Long‐acting growth hormone in 2022

ABSTRACT

After the isolation of pituitary growth hormone (GH) in 1957, this form of GH, always in limited supply, was the only drug available for the treatment of GH deficiency. In 1985, recombinant GH became available, and the modalities of GH therapies changed dramatically as the supply was unlimited. New indications for GH in pediatrics and adult medicine were developed. Treatment was daily. Now in 2021 long‐acting GH (LAGH) became available the world over making GH therapy more patient‐friendly and even showing slightly greater efficacy than daily GH therapy. We are now entering a new era of LAGH therapy for pediatric and adult use with new formulations of GH, which will predictably be the preferred form of GH therapy for years to come increasing adherence to GH therapy and possibly even efficacy, that is, better growth rate. The continued availability of new safety data will further solidify the use of LAGH in clinical medicine.

After successful clinical use of growth hormone (GH) for nearly 70 years, we are now able to use long‐acting GH (LAGH) with identical or even slightly greater efficacy in clinical medicine in GH deficiency in children and adults.

HISTORIC PERSPECTIVE AND ENDOCRINE RATIONALE FOR GROWTH HORMONE THERAPY

In the late 1950s, Raben ¹ , ² was able to isolate and subsequently purify growth hormone (GH) from cadaveric human pituitaries. However, its clinical use was restricted due to the limited availability of supplies, and the main beneficiaries were a limited number of children with GH deficiency (GHD). For the next 40 years, all GH was provided in the US by the National Pituitary Agency free of charge. In 1985 the first patients with lethal Creutzfeldt‐Jakob disease led to an immediate stop in the use of pituitary‐derived GH. ³ Fortunately, recombinant DNA‐generated GH became available in that same year. Recombinant DNA technology became the standard to produce a large supply of the native, 22‐kDa, 191 amino‐acid long human GH (hGH), and hundreds of thousands of patients benefited from the growth‐promoting and metabolic effects of hGH on the human body. ² , ⁴ , ⁵

There is a complex regulatory system that controls the pulsatile release of GH bursts into the peripheral circulation approximately every 3 h (6–8 discrete pulses daily). Many pulses occur during slow‐wave sleep. The majority of smaller pulses occur during times other than slow wave sleep (stage 3 sleep). Even though GH‐releasing hormone and somatostatin have been recognized as the main modulators of this axis, there are a number of other key players that seem to be important to achieve the optimal biological effects of this hormone including ghrelin, glucocorticoids, thyroid hormones, nutritional and pubertal status, bone age, as well as other metabolic and age‐related mechanisms. ² , ⁶ , ⁷ This complex physiological regulation system has not only a theoretical interest but also clinical implications. The clinical practice used across the world (three times per week, or daily) documents that none of the previously used or currently recommended GH regimens to treat GHD in pediatric or adult populations are actually physiological. Nevertheless, these non‐physiological replacement therapies have many years of safety data records and have documented that they promote linear growth in children without major safety concerns and excellent metabolic effects in children and adults. ²

Daily subcutaneous injections are at least as effective to generate insulin‐like growth factor 1 (IGF‐1) production and promote linear growth as earlier attempts to treat GHD patients with twice or thrice weekly intramuscular injections, continuous intravenous infusions or even more “physiological” pulsatile replacement. ⁸ , ⁹ The current standard daily regimen also implies adherence concerns, particularly in the long‐term, multi‐year use of daily GH, ² , ⁸ , ⁹ and particularly adherence may falter after years of GH therapy, leading possibly to suboptimal auxiological outcomes.

LONG‐ACTING GH PREPARATIONS

For many years, the pediatric endocrinology community has longed for long‐acting recombinant hGH (rhGH) formulations that would decrease the inconvenience of daily injections and potentially optimize patients’ compliance with such therapy. Over the last two decades, this has now finally become a reality.

Lippe et al. ² , ¹⁰ studied the utilization of an intramuscular GH gel (15%) as a depot hGH formulation twice per week with similar growth rate results compared to a thrice‐weekly regimen of the standard aqueous GH solution during the 1st year, but a waning effect of growth velocity was noted in the 2nd year of treatment, even after adjusting dosing by weight.

Genentech developed in 1999 a long‐acting GH (LAGH) preparation Nutropin Depot, which was approved for the treatment of GHD. The preparation was unmodified rhGH linked to biodegradable microspheres which led to a sustained rhGH release over 4 weeks. The children showed catch‐up growth and IGF‐1 peaked at 14–17 days. There were adverse reactions such as atrophy and nodules at the injection sites, a very painful injection, large injection volumes, and over 1 mL in children above 30 kg body weight necessitated multiple injections. Manufacturing issues plagued the product and the product was discontinued in 2004. ¹¹ Nutropin Depot was only approved in the US.

A prototype LAGH was developed by LG Life Sciences and very successful height data were published in 2014. ² , ¹² , ¹³ This prototype was approved by the European Medicines Agency for Europe in 2016, however, has not been marketed except in South Korea.

Multiple formulations of LAGH are currently at advanced stages of development. Two have been recently approved by regulatory agencies in the US and elsewhere (Ascendis and Pfizer) in randomized non‐inferiority trials. ¹⁴ , ¹⁵ , ¹⁶

The benefit of LAGH is to decrease the burden of injections, as GH currently is given daily. The hope for LAGH is to decrease the frequency from daily to weekly. LAGH preparations include molecular changes to the weight and ionic charge, as well as binding to other molecules. These molecular changes could affect the way the molecule interacts with the intended target tissues. Furthermore, the peak GH and IGF‐1 levels may vary based on the formulation. Some LAGH preparations have undergone randomized clinical control studies and are non‐inferior in terms of height velocity and body composition to the daily rhGH injections.

The use of LAGH in place of daily rhGH will be feasible now, however, there are still questions that need to be answered. Dose adjustments, the timing of IGF‐1 serum level monitoring, safety, and long‐term evaluation of metabolic parameters of long‐term GH action, efficacy, and cost‐effectiveness all need to be further evaluated. LAGH will need long‐term post‐marketing surveillance before it is safely used as a replacement for daily rhGH injections.

MECHANISMS OF PROLONGATION OF GH ACTION

Mechanisms that have been explored for LAGH action include formulations that create a subcutaneous depot which allows for native or modified GH to slowly diffuse into surrounding tissues and vasculature. The other mechanism explored includes preparations that are rapidly absorbed into the bloodstream but provide slow removal from the circulatory system. (Table 1)

TABLE 1.

Summary of long‐acting growth hormone product development history

Company	Product	Modification to GH molecule (Molecular weight)	Frequency of administration	Current status	Research
PEGylated formulations: PEGylation prolongs in vivo mean residence time of GH, though slowing absorption and protection from proteolysis
GeneScience Pharmaceuticals Co., Ltd	Jintrolong	40‐kDa PEG attached to GH	7 days	Marketed in China for CGHD	Phase 3 studies show good IGF‐1 profile
Prodrug Formulation: Mechanism of conversion to active drug
Ascendis	Lonapegsomatropin	Unmodified rhGH transiently bound to a PEG carrier molecule via a self‐cleaving linker that is dependent upon pH and temperature (22 kDa)	7 days	Phase 2 studies in CGHD and AGHD showed comparable IGF‐1 profile to daily GH dosing; Phase 3 studies in CGHD show positive growth response and was approved for treatment of children with GH in the fall of 2021 in the US.	Phase 3 study in CGHD ongoing and phase 3 study in AGHD planned. SGA and Turner studies are planned.
Noncovalent albumin binding GH compound(s): Albumin binding
Novo Nordisk A/S	Somapacitan	Single‐point mutation in GH, with albumin binding moiety attached (noncovalent albumin‐binding properties) (23 kDa)	7 days	Phase 2 studies in CGHD showed comparable IGF‐1 profile to daily GH dosing; Phase 3 studies in AGHD well tolerated	Phase 3 studies in CGHD and extension study in AGHD ongoing
GH fusion proteins: Protein fused with GH
OPKP Health and Pizfer	Somatrogon	rhGH fused to 3 copies of carboxy‐terminal peptide of hCG B‐subunit (47.5 kDa)	7 days	Phase 2 studies in CGHD; Phase 3 studies in AGHD did not meet primary endpoint	Approved in Europe and Canada

Abbreviations: GH, growth hormone; AGHD, adult growth hormone deficiency; CGHD childhood growth hormone deficiency; PEG, polyethylene glycol; IGF‐1, insulin‐like growth factor 1; rhGH, recombinant human growth hormone; hCG, human chorionic gonadotropin.

Jintrolong

Jintrolong is an irreversibly PEGylated LAGH, and has been approved in China (Gene Sciences). Clinical trials have been performed in children using weekly Jintrolong, and it has been found to produce high levels of GH. Phase 3 trials in children have shown higher IGF‐1 levels in comparison to daily rhGH, and a good height velocity. ¹⁷ Currently, Jintrolong is being used extensively in China to treat childhood GHD (CGHD). Reported efficacy and safety are identical to daily rhGH. ¹⁷ It should be noted that the long‐acting PEGylated GH preparations were abandoned in Europe and the US and the European Medicines Agency published a critical review of PEGylated GH. ¹⁸

Lonapegsomatropin

Lonapegsomatropin (Ascendis) ¹⁴ is a reversible PEGylation of rhGH. This reversibility leads to the release of an unmodified rhGH. Lonapegsomatropin has completed phase 3 clinical trials, and it has been shown to have a superior height velocity in comparison to daily rhGH injections. There have been no identified safety concerns, and no antidrug antibodies have been reported. ¹⁴

Lonapegsomatropin‐tcgd (Skytrofa) is a once‐weekly treatment for GHD. The Food and Drug Administration (FDA) approval of lonapegsomatropin was based on an open‐label trial (heiGHt) in 161 treatment‐naive prepubertal children with GHD, defined as a peak serum GH ≤ 10 ng/mL. ¹⁴ Patients were required to have a height standard deviation score (SDS) of ≤ 2.0. Patients were randomized 2:1 to receive treatment with 0.24 mg/kg lonapegsomatropin once weekly or the equivalent dose of somatropin (Genotropin) given daily (0.034 mg/[kg⋅day]). Annualized height velocity at 52 weeks, the primary endpoint, was 11.2 cm/year in the lonapegsomatropin group and 10.3 cm/year in the somatropin group. Lonapegsomatropin met the prespecified criteria for noninferiority and superiority compared to somatropin. Change in height SDS from baseline, a secondary endpoint, increased by 1.1 with lonapegsomatropin and 0.96 with somatropin (Table 1).

A clinical trial evaluating lonapegsomatropin for adults with GHD is ongoing. No GH antibodies, and more importantly, no neutralizing antibodies were found in clinical studies. ¹⁴

The FDA has now approved, in the fall of 2021, lonapegsomatropin‐tcgd (Skytrofa, Ascendis), a long‐acting rhGH, for once‐weekly treatment of growth failure due to inadequate secretion of endogenous GH in children ≥ 1‐year‐old who weigh ≥ 11.5 kg. It is the first once‐weekly treatment approved for CGHD.

Lonapegsomatropin is a long‐acting prodrug of somatropin that consists of somatropin bound to an inert methoxypolyethylene glycol (mPEG) carrier by proprietary transient conjugation (TransCon) linker. The mPEG carrier minimizes renal excretion and receptor‐mediated clearance of the drug. Under physiologic conditions, the methoxypolyethylene glycol carrier is cleared by the kidneys, the linker is hydrolyzed, and therapeutic levels of somatropin are released over one week. The half‐life of the drug is approximately 25 h compared to about 3 h for somatropin. Height velocity was 11.2 cm/year in LAGH compared to 10.13 cm/year for daily GH therapy demonstrating not only non‐inferiority but even superiority over daily GH. ¹⁴

Somapacitan

Somapacitan (Novo Nordisk) is a modified GH so that there is a higher affinity to bind albumin. Somapacitan has been shown to decrease fat composition in comparison to daily rhGH when used in adults. ¹⁹ , ²⁰ Currently, somapacitan is in phase 3 studies for CGHD and phase 2 studies for children with a history of small for gestational age and failure to show catch‐up growth. ²⁰ During phase 2 and phase 3 studies in CGHD, somapacitan and daily rhGH had similar IGF‐1 values, and it was found that somapacitan had an improved growth velocity in comparison to daily rhGH. Sävendahl et al. ¹⁹ , ²⁰ recently report a height velocity SDS for somapacitan of 8.6 compared to daily GH therapy of 7.4.

Somapacitan has recently been approved for adult GHD in the US. Pediatric studies are still underway. In adult GHD, no antibodies to GH or neutralizing antibodies to GH were found. The molecular weight of somapacitan is 23 kDa, thus very close to native GH, which is 22 kDa.

Fusion proteins

Fusion proteins have been used in the development of rhGH structure to prolong the half‐life of the molecule as well as to decrease the clearance of rhGH from circulation. The lingering concern with fusion proteins is that it increases the molecular weight of the molecule, which could potentially hinder the absorption of rhGH into the target tissues.

GH structure and size are highly conserved among various species from fish to man with molecular weights ranging from 19.4 kDa to 22 kDa. Studies with labeled dextran show a 40 kDa molecular weight cut‐off for diffusion into the growth plate of mice. ²¹ , ²² Fusion proteins prolong the half‐life and reduce the renal clearance of rhGH but may dramatically increase molecular weight, ²¹ , ²² which may affect tissue penetrance.

The conservation of size may represent evolutionary control to allow GH to transit less well‐vascularized tissues (fat, bone, growth plates). Theoretically, GH analogs > 40 kDa, e.g. VRS‐317, ²³ an abadonded LAGH studied by Versartis, may be capable of generating hepatic IGF‐1 but not able to activate lipolysis in adipose tissues or promote the entry of resting chondrocytes into the proliferative zone of the growth plate. Thus, large GH fusion proteins may create a response that is more characteristic of IGF‐1 therapy with sub‐optimal growth and increased fat mass/body mass index. ²⁴ , ²⁵ However, the ability of LAGH to reach different target tissues may also depend upon characteristics other than molecular size, including the charge of the molecule. ²¹ , ²² , ²³ , ²⁴ , ²⁵ The fact that the VRS‐317 ²³ product did not meet non‐inferiority criteria in clinical trials may have been due to the large molecular size of 115 kDa. ²¹ , ²³

Somatrogon (MOD‐4023; Pfizer) is a fusion protein with a weight of 47.5 kDa. It contains the amino acid sequence of hGH and three copies of the C‐terminal peptide (CTP) ¹⁵ , ¹⁶ of human chorionic gonadotropin. It was previously shown that the inclusion of CTP proteins, such as follicular stimulating hormone ²⁶ and erythropoietin ²⁷ led to increased drug half‐life. Height velocity was 10 cm/year compared to 9.8 cm/year for subjects treated with daily GH. ¹⁵ , ¹⁶

CONSIDERATIONS WHEN PLANNING LAGH THERAPY

As LAGH use becomes more prevalent, there are issues to still consider. As of now, it is unknown what the long‐term metabolic consequences and side effects are of LAGH. The molecular composition of LAGH and rhGH differ, and it is unknown if there will be differences in metabolism between the two molecules. Currently, it is recommended to monitor routine IGF‐1 values while on rhGH therapy with e.g., lonapegsomatropin on day 4.5 after the injection, ²⁸ however there is no such recommendation for monitoring other biomedical markers of therapy, such as carbohydrate metabolism in patients on LAGH. The safety profile of LAGH is also not yet defined in comparison to rhGH and only post‐marketing studies for all LAGH products approved and marketed will provide much‐needed data.

It is also important to consider the cost‐benefit analysis of rhGH and LAGH therapies. As of now, it is not yet known if LAGH is a more cost‐effective treatment in comparison to rhGH. As the first US‐approved LAGH from Ascendis is coming to the market, the price of above $ 80 000 for one year of treatment for an average child is consideribly higher than daily GH.

Although a weekly injection may provide ease of administration when compared to daily injections, we do not yet know if LAGH will indeed improve compliance with GH therapy compared to daily injections of rhGH. Preliminary data by the Brod group and others ²⁹ , ³⁰ are interesting, however, there are no data detailing if and how LAGH increased compliance in comparison to daily GH. These data are sorely needed.

It should be noted that all studies used daily GH as comparators and used a GH dose of 0.025 mg/(kg · day). This is slightly less than the widely used US dose of 0.042 mg/(kg · day). The European Medicines Agency set these daily GH doses for all LAGH studies performed to date.

SUMMARY AND OUTLOOK

The major benefit of LAGH is to decrease the burden of injections, as GH currently is given daily. The hope for LAGH is to decrease the frequency from daily to weekly and then to monthly. LAGH preparations include molecular changes to the weight and ionic charge, as well as the binding to other molecules. These molecular changes could affect the way the molecule interacts with the intended target tissues. Furthermore, the peak GH and IGF‐1 levels may vary based on the formulation. Some LAGH preparations that have undergone randomized clinical control studies are inferior for growth velocity and body composition to the daily rhGH injections. ²³ There have not to date been additional adverse reactions noted from LAGH compared to rhGH.

The use of LAGH in place of rhGH could be feasible in the future, however, there are still questions that need to be answered. Dose adjustments, the timing of IGF‐1 serum level monitoring, ²⁸ safety, efficacy, insurance approval, and cost‐effectiveness all need to be further evaluated. LAGH will need long‐term surveillance before it is used as a replacement for daily rhGH injections. In particular, IGF‐1 monitoring is important in all LAGH preparations. Recent research by Lin et al. ²⁸ provides a formula to predict IGF‐1 levels. They recommend IGF‐1 sampling 4.5 days after dosing. This goal may be difficult to achieve in the clinical setting, therefore, phase 4 studies evaluating IGF‐1 levels in children on LAGH are mandatory.

At ENDO (the Endocrine Society's annual meeting) held in Atlanta in June 2022, both Ascendis and Novo presented 2.5 and 4‐year follow‐up data that were reassuring to the clinician providing a high degree of retention in clinical trials and a good safety profile with average IGF‐1 SDS at +1.462 in the Ascendis study, thus well below the limit of +2 SDS. ³¹ , ³²

To date, the only US‐approved LAGH was not associated with increased adverse events, immunogenicity, or metabolic complications. Only a low incidence of GH‐binding antibodies but no neutralizing antibodies were observed following lonapegsomatropin treatment. ¹⁴

Switching to weekly LAGH from daily rhGH is well tolerated and maintains the known high safety profile of daily rhGH, ³³ as shown in a recently published study.

The clinical use of GH is an exciting success story beginning with pituitary‐derived GH in the mid‐1950s to the regulatory approval of recombinant DNA‐generated GH in 1985. We now have as of 2022 several new drugs in development for LAGH for children and adults with GHD. Children achieve similar height outcomes, or in some studies even better one‐year height data compared to daily use in children. This is a real success story.

Much‐needed improved adherence and safety data will further solidify the use of LAGH in clinical medicine, as we predicted in a 2016 consensus paper. ³⁴

CONFLICT OF INTEREST

The authors declare that they have no conflict of interest.

Steiner M, Frank J, Saenger P. Long‐acting growth hormone in 2022. Pediatr Investig. 2023;7:36–42. 10.1002/ped4.12358