Somapacitan administered once weekly in the treatment of children with growth hormone deficiency – current understanding
Somapacitan is a long-acting derivative of recombinant human growth hormone approved for the treatment of children and adults with growth hormone (GH) deficiency. Dr. Reiko Horikawa from Japan's National Center for Child Health and Development in Tokyo, during the 24th Pediatric Endocrinology Days held in Brno in January 2024, showed that it is a promising therapeutic option for pediatric patients from 3 years of age, thanks to its efficacy, safety, and potential to improve therapy adherence. However, careful long-term monitoring of the safety of long-acting growth hormone (LAGH) products is still necessary.
The need for GH formulations with lower administration frequency
Adherence to growth hormone (GH) treatment reaches only 40–60%. The main reason is the need for daily subcutaneous injections in long-term therapy, which can hinder the child's gradual independence from parental care. A medication with a lower administration frequency could provide a solution. Out of the 18 LAGH molecules developed so far, 5 have been brought to market. These include depot forms, pegylated molecules, prodrugs, and GH linked to a fusion protein. In the EU, 3 LAGH products are registered.
Somapacitan in the treatment of GH deficiency from 3 years of age
In July 2023, somapacitan was approved in the EU for the treatment of GH deficiency (GHD) with once-weekly administration. The drug is similar to endogenous human GH, with a single amino acid substitution to which an albumin-binding site is attached. This side chain allows reversible binding to endogenous albumin after injection. The serum concentration of somapacitan is dose-dependent – different serum concentrations were found after a single dose in children and adults with or without GH deficiency, likely due to different tissue distributions. The level of insulin-like growth factor 1 (IGF-1) peaks on the second day after somapacitan administration. After the highest dose (0.16 mg/kg/week), the peak IGF-1 level (the second day post-administration) is higher than with daily GH administration, drops to its level by the fifth day, and returns to baseline over the next two days.
Phase II study in children with GHD and its 4-year extension
Comparison of the change in standard deviation score (SDS) of growth rate in GHD patients after 52 weeks of treatment in the registration study showed comparable results for the 0.16 mg/kg/week dose of somapacitan with daily GH administration at a dose of 0.034 mg/kg/day. After 1 year of treatment, patients from the lower somapacitan doses (0.04 and 0.08 mg/kg/week) were switched to the 0.16 mg/kg/week dose. Three years into the study, the growth rate and growth rate SDS with somapacitan administration were still comparable (and numerically slightly higher) to GH administered at 0.034 mg/kg/day. At that time, all patients were switched to somapacitan 0.16 mg/kg/week. After 4 years of treatment, participants in all initial somapacitan groups achieved an average growth rate of 7.4 cm/year, while those originally randomized to daily GH administration grew 6.6 cm/year.
The average change in the GHD-CIM score, an indicator of GHD impact in children, was also compared after 3 and 4 years of somapacitan and daily GH administration. The overall GHD-CIM score, including physical functioning and emotional and social well-being, decreased by 12.5 points with somapacitan and by 5.9 points with daily GH administration after 3 years. After the 4th year of treatment, when all participants were using somapacitan, the score decrease was 15.2 points in those treated with somapacitan from the start of the study and 11.4 points in those originally randomized to daily GH administration.
Phase III study in GH pre-treated and treatment-naive children
Somapacitan has also been evaluated in the international randomized open-label Phase III REAL4 study, which included 200 pre-pubertal children with untreated GHD. During the first year, participants used somapacitan at a dose of 0.16 mg/kg/week or GH at a dose of 0.034 mg/kg/day. After that, patients initially randomized to daily GH administration were switched to somapacitan, and all used somapacitan for the next 3 years. The study aimed to evaluate the efficacy and safety of somapacitan 2 years after study initiation and assess its long-term efficacy.
After 2 years, comparable growth rates were observed in both groups: 8.7 cm/year with somapacitan and 8.4 cm/year with daily GH administration. The mean change in height SDS and IGF-1 levels was also comparable between groups. The pharmacokinetic-pharmacodynamic model suggested similar average weekly IGF-1 levels in both therapeutic groups. The mean IGF-1 SDS was within the normal range (–2 to +2 SDS) throughout the 2-year study period. Regarding patient-reported outcomes, the overall GHD-CIM score decreased by 9.6 points with somapacitan and by 9.4 points with daily GH administration in the first year. A greater decrease (i.e., improvement) was observed in the emotional and social well-being domains with somapacitan. Somapacitan was well tolerated and was not associated with a higher incidence of adverse events or injection site reactions compared to daily GH administration. No cases of injection site pain were reported in the second year of treatment.
Safety of LAGH products
No serious adverse effects have been reported for the 4 LAGH products registered globally (somatrogon, somapacitan, lonapegsomatropin, pegylated recombinant human GH), including no significant impact on glucose metabolism, lipid metabolism, thyroid function, bone age, or BMI. Transient formation of neutralizing antibodies was observed with somatrogon, and non-neutralizing antibodies in low titers were found with somapacitan and lonapegsomatropin.
However, LAGHs have different pharmacokinetics compared to daily GH administration, and each product has a distinct structure. The development of several LAGHs was halted due to neutralizing antibody formation. Therefore, long-term monitoring of registered products is necessary. It is also critical to evaluate the potential impact of transiently increased IGF-1 levels with LAGH administration and whether IGF-1 levels are a reliable marker of potential LAGH overdosing. Long-term safety monitoring is also needed to assess the effects of LAGH on GH tissue distribution and heart function, their long-term metabolic effects, effects on malignancy development, and local reactions with long-term administration (e.g., lipodystrophy or skin tumors).
The long-term safety of somapacitan in children with GHD is currently being evaluated in a 7-year follow-up study involving 50 prepubertal patients. An international electronic platform, Globe-Reg LAGH, has been created to monitor the efficacy and safety of LAGH in real-world practice.
Conclusion
The effect of somapacitan administered once weekly to support physical growth in children with GHD is comparable to daily GH administration. Four-year treatment results are already available. Questions regarding the long-term safety of LAGH, such as their impact on individual organs or the risk of neutralizing antibody formation, warrant long-term monitoring of individuals treated with somapacitan and the need to establish a registry for these patients.
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Source: Horikawa R. A summary on somapacitan studies. 24th Pediatric Endocrinology Days, Brno, 26.1.2024.
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