Highlights
· Long-acting growth hormones (LAGHs) improve adherence in children with growth hormone deficiency by reducing injection frequency from daily to weekly. LAGHs show similar efficacy and safety to daily therapies in clinical trials. Careful patient selection is essential to maximize their benefits.
Introduction
Children with growth hormone deficiency (GHD) are typically treated with daily growth hormone (GH) injections. The need for 365 injections a year and the requirement for cold storage often lead to poor adherence to treatment. Long-acting GHs (LAGHs) have been developed to reduce the frequency of injections to improve patient compliance. This paper explores the LAGH options currently available and their mechanisms of action and highlights the patient populations most likely to benefit from this treatment approach.
The origins of GHD therapy date back to 1956, when the hormone was first isolated and purified from the pituitary gland of a human cadaver [1]. Because the GH extracted from animal pituitaries was ineffective (unlike other protein hormones such as insulin), starting in the 1960s, thousands of children with severe GHD were treated with GH extracted from human pituitary glands (cadaveric human GH, c-hGH). However, concerns regarding the safety of this treatment arose in 1985, when the first case of Creutzfeldt-Jakob disease linked to the use of c-hGH was reported [2]. Subsequent cases confirmed this association. In the 1980s, the production of recombinant huSomatrogon: After 12 months, the growthman GH (rhGH or somatropin) using molecular engineering techniques began, allowing large-scale use and providing an almost unlimited supply of the hormone, which has become the cornerstone of GHD therapy in children [3].
To date, somatropin remains an effective drug with relatively few side effects; however, daily subcutaneous injections are required, often resulting in poor therapeutic adherence. In a study conducted on 2,263 patients older than 9 years, only 30% maintained good long-term adherence [4]. Other factors that negatively affect patient compliance, aside from the frequency of dosing, include the pain associated with injections, difficulties in storing the medication, and challenges when traveling [5]. These reasons explain why only one-third of patients achieve good adherence, defined as missing fewer than one dose per week [6]. In a multicenter Italian study conducted on 1,007 patients, nearly 25% skipped one or more injections per week. The most frequently cited reasons for poor adherence to therapy were being away from home, forgetting, not feeling well, and pain [7].
The documented issue regarding therapeutic adherence provides a reason for the years-long efforts to develop alternative therapies requiring less frequent administration. This research has led to the development of several types of LAGHs, 3 of which have recently been approved by the U.S. Food and Drug Administration and/or the European Medicines Agency: somatrogon, somapacitan, and lonapegsomatropin (Table 1).
Somatrogon is an LAGH fusion protein characterized by fusion of an rhGH with 3 copies of the C-terminal peptide of human chorionic gonadotropin [8]. Fusion proteins are designed to have a prolonged half-life and reduced clearance. The inclusion of C-terminal peptides has been used to extend the half-life of other proteins such as follicle-stimulating hormone [9] and erythropoietin [10]. Somatrogon has an action peak between 6 and 18 hours and a half-life of 28.2 hours [11].
Somapacitan is another LAGH that works by increasing the binding affinity of GH to albumin [12]. A single amino acid (leucine) is replaced by cysteine at position 101 in the somatropin molecule, allowing attachment of a hydrophilic spacer and a fatty acid chain. This modification enables noncovalent reversible binding with albumin, which slows elimination and increases the hormone's half-life and duration of action [6]. A similar mechanism has been used in other drugs including insulin detemir [13], degludec [14], liraglutide, and semaglutide [15]. Somapacitan has an action peak between 4 and 24 hours and a half-life around 34 hours in pediatric patients with GHD [16].
Lonapegsomatropin is an LAGH in which GH is reversibly PEGylated with attachment of the hydrophilic polymer methoxypolyethylene glycol (mPEG) [17]. This compound is a prodrug, with the somatropin bound to the mPEG carrier via a hydrolyzable linker. The properties of the linker determine the pH, temperature, and timeframe in which the GH is released. Lonapegsomatropin has an action peak of 12 days and a half-life of 25 hours [18].
Questions that naturally arise when a long-acting drug is presented include whether the long-acting version is as effective as the short-acting drug and if there are relevant side effects due to the less frequent and possibly fewer physiological administration intervals.
Phase 3 clinical trials for all these LAGHs have demonstrated their noninferiority compared with daily-administered rhGH (somatropin), with similar safety and tolerability profiles as outlined below [12,17,19,20].
• Somatrogon: After 12 months, the growth velocity was 10.10 cm/yr in patients treated with somatrogon compared with 9.78 cm/yr in subjects treated with daily somatropin. This treatment difference of 0.33 (95% confidence interval, -0.24 to 0.89) supports the noninferiority of somatrogon to daily-administered GH [19].
• Somapacitan: After 1 year, the growth velocity was similar between the 2 groups (10.3 cm/yr for somapacitan vs. 9.8 cm/yr for somatropin). After 2 years of treatment, patients continuously treated with somapacitan had a growth velocity of 7.4 cm/yr compared with 7.9 cm/yr in subjects who switched from somatropin to somapacitan [20].
• Lonapegsomatropin: After 1 year, patients treated with lonapegsomatropin had a growth velocity of 11.2 cm/yr compared with 10.3 cm/yr in subjects treated with somatropin, demonstrating both noninferiority and superiority of lonapegsomatropin over daily GH administration [17]. In an open-label extension, patients who continued treatment with lonapegsomatropin showed an increase of +1.61 in height standard deviation score (SDS) compared with baseline after 2 years as well as an increase of +1.49 SDS in subjects who switched from somatropin after the first year.
All trials in which LAGHs were compared with daily somatropin used a dose of somatropin at the lower end of the therapeutic range (25–35 μg/kg/day) [12].
A possible side effect of LAGH is lipoatrophy at the injection site, a complication that can also occur with rhGH if injections are repeated in the same area and is observed during treatment with PEGylated formulations [21]. To prevent this, the recommendation, particularly with lonapegsomatropin, is to change the injection site with each use [17].
Another potential side effect of LAGH treatment is the development of antibodies against the drug. The likelihood of this increases if more than one LAGH is used simultaneously[6]. Antidrug antibodies were shown to develop in 77% of patients but do not appear to affect safety or efficacy because they are nonneutralizing [19].
A theoretical concern regarding weekly LAGH administration is that it does not mirror the body's natural pulsatile GH secretion or the nightly peak that accompanies daily evening rhGH dosing. This could hypothetically affect metabolism due to the role of GHs in regulating fat tissue and body composition. However, natural GH secretion occurs in pulses roughly every 3 hours, and daily rhGH does not fully replicate physiological patterns. Additionally, human studies have not demonstrated any significant effects of GH pulsatility on metabolism, indicating this concern may be more theoretical than clinically relevant [22,23].
Some children with GHD develop hypoglycemia due to diminished hepatic output through decreased gluconeogenesis or abnormal glucose mobilization. These episodes of hypoglycemia are prevented by daily rhGH therapy, and such cases might not experience the typical LAGH protective effect, particularly at the end of the dosing interval when GH levels may be too low [6,12,24,25].
Prescription of the LAGHs somatrogon, somapacitan, and lonapegsomatropin are currently available in Europe. Somatrogon is also marketed in the United Kingdom, Canada, Australia, and Japan; somapacitan is available in the United States (US) and Japan (for adult patients); and lonapegsomatropin is available in the US. In Italy, only somatrogon is currently available and prescribable.
Treatment with an LAGH to a patient with GHD involves IGF-1 monitoring 4 days after the injected dose to reflect the average level during therapy [11,16,18]. In Italy, the advice is to monitor insulin-like growth factor-1 (IGF-1) levels every 3 months in patients treated with somatrogon. For patients whose serum IGF-1 concentrations exceed +2 standard deviations, the somatrogon dose should be reduced by 15%; in some cases, more than one dose reduction is necessary.
A study on the burden of somatrogon was conducted to understand if LAGHs are preferred by patients and families: parents reported greater satisfaction with weekly administration compared with daily administration. The parents stated 8.63 of 44 times that weekly treatment with somatrogon interfered with daily activities compared with 24.13 of 43 times for daily somatropin [26].
Similarly, in a somapacitan study, 81.8% of parents expressed preference for weekly treatment over daily GH administration [27]. Parents also preferred lonapegsomatropin over somatropin [28].
In some pharmacoeconomic studies, the overall costs (both general and per cm of height gained) were lower for weekly somatrogon treatment compared with daily somatropin treatment [29].
Considering the preference of patients and families for the long-acting drug, an LAGH should be suitable for children requiring rhGH; however, LAGH can only be prescribed to patients with GHD as it is not currently approved for other indications (e.g., Turner syndrome, Noonan syndrome). Weekly LAGH therapy can be initiated in treatment-naïve GHD patients or a switch from somatropin therapy can be made. In the latter case, weekly therapy can begin the day after the last daily somatropin injection.
In the absence of precise guidelines regarding prescription of LAGH by subcategory of GHD patients, specific categories of children with GHD are needed to determine candidates for LAGH therapy, either as a switch from somatropin or for treatment-naïve patients [30]. At our center, the categories of patients who are at risk of poor adherence to daily therapy are indicated as candidates for LAGH treatment (Table 2).
Conclusions
LAGHs represent a significant advancement in pediatric therapy, particularly in reducing the number of injections required, which helps improve therapeutic adherence in children with GHD. Currently, somatrogon is the only LAGH available and prescribable in Italy, and the country has no national recommendations regarding the categories of patients to be offered LAGH as an alternative to daily recombinant GH. Therefore, individual pediatric endocrinologists have to identify the patients who would benefit most from reduced frequency of injections.
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