Long-acting growth hormone in 2022.

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.

Long acting growth hormone (LAGH), an update.

In 1957, Maurice Raben at Yale was able to isolate and purify growth hormone from cadaveric pituitary glands. Pituitary growth hormone was the only way to treat children with growth hormone (GH) deficiency, until 1985 when recombinant GH became available for daily subcutaneous injection. For many years, the pediatric endocrine community longed for a long-acting recombinant GH formulation that would decrease the inconvenience of daily injections. Several mechanisms were employed to develop a GH that is rapidly absorbed into the blood stream after subcutaneous injection, but provides slow removal from the circulatory system to potentially optimize patient adherence to GH therapy. Four long-acting growth hormones are currently available in the world, or are close to regulatory approval. They are: (1) Pegylated formulations, (2) Prodrug formulations which are converted into active drug, (3) Nonvalent transient albumin binding GH compounds and (4) GH fusion proteins where a protein si fused with GH. All four formulations have undergone detailed phase 3 studies and were found to show non-inferiority in these clinical studies. All four demonstrate a safety and tolerability profile that is comparable to that of daily somatropin with an excellent adherence profile.

Weekly Somapacitan in GH Deficiency: 4-Year Efficacy, Safety, and Treatment/Disease Burden Results From REAL 3.

CONTEXT: Growth hormone deficiency (GHD) in children is currently treated with daily injections of GH, which can be burdensome for patients and their parents/guardians. Somapacitan is a GH derivative in development for once-weekly treatment of GHD. OBJECTIVE: This work aimed to assess the efficacy and safety of somapacitan, and associated disease/treatment burden, after 4 years of treatment and 1 year after switching to somapacitan from daily GH. METHODS: This long-term safety extension of a multicenter, controlled phase 2 trial (NCT02616562) took place at 29 sites in 11 countries. Patients were prepubertal, GH-naive children with GHD. Fifty patients completed 4 years of treatment. Patients in the pooled group received somapacitan (0.04, 0.08, 0.16 mg/kg/week) for 1 year, followed by the highest dose (0.16 mg/kg/week) for 3 years. Patients in the switched group received daily GH 0.034 mg/kg/day for 3 years, then somapacitan 0.16 mg/kg/week for 1 year. Main outcome measures were height velocity (HV), change from baseline in HV SD score (SDS), change from baseline in height SDS, disease burden, and treatment burden for patients and parents/guardians. RESULTS: Changes from baseline in HV and HV SDS were similar and as expected in both groups. Observer-reported outcomes showed that patients and parents/guardians seem to have experienced a reduced treatment burden when switching from daily GH to somapacitan. Most parents/guardians (81.8%) strongly/very strongly preferred somapacitan over daily GH. CONCLUSIONS: Somapacitan showed similar efficacy and safety in patients who continued somapacitan treatment and those who switched from daily GH to somapacitan. Once-weekly injections may lead to a reduced treatment burden relative to once-daily injections. A plain-language summary of this work is available.

Turner Syndrome: An Update.

Turner syndrome is the most common sex chromosome abnormality in women. Infertility and short stature are the most striking findings seen in these patients. Unfortunately, many girls are still being diagnosed too late and therefore early diagnosis and treatment key. Turner syndrome affects many systems of the body; therefore, a comprehensive approach is key for therapeutic intervention.

Effective GH Replacement With Once-weekly Somapacitan vs Daily GH in Children with GHD: 3-year Results From REAL 3.

CONTEXT: Current GH therapy requires daily injections, which can be burdensome. Somapacitan is a long-acting GH derivative in development for treatment of GH deficiency (GHD). OBJECTIVE: Evaluate the efficacy, safety, and tolerability of once-weekly somapacitan after 3 years of treatment. DESIGN: A multicenter, randomized, controlled, phase 2 study comparing somapacitan and once-daily GH for 156 weeks (NCT02616562). SETTING: Twenty-nine sites in 11 countries. PATIENTS: Fifty-nine children with GHD randomized (1:1:1:1) and exposed to treatment. Fifty-three children completed the 3-year period. INTERVENTIONS: Patients received somapacitan (0.04 [n = 14], 0.08 [n = 15], or 0.16 [n = 14] mg/kg/wk) or daily GH (n = 14) (0.034 mg/kg/d, equivalent to 0.238 mg/kg/wk) subcutaneously during the first year, after which all patients on somapacitan received 0.16 mg/kg/wk. MAIN OUTCOME MEASURES: Height velocity (HV) at year 3; changes from baseline in height SD score (HSDS), HVSDS, and IGF-I SDS. RESULTS: The estimated treatment difference (95% CI) in HV for somapacitan 0.16/0.16 mg/kg/wk vs daily GH at year 3 was 0.8 cm/y (-0.4 to 2.1). Change in HVSDS from baseline to year 3 was comparable between somapacitan 0.16/0.16 mg/kg/wk, the pooled somapacitan groups, and daily GH. A gradual increase in HSDS from baseline was observed for all groups. At year 3, mean HSDS was similar for the pooled somapacitan groups and daily GH. Change from baseline to year 3 in mean IGF-I SDS was similar across treatments. CONCLUSIONS: Once-weekly somapacitan in children with GHD showed sustained efficacy over 3 years in all assessed height-based outcomes with similar safety and tolerability to daily GH. A plain language summary (1) is available for this study. CLINICAL TRIAL INFORMATION: This study has been registered at ClinicalTrials.gov, number NCT02616562 (REAL 3).

Switching to Weekly Lonapegsomatropin from Daily Somatropin in Children with Growth Hormone Deficiency: The fliGHt Trial.

INTRODUCTION: The phase 3 fliGHt Trial evaluated the safety and tolerability of once-weekly lonapegsomatropin, a long-acting prodrug, in children with growth hormone deficiency (GHD) who switched from daily somatropin therapy to lonapegsomatropin. METHODS: This multicenter, open-label, 26-week phase 3 trial took place at 28 sites across 4 countries (Australia, Canada, New Zealand, and the USA). The trial enrolled 146 children with GHD, 143 of which were previously treated with daily somatropin. All subjects received once-weekly lonapegsomatropin 0.24 mg human growth hormone/kg/week. The primary outcome measure was safety and tolerability of lonapegsomatropin over 26 weeks. Secondary outcome measures assessed annualized height velocity (AHV), height standard deviation score (SDS), and IGF-1 SDS at 26 weeks. RESULTS: Subjects had a mean prior daily somatropin dose of 0.29 mg/kg/week. Treatment-emergent adverse events (AEs) reported were similar to the published AE profile of daily somatropin therapies. After switching to lonapegsomatropin, the least-squares mean (LSM) AHV was 8.7 cm/year (95% CI: 8.2, 9.2) at Week 26 and LSM height SDS changed from baseline to Week 26 of +0.25 (95% CI: 0.21, 0.29). Among switch subjects, the LSM for average IGF-1 SDS was sustained at Weeks 13 and 26, representing an approximate 0.7 increase from baseline (prior to switching from daily somatropin therapy). Patient-reported outcomes indicated a preference for weekly lonapegsomatropin among both children and their parents. CONCLUSIONS: Lonapegsomatropin treatment outcomes were as expected across a range of ages and treatment experiences. Switching to lonapegsomatropin resulted in a similar AE profile to daily somatropin therapy.

Safety and Efficacy of Lonapegsomatropin in Children With Growth Hormone Deficiency: enliGHten Trial 2-Year Results.

PURPOSE: The objectives of the ongoing, Phase 3, open-label extension trial enliGHten are to assess the long-term safety and efficacy of weekly administered long-acting growth hormone lonapegsomatropin in children with growth hormone deficiency. METHODS: Eligible subjects completing a prior Phase 3 lonapegsomatropin parent trial (heiGHt or fliGHt) were invited to participate. All subjects were treated with lonapegsomatropin. Subjects in the United States switched to the TransCon hGH Auto-Injector when available. Endpoints were long-term safety, annualized height velocity, pharmacodynamics [insulin-like growth factor-1 SD score (SDS) values], and patient- and caregiver-reported assessments of convenience and tolerability. RESULTS: Lonapegsomatropin treatment during enliGHten was associated with continued improvements in height SDS through week 104 in treatment-naïve subjects from the heiGHt trial (-2.89 to -1.37 for the lonapegsomatropin group; -3.0 to -1.52 for the daily somatropin group). Height SDS also continued to improve among switch subjects from the fliGHt trial (-1.42 at fliGHt baseline to -0.69 at week 78). After 104 weeks, the average bone age/chronological age ratio for each treatment group was 0.8 (0.1), showing only minimal advancement of bone age relative to chronological age with continued lonapegsomatropin treatment among heiGHt subjects. Fewer local tolerability reactions were reported with the TransCon hGH Auto-Injector compared with syringe/needle. CONCLUSIONS: Treatment with lonapegsomatropin continued to be safe and well-tolerated, with no new safety signals identified. Children treated with once-weekly lonapegsomatropin showed continued improvement of height SDS through the second year of therapy without excess advancement of bone age.

Small for gestational age: short stature and beyond.

Depending on the definitions used, up to 10% of all live-born neonates are small for gestational age (SGA). Although the vast majority of these children show catch-up growth by 2 yr of age, one in 10 does not. It is increasingly recognized that those who are born SGA are at risk of developing metabolic disease later in life. Reduced fetal growth has been shown to be associated with an increased risk of insulin resistance, obesity, cardiovascular disease, and type 2 diabetes mellitus. The majority of pathology is seen in adults who show spontaneous catch-up growth as children. There is evidence to suggest that some of the metabolic consequences of intrauterine growth retardation in children born SGA can be mitigated by ensuring early appropriate catch-up growth, while avoiding excessive weight gain. Implicitly, this argument questions current infant formula feeding practices. The risk is less clear for individuals who do not show catch-up growth and who are treated with GH for short stature. Recent data, however, suggest that long-term treatment with GH does not increase the risk of type 2 diabetes mellitus and the metabolic syndrome in young adults born SGA.

Once-Weekly Somapacitan vs Daily GH in Children With GH Deficiency: Results From a Randomized Phase 2 Trial.

CONTEXT: Daily growth hormone (GH) injections can be burdensome for patients and carers. Somapacitan is a long-acting, reversible albumin-binding GH derivative in development for once-weekly administration in patients with growth hormone deficiency (GHD). OBJECTIVE: The objective of this study is to evaluate the efficacy, safety, and tolerability of once-weekly somapacitan vs once-daily GH. DESIGN: REAL 3 is a multicenter, randomized, controlled, double-blind (somapacitan doses), phase 2 study with a 26-week main and 26-week extension phase (NCT02616562). SETTING: This study took place at 29 sites in 11 countries. PATIENTS: Fifty-nine GH treatment-naive prepubertal children with GHD were randomly assigned; 58 completed the trial. INTERVENTIONS: Interventions comprised 3 somapacitan doses (0.04 [n = 16], 0.08 [n = 15], or 0.16 mg/kg/wk [n = 14]) and daily GH (0.034 mg/kg/d [n = 14]), administered subcutaneously. MAIN OUTCOME MEASURES: The primary end point was height velocity (HV) at week 26. Secondary efficacy end points included HV SD score (SDS) and insulin-like growth factor-I (IGF-I) SDS. RESULTS: At week 26, mean (SD) annualized HV for the somapacitan groups was 8.0 (2.0), 10.9 (1.9), and 12.9 (3.5) cm/year, respectively, vs 11.4 (3.3) cm/year for daily GH; estimated treatment difference (somapacitan 0.16 mg/kg/week-daily GH): 1.7 [95% CI -0.2 to 3.6] cm/year. HV was sustained at week 52, and significantly greater with somapacitan 0.16 mg/kg/week vs daily GH. Mean (SD) change from baseline in HV SDS at week 52 was 4.72 (2.79), 6.14 (3.36), and 8.60 (3.15) for the somapacitan groups, respectively, vs 7.41 (4.08) for daily GH. Model-derived mean (SD) IGF-I SDS for the somapacitan groups was -1.62 (0.86), -1.09 (0.78), and 0.31 (1.06), respectively, vs -0.40 (1.50) observed for daily GH. Safety and tolerability were consistent with the profile of daily GH. CONCLUSIONS: In children with GHD, once-weekly somapacitan 0.16 mg/kg/week provided the closest efficacy match with similar safety and tolerability to daily GH after 26 and 52 weeks of treatment. A short visual summary of our work is available (1).

Growth hormone therapy in children; research and practice - A review.

Short stature remains the most common reason for referral to a pediatric Endocrinologist and its management remains a challenge. One of the main controversies is the diagnosis of idiopathic short stature and the role of new technologies for genetic investigation of children with inadequate growth. Complexities in management of children with short stature includes selection of who should receive interventions such as recombinant human growth hormone, and how should this agent dose be adjusted during treatment. Should anthropometrical data be the primary determinant or should biochemical and genetic data be used to improve growth response and safety? Furthermore, what is considered a suboptimal response to growth hormone therapy and how should this be managed? Treatment of children with short stature remains a "hot" topic and more data is needed in several areas. These issues are reviewed in this paper.

GHD Diagnostics in Europe and the US: An Audit of National Guidelines and Practice.

INTRODUCTION: Almost 20 years after the first international guidelines on the diagnosis and treatment of GHD have been published, clinical practice varies significantly. The low accuracy of endocrine tests for GHD and the burden caused by ineffective treatment of individual patients were strong motives for national endocrine societies to set up national guidelines regarding how to diagnose GHD in childhood. This audit aims to review the current state and identify common changes, which may improve the diagnostic procedure. METHODS: A group of eight German pediatric endocrinologists contacted eight pediatric endocrinologists from Spain, France, Poland, the UK, the Netherlands, Denmark, Italy, and the US. Each colleague responded as a representative for the own country to a detailed questionnaire containing 22 open questions about national rules, guidelines, and practice with respect to GHD diagnostics and GH prescription. The results were presented and discussed in a workshop and then documented in this study which was reviewed by all participants. RESULTS: National guidelines are available in 7 of 9 countries. GH is prescribed by pediatric endocrinologists in most countries. Some countries have established boards that review and monitor prescriptions. Preferred GH stimulation tests and chosen cutoffs vary substantially. Overall, a trend to lowering the GH cutoff was identified. Priming is becoming more popular and now recommended in 5 out of 9 countries; however, with different protocols. The definition of pretest-conditions that qualify the patient to undergo GH testing varies substantially in content and strictness. The most frequently used clinical sign is low height velocity, but definition varies. Height, IGF-1, and bone age are additional parameters recommended in some countries. CONCLUSIONS: GHD diagnostics varies substantially in eight European countries and in the US. It seems appropriate to undertake further efforts to harmonize endocrine diagnostics in Europe and the US based on available scientific evidence.

Diagnosis, Genetics, and Therapy of Short Stature in Children: A Growth Hormone Research Society International Perspective.

The Growth Hormone Research Society (GRS) convened a Workshop in March 2019 to evaluate the diagnosis and therapy of short stature in children. Forty-six international experts participated at the invitation of GRS including clinicians, basic scientists, and representatives from regulatory agencies and the pharmaceutical industry. Following plenary presentations addressing the current diagnosis and therapy of short stature in children, breakout groups discussed questions produced in advance by the planning committee and reconvened to share the group reports. A writing team assembled one document that was subsequently discussed and revised by participants. Participants from regulatory agencies and pharmaceutical companies were not part of the writing process. Short stature is the most common reason for referral to the pediatric endocrinologist. History, physical examination, and auxology remain the most important methods for understanding the reasons for the short stature. While some long-standing topics of controversy continue to generate debate, including in whom, and how, to perform and interpret growth hormone stimulation tests, new research areas are changing the clinical landscape, such as the genetics of short stature, selection of patients for genetic testing, and interpretation of genetic tests in the clinical setting. What dose of growth hormone to start, how to adjust the dose, and how to identify and manage a suboptimal response are still topics to debate. Additional areas that are expected to transform the growth field include the development of long-acting growth hormone preparations and other new therapeutics and diagnostics that may increase adult height or aid in the diagnosis of growth hormone deficiency.

Predictors of first-year growth response to a fixed-dose growth hormone treatment in children born small for gestational age: results of an open-label, multicenter trial in the United States.

BACKGROUND: Previous studies of varied populations of non-uniformly defined children born small for gestational age (SGA) receiving different growth hormone (GH) regimens have found that GH treatment increased growth velocity and adult height and was safe. The GH dose was the major predictor of first year growth response. AIM: To identify pre- and within-treatment predictors of growth in well defined children born SGA treated with a fixed dose of GH. METHODS: 139 short, prepubertal children born SGA (i.e. birth weight and/or length > or =2 standard deviations below the mean) received Genotropin (rhGH) at 0.24 mg/kg/wk for 1 month then an additional 11 months at a dose of 0.48 mg/kg/wk, the FDA-approved dose of GH for children born SGA. RESULTS: Height improved significantly by month 3, with progressive improvement over the entire 12 months (median height SDS change of 0.78). Pretreatment predictors of growth included baseline bone age, IGFBP-3, total cholesterol, WBC and height SDS minus mid-parental height SDS. Within-treatment predictors of the change (Delta) height SDS at month 12 were the A height SDS at months 3 and 6 and growth velocity SDS at months 3 and 6. CONCLUSION: GH at 0.48 mg/kg/wk was well tolerated and improved growth in children born SGA; the Delta IGF-I was not predictive of the 12 month height SDS gain, while the Delta height SDS at 3 and 6 months were predictive. Underweight children grew as well as normal weight children, and both groups showed improved body composition following GH treatment.

Growth hormone therapy in children born small for gestational age: results from the ANSWER program.

Growth hormone (GH) is used to treat short stature and growth failure associated with growth disorders. Birth size and GH status variably modulate response to GH therapy. The aim of this study was to determine the effect of birth size on response to GH therapy, and to determine the impact of GH status in patients born small for gestational age (SGA) on response to GH therapy. Data from the prospective, non-interventional American Norditropin® Studies: Web-Enabled Research (ANSWER) Program were analyzed for several growth outcomes in response to GH therapy over 3 years. GH-naïve children from the ANSWER Program were included in this analysis: SGA with peak GH ≥10 ng/mL (20 mIU/l), SGA with peak GH <10 ng/mL (20 mIU/l), isolated growth hormone deficiency (IGHD) born SGA, IGHD not born SGA, and idiopathic short stature. For patients with IGHD, those who did not meet criteria for SGA at birth showed greater improvements in height SDS and BMI SDS than patients with IGHD who met criteria for SGA at birth. For patients born SGA, response to GH therapy varied with GH status. Therefore, unlike previous guidelines, we recommend that GH status be established in patients born SGA to optimize GH therapy.

Efficacy and safety of histrelin subdermal implant in children with central precocious puberty: a multicenter trial.

CONTEXT: GnRH analog (GnRHa) therapy for central precocious puberty (CPP) typically involves im injections. The histrelin implant is a new treatment that provides a continuous slow release of the GnRHa histrelin. OBJECTIVE: The objective of the study was to investigate the safety and efficacy of the subdermal histrelin implant for the treatment of CPP in treatment naive and previously treated children. DESIGN: This was a phase III, open-label, prospective study of 1-yr duration. SETTING: The study was conducted at nine U.S. medical centers. PATIENTS: Girls ages 2-8 yr (naive) or 2-10 yr (previously treated) and boys 2-9 yr (naive) or 2-11 yr (previously treated) with clinical evidence of CPP and a pretreatment pubertal response to leuprolide stimulation were eligible. INTERVENTION: A 50-mg histrelin implant was inserted sc in the inner upper arm. MAIN OUTCOME MEASURES: Peak LH after GnRHa stimulation testing and estradiol (girls) and testosterone (boys) were the main outcome measures. RESULTS: Thirty-six subjects (20 naive) were enrolled. By 1 month, peak LH fell from 28.2 +/- 19.97 (naive) to 0.8 +/- 0.39 mIU/ml (P < 0.0001) and from 2.1 +/- 2.15 (previously treated) to 0.5 +/- 0.32 mIU/ml (P < 0.0056). Estradiol suppressed from 24.5 +/- 22.27 (naive) to 5.9 +/- 2.37 pg/ml (P = 0.0016) and remained suppressed in previously treated subjects, as did testosterone. Suppression was maintained throughout the study. No significant adverse events occurred. CONCLUSIONS: The subdermal histrelin implant achieves and maintains excellent suppression of peak LH and sex steroid levels for 1 yr in children with CPP. The treatment is well tolerated. Long-term studies are needed to confirm these results.

A randomized, double-blind study to assess the efficacy and safety of valtropin, a biosimilar growth hormone, in children with growth hormone deficiency.

Valtropin is a recombinant human GH (rhGH) manufactured using a novel yeast expression system, classed as a 'biosimilar'. Valtropin was compared with Humatrope in children with GH deficiency (GHD). Treatment-naive, prepubertal children with GHD were randomized to Valtropin (n = 98) or Humatrope (n = 49) for 1 year. Standing height was measured 3-monthly and height velocity (HV) calculated. Serum IGF-I, IGFBP-3 and GH antibodies were determined centrally. HV at 1 year was 11.3 +/- 3.0 cm/year with Valtropin and 10.5 +/- 2.8 cm/year with Humatrope. Treatment difference was 0.09 cm/year with 95% confidence limits of -0.71, 0.90, within the preset non-inferiority limit of -2.0 cm/year. Height standard deviation (SD) scores were increased in both treatment arms with no acceleration of bone maturation. IGF-I and IGFBP-3 were increased comparably for both treatments. Adverse events showed no clinically relevant differences between treatment groups. Anti-GH antibodies were detected in 3 (3.1%) Valtropin and 1 (2.0%) Humatrope patients and the growth pattern was indistinguishable from the rest of the cohort. The 1-year efficacy and safety profile of Valtropin, a new biosimilar rhGH, are equivalent to the comparator rhGH, Humatrope. Valtropin can be used for the treatment of children with GHD and longer term data will fully establish its efficacy and safety profile.

Ten years of biosimilar recombinant human growth hormone in Europe.

Recombinant human growth hormone (rhGH) has been in clinical use for more than 30 years. With the expiration of patent exclusivity for the first wave of rhGH products and other biopharmaceuticals, the opportunity emerged for the development of biosimilar medicines. A biosimilar is defined by the European Medicines Agency (EMA) as a biological medicine that is similar to another biological medicine that has already been authorized for use. The EMA led the way (well ahead of the Food and Drug Administration in the US) in developing the biosimilar concept, and the type of science-based regulatory framework required to ensure high-quality, safe, and effective biosimilar medicines; the provisions for approval of biosimilars have been in place in Europe since 2005. Under these provisions, Omnitrope® was approved by the EMA in 2006 as the world's first biosimilar medicine; 2016 therefore marks the 10th anniversary of its approval in Europe. A substantial data set, based on clinical development studies and 10 years of postapproval use, has now accumulated for biosimilar rhGH; this data set shows that the product is an effective treatment option for children who require rhGH treatment, and has a safety profile that is consistent with the rhGH class. The decade since the EMA approved biosimilar rhGH has seen the successful approval and clinical use of 20 biosimilar medicines, confirming the integrity of the scientific basis for the biosimilar concept, as well as the quality of regulatory decision-making.