stature girls with Turner syndrome, and short-stature children with Noonan syndrome. In the first of these studies (ID: NCT05330325, REAL8), 399 prepubertal children were enrolled: girls aged 2.5–10 years and boys aged 2.5–11 years, recruited from 166 sites worldwide. During the main 52-week period, children were randomised to receive somapacitan (once weekly) or Norditropin® (daily rhGH). The study has currently entered the extension phase, and all children are receiving the investigational drug, i.e. somapacitan. The total duration of the study will be 5.5 years, and the results of the first year of therapy will be presented soon. The study evaluates the efficacy and safety of treatment.
The second study (ID: NCT05723835, REAL9) is dedicated to older children, i.e. girls >10 years and boys > 11 years old, but younger than 18 years, with bone age < 14 years in girls and < 16 years in boys. In this study, all children receive somapacitan, and children previously treated with daily rhGH could also be included. The somapacitan dose used in both studies was selected based on data from an earlier phase 2 study in children born SGA and equals 0.24 mg/kg/week, whereas the Norditropin® dose used in the main phase was 0.05 mg/kg/day for children with Turner syndrome, Noonan syndrome, and ISS, and 0.035 or 0.067 mg/kg/day in children born SGA. The aim of the study is also to analyse the safety and efficacy of therapy. The study will last 3 years, and the results of the first year of treatment have already been preliminarily presented as promising. Both studies are also being conducted in Poland. Recruitment is currently ongoing for another clinical trial with somapacitan in adult patients with gastroparesis.
Somatrogon (Ngenla®)
With regard to somatrogon, at the time of preparing the article, a phase 3 clinical trial (ID: NCT07226089) had been registered, planned to enrol 254 prepubertal short children aged ≥ 3 years and < 9 years (girls) or < 11 years (boys), including 114 with ISS and 140 born SGA. Children will be randomised 1 : 1 to receive Genotropin® or somatrogon. At present, the study is planned for 12 months.
Overview of clinical trials assessing the use of ibutamoren in partial growth hormone deficiency in children
As is known, ghrelin is the natural ligand for isoform 1a of the growth hormone secretagogue receptor (GHS-R1a), which, similarly to receptors for GHRH, is located on pituitary somatotroph cells. GHS-R1a binds primarily ghrelin, but its ligands also include peptide (e.g. growth hormone-releasing hexapeptide, GHRP-6) and non-peptide (ibutamoren or macimorelin) GH secretagogues. In pituitary cells, both endogenous and exogenous GHS-R1a agonists stimulate GH release. However, the possibility of using GH secretagogues for the treatment of GH deficiency requires the assumption that pituitary somatotroph cells retain a normal capacity for GH synthesis but are not adequately stimulated by GHRH or secretagogues [39]. LUM-201, i.e. ibutamoren mesylate, is a potent non-peptide GH secretagogue and a GHRP-6 mimetic; moreover, it also inhibits somatostatin (SST) release by acting via SST receptor subtypes 2 and 5. The main phase of a phase 2 clinical trial (ID: NCT04614337) assessing LUM-201 (ibutamoren) in children with idiopathic partial GHD has recently been completed. An important advantage of this drug is that it can be administered orally.
For the study 82 prepubertal children were qualified: girls aged ≥3.0 and ≤11 years and boys aged ≥3.0 and ≤12 years. Children randomised to receive the investigational drug were divided into three groups, each receiving oral tablets containing LUM-201 at one of three doses: 0.8, 1.6, or 3.2 mg/kg/day, while the control group received Norditropin® 0.24 mg/kg/week (0.034 mg/kg/day). After the 12-month main phase, all children continued treatment with the investigational drug for another year, and children who responded well continue therapy for an additional 3 years. Preliminary results have already been published as a congress report and are promising [40].
For this reason, a phase 3 clinical trial (ID: NCT06948214) with this preparation was recently initiated. In the same age group, 150 children with partial GHD will be recruited; children in the investigational group will receive tablets containing ibutamoren at 1.8 mg/kg/day, while the control group will receive placebo tablets. The study will last one year, followed by another 3-year extension phase (ID: NCT07129759), in which all children will receive the investigational drug. The results of these studies are still awaited.
Discussion of the possibility of using ghrelin analogues in growth hormone secretion stimulation tests
At this point, it is also worth citing the results of clinical trials assessing another secretagogue, macimorelin, as a stimulation test for GH secretion in individuals with GHD (ID: NCT00448747). Based on the results of a clinical trial conducted in 101 adults with suspected GHD, this substance was approved by the FDA in 2017 and by the EMA in 2019 (under the name Ghryvelin) as a reliable GH stimulation test. However, an analogous trial conducted in children with suspected GHD (ID: NCT04786873) has not yet resulted in approval of this preparation for use in this age group.
