Somatrogon in pediatric growth hormone deficiency: a comprehensive review of clinical trials and real-world considerations
Article information
Abstract
Growth hormone (GH) is crucial for childhood growth and body composition. In pediatric GH deficiency (pGHD), the pituitary gland fails to produce sufficient GH, which affects linear growth in childhood. pGHD is conventionally treated with daily recombinant human GH (rhGH); however, because GH therapy lasts throughout childhood, adherence to daily rhGH treatment can be low, resulting in suboptimal effectiveness. Somatrogon is a long-acting GH analog designed to address the challenges associated with daily GH therapy for pGHD. Somatrogon administered once per week is a potential alternative to daily GH therapy. The use of somatrogon is supported by phase II and III clinical trials demonstrating that once-weekly injections are noninferior to once-daily somatropin injections in terms of efficacy, safety, and tolerability and have the advantage of reduced treatment burden. This review summarizes the clinical trials of somatrogon and discusses the therapeutic profile and effects of treating pGHD with reduced injection frequency.
Highlights
· Pediatric growth hormone deficiency (pGHD) affects linear growth in childhood, potentially leading to suboptimal adult stature. Recombinant growth hormone (GH), or somatropin, is a conventional once-daily pGHD treatment that has been used since 1985. However, daily injections can be burdensome, and adherence decreases with long-term use, ultimately reducing treatment efficacy. Somatrogon, a once-weekly long-acting GH treatment, has safety and efficacy similar to somatropin and might improve adherence and health-related quality of life by reducing injection frequency.
Introduction
Growth hormone (GH) is a pituitary protein that stimulates the hepatic production of insulin-like growth factor-1 (IGF-1), controlling body composition and contributing to linear growth in children [1]. Pediatric GH deficiency (pGHD) is due to low secretion or complete absence of GH, which results in inadequate circulating IGF-1 levels and abnormal linear growth in children. Recombinant human GH (rhGH), developed in the 1980s, has a well-established safety and efficacy profile and promotes linear growth in children with pGHD, allowing them to achieve a normal height [2]. rhGH effectively replaces naturally occurring GH, promoting linear growth and improving cardiovascular function and body composition without causing critical safety issues [3]. Additionally, rhGH treatment mitigates the psychological and social challenges caused by short height in children, ultimately enhancing patients' overall quality of life [2,4,5]
However, conventional rhGH products for pGHD require daily subcutaneous injections due to their short half-life [6]. Daily GH injections through the long duration of typical therapy impose a substantial emotional and physical burden on both children and their caregivers [7]. Furthermore, clinical outcomes suggest that the long-term use of daily GH therapy can lead to noncompliance and adherence issues [2,8]. Those issues are critical because they can significantly diminish the overall efficacy of the treatment [2,7,8]. According to Cutfield et al. [8] a national survey of GH compliance in New Zealand highlighted poor compliance as a critical issue that should be actively managed because it contributes to suboptimal growth during GH therapy. Additionally, the GH Research Society developed a consensus statement from 55 international GH experts, who agreed that the requirement for daily injections can act as a barrier to initiating and adhering to therapy for patients with pGHD [9]. In this context, the development of long-acting GH analogs holds promise to address the unmet needs linked to daily GH by decreasing the injection frequency and treatment burden.
Somatrogon, a novel long-acting GH analog, is a fusion protein that combines rhGH with carboxy-terminal peptide (CTP) from the β-chain of human chorionic gonadotropin. In somatrogon, the rhGH has one CTP copy at the N-terminus and 2 CTP copies at the C-terminus, extending its half-life to enable once-weekly subcutaneous injections [10]. Currently, somatrogon is approved for pGHD in the following countries (in alphabetical order): Australia, Brazil, Canada, Croatia, European Union, Iceland, India, Israel, Japan, Liechtenstein, Mexico, Norway, Saudi Arabia, South Korea, Switzerland, Taiwan, Türkiye, United Arab Emirates, United Kingdom, and United States. Several clinical studies have shown that somatrogon is noninferior to somatropin in terms of efficacy, with a comparable safety profile in Asian (Japanese) and Caucasian patients with pGHD [2,4]. Somatrogon has the potential to decrease the treatment burden and improve patient quality of life by obviating the need for the daily injections required in the conventional treatment of pGHD [7,11].
The aim of this review is to summarize key findings from somatrogon clinical trials comparing the relative safety and efficacy of once-weekly somatrogon with that of once-daily somatropin for the treatment of pGHD. Additionally, this manuscript reviews published literature on patient and caregiver perspectives of the treatment burden and improvements in health-related quality of life (HRQoL) associated with once-weekly somatrogon versus once-daily somatropin.
Dose-finding phase II global trial
Zelinska et al. [1] published the safety and pharmacokinetic/pharmacodynamic profile of somatrogon in a phase II dose-finding study (NCT01592500) involving prepubertal children with pGHD. The study evaluated 3 doses (0.25, 0.48, and 0.66 mg/kg/wk) of somatrogon based on the no observed adverse effect level from preclinical studies and compared them with somatropin (0.24 mg/kg/wk). Subjects (n=54) were randomized in a 1:1:1:1 ratio, stratified by peak stimulated plasma GH levels and age, and underwent a 4-week screening period followed by 12 months of active treatment. To gradually acclimate treatment-naïve subjects to their assigned somatrogon dose, a stepwise dose escalation approach was used for the 2 higher doses during the first 6 weeks (pharmacokinetics/ pharmacodynamics analysis period). Subjects receiving one of the 3 somatrogon doses began with a 2-week treatment period at the lowest dose (0.25 mg/kg/wk), followed by a dose increase every 2 weeks until they reached their final assigned dose. The comparator group received somatropin at a dose of 0.24 mg/kg/ wk for 12 months.
All 4 groups exhibited significant catch-up growth after 12 months of treatment. The somatrogon dose of 0.66 mg/kg/wk achieved the highest annualized height velocity (HV), most closely resembling the somatropin results (mean±standard error: 11.9±3.5 cm/yr vs. 12.5±2.1 cm/yr, respectively). Additionally, the 0.66-mg/kg/wk dose demonstrated the best HV standard deviation score (SDS) and improved height (ΔHt) SDS, with values close to those of somatropin. During 12 months of treatment, somatrogon was shown to be safe, with no serious adverse events (SAEs), and its tolerability was consistent with that of somatropin. Somatrogon exhibited a promising immunogenic profile: the overall antidrug antibody incidence was similar to that of somatropin, and no antidrug antibodies against the CTP moiety or neutralizing activity were detected. No antibody-related adverse events were reported. The subjects who developed antibodies against somatrogon maintained adequate annual HV and HV SDS ranges, suggesting that antibody development had no effect on somatrogon efficacy. In the pharmacokinetics analysis, somatrogon showed a notably longer (5–10 fold) estimated half-life (36.1 hours, 18.3 hours, and 22.4 hours for the 0.25 mg/kg/wk, 0.48 mg/kg/wk, and 0.66 mg/kg/wk doses, respectively) than somatropin (3.5 hours ), with a maximal concentration at 12 hours for somatrogon versus 2 hours for somatropin. Somatrogon achieved steady-state levels after 7–10 weeks without a subsequent increase in plasma levels.
GH stimulates IGF-1 secretion [1], and IGF-1 is an important surrogate biomarker of rhGH activity. Regular IGF-1 sampling plays a critical role in guiding dose titration [12] because maintaining IGF-1 levels within the normal range is vital for patient safety. Because elevated IGF-1 levels can pose potential risks, periodic monitoring throughout the treatment period is imperative to ensure that the levels remain within a safe and normal range [12,13]. For somatropin treatment, most sampling times yield reasonable estimates of the mean IGF-1 SDS, given the modest fluctuations across the 24-hour dosing interval. However, fluctuations in IGF-1 levels for once-weekly GH preparations are likely to be greater than those for somatropin treatment. Due to this fluctuation, the precise timing of IGF-1 sampling is crucial for accurately estimating the mean IGF-1 SDS over the 1-week somatrogon dosing period. According to Fisher et al. [14], IGF-1 sampling 4 days (96 hours) after somatrogon administration provides the best approximation of the mean IGF-1 SDS, with a high correlation (>0.99) and minimal deviation from the line of unity [14]. IGF-1 levels observed on days 2 and 3 after administration represent the peak and overestimate the mean IGF-1 SDS, whereas those observed on days 6 and 7 represent the trough and underestimate it [14]. Therefore, IGF-1 was analyzed 4 days after somatrogon administration in the study of Zelinska et al. [1]. The results revealed that the mean IGF-1 SDS increased gradually in a dose-dependent manner during treatment with somatrogon, consistent with the results of Peter et al. [15]. Moreover, the mean IGF-1 SDS remained below +2 SDS during most of the analysis period. Somatropin also showed an increasing trend in the mean IGF-1 SDS, which is in line with results published by Cohen et al. [16].
The 12-month data from that phase II study suggest that a weekly somatrogon dose of 0.66 mg/kg/wk is likely to yield the best annualized HV, ΔHt SDS, HV, and IGF-I SDS, comparable to those achieved with somatropin and with a similar safety and tolerability profile. That study provided evidence for the initial dose in a phase III study of children with pGHD using a once-weekly dosing regimen of somatrogon.
Global and Japanese phase III trials
Based on the dose-finding phase II study, a global phase III study (NCT02968004) was conducted, and it confirmed the noninferiority of somatrogon (0.66 mg/kg/wk) to somatropin (0.24 mg/kg/wk) in children with pGHD, as reported by Deal et al. [2]. This multicenter, randomized, active-controlled study was conducted across 21 countries with the primary objective of demonstrating that the 12-month HV following somatrogon administration was noninferior to that following somatropin therapy in children with pGHD. The secondary endpoints were the 6-month HV change, 6- and 12-month height SDS changes, 12-month bone maturation change, mean IGF-1 SDS score, and safety. The subjects (n=224) were prepubertal males aged 3–11 years and females aged 3–10 years. They were randomized in a 1:1 ratio and stratified by peak stimulated plasma GH levels, region, and age. The subjects then underwent a 12-week screening followed by a 12-month active treatment period with subcutaneous doses of either somatrogon (0.66 mg/kg/wk) or somatropin (0.24 mg/kg/wk). Both somatrogon and somatropin were administered using a single-patient-use, multidose, disposable, prefilled pen.
The primary objective of the phase III study was evaluated based on the least squares (LS) mean annualized HV. The 12-month LS mean estimate of the annualized HV was 10.10 cm/yr for somatrogon and 9.78 cm/yr for somatropin. The LS mean difference (somatrogon − somatropin) was 0.33 cm (95% confidence interval [CI], -0.24 to 0.89). Because the lower bound of the 2-sided 95% CI in the primary endpoint was greater than the prespecified noninferiority margin (-1.8 cm/yr), the study met its primary objective. The secondary endpoints were comparable between the somatrogon and somatropin cohorts, and the safety of somatrogon was similar to that of somatropin. The most frequently reported treatment-emergent adverse event (TEAE) was injection site pain (somatrogon: 39.4% vs. somatropin: 25.2%). The 2 treatment cohorts had comparably low rates of SAEs (somatrogon: 2.8% vs. somatropin: 1.7%), and none were considered to be related to somatrogon or somatropin. To estimate the mean IGF-1 SDS, blood sampling was performed 4 days (96 hours) after somatrogon administration. The results from the somatrogon cohort revealed that the mean IGF-1 SDS increased from the baseline value of -1.95 SDS to near 0 at 1 month postbaseline and reached 0.65 SDS (range, -3.64 to 3.22) at 12 months postbaseline. Conversely, in the somatropin cohort, the mean IGF-1 SDS at baseline was -1.72 SDS, and it remained near 0 throughout the postbaseline visits.
This 12-month, phase III global study confirmed that somatrogon is noninferior to somatropin in terms of efficacy, as assessed by increased HV. The study also demonstrated a comparable safety profile and IGF-1 levels maintained within the normal range in a global cohort of pGHD patients.
Another phase III open-label study (NCT03874013) was conducted to assess the comparability of somatrogon and somatropin in a Japanese population. In this open-label, randomized, active-controlled study, 44 pGHD children (males aged 3 to <11 years; females aged 3 to <10 years) were assigned in a 1:1 ratio to receive either somatrogon or somatropin for a period of 12 months. The study outcomes were reported by Horikawa et al. [4]. In the Japanese study, the somatrogon doses remained consistent with those used in the global phase III study, but the somatropin dose was lower (0.175 mg/kg/week) based on the dosage approved in Japan. Subjects in the somatrogon cohort received escalating doses of somatrogon (0.25, 0.48, and 0.66 mg/kg/wk; 2 weeks each) for 6 weeks, followed by a maintenance dose of 0.66 mg/kg/wk for 46 weeks. The dosage adjustment, study objectives, and subject disposition mirrored those of the global phase III study (NCT02968004).
At 12 months, somatrogon exhibited an LS mean of HV that was higher than that of somatropin (9.65 cm/yr vs. 7.87 cm/yr). The mean treatment difference (somatrogon − somatropin) in HV was +1.79 cm/yr (95% CI, 0.97−2.61), exceeding the pre-established noninferiority margin of -1.8 cm/yr. Additionally, somatrogon showed a higher LS mean change in height SDS (0.94 vs. 0.52) than somatropin, and the mean treatment difference was +0.42 (95% CI, 0.23−0.61). At 12 months, the mean±standard deviation (SD) change in bone maturation was 0.052±0.065 for the somatrogon cohort and 0.035±0.062 for the somatropin cohort. The mean IGF-1 SDS increased in the somatrogon cohort throughout all postbaseline visits and remained above 0, whereas that in the somatropin cohort increased until month 6, decreased after month 9, and remained below 0 at all postbaseline visits. In terms of safety, injection site pain was the most prevalent TEAE in the somatrogon cohort (somatrogon: 72.7% vs. somatropin: 13.6%). Two subjects (9.1%) in the somatrogon cohort reported SAEs, including hypoparathyroidism, influenza, traumatic fracture, and febrile convulsions, and an equal number of subjects in the somatropin cohort reported SAEs, including craniopharyngioma and asthma. Five subjects in the somatrogon cohort required dose reduction because their IGF-1 SDS exceeded +2, compared with none in the somatropin cohort. Overall, no significant differences were noted among the treatment cohorts in terms of glucose metabolism, hematology, chemistry, thyroid function, lipid profiles, or urinalysis parameters.
The Japanese study revealed that once-weekly somatrogon was comparable in terms of 12-month annualized HV and safety to once-daily somatropin in the Japanese population, consistent with those of the global phase III study.
Open-label extension (OLE) phase II trial
To evaluate long-term efficacy following completion of the main study, subjects who completed the 12-month phase II global dose-finding study of somatrogon were eligible to participate in the OLE study (an additional 5 years of somatrogon treatment; NCT01592500). Zadik et al. [13] reported the results of that study in subjects with pGHD. The purpose of the OLE study was to evaluate the growth outcomes of long-term treatment with somatrogon and the transition from a single-use vial to a prefilled pen device.
During the first year of the OLE study, after the initial 1-year main study, subjects previously treated with somatropin were rerandomized to one of the 3 somatrogon dose regimens, and those already on somatrogon continued their original doses. After completing the first year of the OLE, all subjects transitioned to a somatrogon dose of 0.66 mg/kg/week and were treated and monitored for an additional 2 to 4 years. Among the subjects in the OLE study, 3 in the third year and 37 in the fourth year switched from using a single-use vial to a prefilled pen device at the same dose (0.66 mg/kg/wk) of somatrogon. In the fifth year of the OLE, all subjects maintained their use of the prefilled pen device injection.
Following long-term treatment with either the somatrogon single-use vials or pen devices during the 5 years of the OLE study, sustained improvement in growth parameters was demonstrated, including annualized HV, height SDS, and change in height SDS. After the first year of the OLE, the annualized HV (mean±SD) for the 0.25 mg/kg/wk and 0.48 mg/kg/wk groups was comparable (7.73± 1.89 cm/yr and 7.54±1.28 cm/yr, respectively). Consistent with the findings from the main study, the 0.66 mg/kg/wk group exhibited the highest annualized HV (8.81±1.12 cm/yr). The height SDS (mean±SD) increased gradually from the baseline of the main study (-3.98±1.22) and eventually reached the normal range (-0.69±0.87) by the end of the fourth year of the OLE study, indicating that the mean height for age and gender was achieved following somatrogon treatment. Subjects in the main study who switched from somatropin to somatrogon after 12 months maintained a sustained growth response, measured by mean annual HV, and it was maintained through the second and fifth years of the OLE, irrespective of whether the participants received somatrogon or somatropin in the main study. Consistent increases in bone maturation were also observed throughout the first and the fifth years of the OLE, indicating ongoing bone maturation over time, and the pace of bone maturation aligned with chronological bone age development.
In the OLE study, 81.3% of the participants experienced at least one TEAE, with most being mild or moderate and largely unrelated to somatrogon treatment. In addition, 6.3% of the participants reported at least one SAE that was generally unrelated to the somatrogon treatment. No deaths occurred during the OLE. No injection site reactions were reported during the first and fourth years of the OLE with the single-use vial, but mild to moderate reactions (bruising and erythema) occurred after the pen device was introduced during the OLE. Although most TEAEs were deemed unrelated to somatrogon treatment, 4 (2 scoliosis, 1 mild hypercholesterolemia, and 1 mild injection site bruising) were potentially related to somatrogon. Two participants discontinued the OLE study because of TEAEs. One subject experienced severe scoliosis during the second and fourth years, which was likely related to somatrogon treatment. The other experienced moderate osteochondrosis after switching to the prefilled pen device in the third and fourth years, which was considered unrelated to somatrogon treatment. Overall, the mean IGF-1 SDS values remained below 2 across all time points during the 5-year OLE period, indicating a favorable safety profile. Some subjects developed antidrug antibodies, but none developed neutralizing antibodies.
Thus, in a long-term 5-year study, somatrogon improved annual HV, height SDS, and change in height SDS. A sustained growth response during the OLE period was observed in participants with pGHD, regardless of whether they received somatrogon or somatropin during the main study. These findings from the OLE study suggest that long-term treatment with once-weekly somatrogon is a safe and effective treatment option for children with pGHD.
Crossover phase III trial for treatment burden
Maniatis et al. [7] conducted a study to assess the treatment burden of the somatrogon injection regimen for children with pGHD and their caregivers across a broad pediatric age range. In addition to the patient’s perspective, this study evaluated the impact of treatment regimens on caregivers, recognizing their crucial role in treatment adherence in children and adolescents. The Dyad Clinical Outcome Assessment (DCOA) questionnaire was used to evaluate the treatment burden of somatrogon and somatropin from the perspectives of the child and caregiver. This phase III, randomized, open-label, multicenter, two-period crossover study (NCT03831880) enrolled 87 treatment-experienced patients (3–18 years) who had received stable somatropin injections for ≥3 months. The subjects were randomly assigned to 2 sequences: sequence 1 started with somatropin (weeks 0–12) and then switched to somatrogon (weeks 12–24), and sequence 2 followed the reverse order. The subjects and caregivers completed the DCOA 1 and the Patient’s Global Impression of Severity—Impact on Daily Activity (PGIS-IDA) questionnaires at baseline and after each 12-week treatment period. Additionally, at 24 weeks, they completed DCOA 2 to indicate their preference for somatropin or somatrogon injections. The somatropin dose was equivalent to the subject’s prestudy dose, and the somatrogon dose was 0.66 mg/kg/wk. The study assessed the life interference (LI) score as the primary outcome, with the results of the DCOA and PGIS-IDA questionnaires used as secondary outcomes to assess the treatment burden perceptions of each dyad (caregiver and child).
The results revealed that somatrogon had a significantly lower LI score than somatropin after 12 weeks of treatment, indicating decreased disruption to daily life. In addition, somatrogon presented a lower treatment burden in the DCOA and PGIS-IDA domains. Specifically, patients and caregivers preferred the once-weekly somatrogon regimen and reported that it was more convenient and easier to follow. Importantly, this preference suggests that the somatrogon regimen is more likely to be adhered to over the long term, highlighting its potential for sustained benefits.
The study of Maniatis et al. [7] confirmed that somatrogon had a lower treatment burden than somatropin and was associated with a more favorable treatment experience. Patients with pGHD require prolonged treatment, typically for several years. The lower treatment burden, robust preference, and higher intention to comply with somatrogon treatment in long-term therapy could enhance adherence and foster an improved treatment response compared with somatropin.
HRQoL results from a global phase III trial
Although the association between pGHD and poor HRQoL in children with normal stature has been inconclusive, some studies have indicated that pGHD negatively affects certain HRQoL domains, such as emotional and social well-being [11,17-19]. Loftus et al. [11] investigated HRQoL in patients with pGHD enrolled in a global phase III trial (NCT02968004). Following that pivotal study, somatrogon and somatropin treatments were evaluated using the Quality of Life in Short Stature Youth (QoLISSY) questionnaire, which aligns with the U.S. Food and Drug Administration guidelines on patient-reported outcome measures for HRQoL assessment in children with short stature. The questionnaire comprises 22 items categorized into physical, social, and emotional subscales, with higher scores indicating better HRQoL. The outcomes reflect data from a targeted sample of participants (N=117) recruited from 8 countries: 47 children aged <7 years (19 on somatrogon, 28 on somatropin) whose caregivers completed the QoLISSY-Parent form and 70 children aged ≥7 years (35 in each treatment cohort) who completed the QoLISSY-Child form. Additionally, 54 caregivers of subjects aged ≥7 years (26 on somatrogon, 28 on somatropin) completed the QoLISSY-Parent form.
Among children aged <7 years, both the somatrogon and somatropin cohorts had higher QoLISSY-Parent total scores after 12 months of treatment. Higher scores were observed in the physical, social, and emotional domains for both cohorts, with comparable mean changes from baseline in QoLISSY-Parent total scores between somatrogon (8.5; 95% CI, 1.1–15.9) and somatropin (8.5; 95% CI, 2.3–14.7). Children aged ≥7 years in both cohorts self-reported higher QoLISSY-Child scores at 12 months than at baseline, and their caregivers also reported higher QoLISSY-Parent scores at 12 months. Interestingly, children consistently reported higher scores than their caregivers at both time points, suggesting that children perceived their HRQoL to be better than did their caregivers. The mean (95% CI) changes from baseline in the total score showed improvement in both cohorts, with a higher numerical change observed among children treated with somatrogon (13.0; 95% CI, 5.8–20.2) than in those treated with somatropin (7.8; 95% CI, 2.7–13.0). Those changes were similar to the ones observed on the QoLISSY-Parent form (13.0; 95% CI, 4.0–22.0 for somatrogon, and 6.6; 95% CI, -0.2 to 13.4 for somatropin). Somatrogon consistently exhibited higher changes from baseline than somatropin across all subscales, with similar changes observed between the QoLISSY-Child and QoLISSY-Parent cohorts.
To summarize, the outcomes of the HRQoL phase III study suggest that the reduced treatment burden offered by somatrogon may be expected to not only maintain the clinical benefits (improved annualized HV) but also improve HRQoL.
Conclusion
Once-weekly somatrogon, at a dose of 0.66 mg/kg/wk, is noninferior to once-daily somatropin in terms of annualized HV, and it has a comparable safety profile, as demonstrated by the global phase II trial, global phase III trial, Japanese phase III trial. and their respective OLE trials. Owing to its long-acting pharmacokinetic/pharmacodynamic profile, once-weekly somatrogon requires fewer injections than daily somatropin. The average IGF-1 level is best estimated with a sample drawn 4 days after the last dose. The crossover phase III treatment burden trial demonstrated that both patient and caregiver preference and satisfaction surveys favored once-weekly somatrogon and revealed reduced treatment burden. The HRQoL questionnaire from the global phase III trial also revealed higher changes from baseline in the somatrogon group than the somatropin group across all subscales. These results are promising for potentially improving long-term treatment adherence. In summary, somatrogon, with its once-weekly subcutaneous injection regimen, is an alternative treatment option for patients with pGHD that offers efficacy and safety comparable to once-daily somatropin injections but with a less frequent injection schedule, reduced treatment burden, and enhanced HRQoL.
Notes
Conflicts of interest
Aristides Maniatis is a principal investigator for clinical trials sponsored by Ascendis, Novo Nordisk, OPKO, and Pfizer. Michael P. Wajnrajch, Marc Thomas, Sung Beom Chung, and Jieun Lee are employees of Pfizer.
Funding
This study was supported by Pfizer Korea (Seoul, Korea). (Editorial medical writing support was provided by Shaheen Amna Kashif of CC&I Research and was funded by Pfizer Korea.
Author Contribution
Conceptualization: AKM; Data curation: MPW; Formal analysis: MT; Funding acquisition: SBC; Methodology: SBC; Visualization: JL; Writing - original draft: SBC & JL; Writing - review & editing: AKM