IGF-1 Standard Deviation Score Research Articles

FRI671 Association Of Insulin-like Growth Factor-1 (igf-1) With Bone Mineral Density (bmd) In Survivors Of Childhood Acute Leukemia

Abstract Disclosure: S. Kim: None. S. Park: None. S. Sim: None. S. Kim: None. M. Ahn: None. K. Shin Hee: None. W. Cho: None. C. Kyung Soon: None. M. Jung: None. B. Suh: None. Purpose: To investigate bone mineral deficit in children survivors of childhood acute leukemia and analyze the association of IGF-1 with BMD status Methods : A total 214 patients (aged 8.47±4.42 for girls and 8.31±4.09 for boys at diagnosis) who were treated for acute leukemia were retrospectively reviewed. Types of leukemia, transplantation, and radiation therapy were investigated. Standard deviation scores (SDSs) of height, weight, body mass index (BMI), and lumbar spine BMD were measured at the end of treatment. Lumbar spine BMD was measured using dual-energy x-ray absorptiometry (DXA). Its relationships with calcium, phosphorus, alkaline phosphatase, bone specific alkaline phosphatase, calcitriol, parathyroid hormone, growth hormone, IGF-1, and insulin-like growth factor-binding protein-3 (IGFBP-3) were analyzed. Low BMD was defined lumbar spine BMD SDS less than -2.0 according to International Society for Clinical Densitometry guideline. Results: The overall prevalence of low BMD was found to be 15% (32/214). Age at diagnosis, transplantation, and radiation therapy were not significantly different between low BMD and normal BMD groups, however, BMI SDS and IGF-1 SDS were different between those two groups (-0.84±1.94 vs. 0.17±2.09, P = 0.012; -1.23 ±0.82 vs. -0.72 ± 0.78, P = 0.001, respectively). Correlation analysis showed that IGF-1 SDS is associated with BMI SDS and lumbar spine BMD SDS (rho=0.19, P=0.006; rho=0.248, P=0.001, respectively). Lumbar spine BMD SDS was related to BMI SDS and IGF-1 SDS by multivariate linear regression analysis (β = 0.15, P = 0.003; β = 0.31, P = 0.021, respectively). Multivariate logistic regression analysis showed that higher IGF-1 SDS was associated with a decreased of prevalence of low BMD (odds ratio: 0.42, 95% confidence interval: 0.24-0.75, P = 0.003). Conclusion: IGF-1 SDS was related to BMD, especially lumbar spine BMD, and a risk of prevalence of low BMD in children and adolescents. IGF-1 SDS seems to be a good tool for evaluating and predicting osteoporosis in children and adolescents. Presentation: Friday, June 16, 2023

THU170 Clinical And Immunological Response To Somatrogon In Two Siblings With A Homozygous Whole Gene Deletion Of The Growth Hormone 1 Gene

Abstract Disclosure: R. Gupta: None. R. Khadgawat: None. R.G. Rosenfeld: Advisory Board Member; Self; Lumos, DNARx, BioMarin. Consulting Fee; Self; OPKO Health. M.T. Dattani: Advisory Board Member; Self; Ferring Pharmaceuticals, Novo Nordisk, Pfizer, Inc., Sandoz. Consulting Fee; Self; Ipsen, Novo Nordisk, Pfizer, Inc. Speaker; Self; Pfizer, Inc., Novo Nordisk, Sandoz, Ipsen. L. Dyer: Employee; Self; GeneDx. B. Friedman: Employee; Self; GeneDx. J. Korth-Bradley: Employee; Self; Pfizer, Inc. Stock Owner; Self; Pfizer, Inc. M. Nijher: Employee; Self; Pfizer, Inc. Stock Owner; Self; Pfizer, Inc. C.L. Roland: Employee; Self; Pfizer, Inc. Stock Owner; Self; Pfizer, Inc. C.T. Taylor: Employee; Self; Pfizer, Inc. Stock Owner; Self; Pfizer, Inc. J.F. Cara: Employee; Self; Pfizer, Inc. Stock Owner; Self; Pfizer, Inc. J. Hsiao: Employee; Self; OPKO Health. Stock Owner; Self; OPKO Health. M.P. Wajnrajch: Employee; Self; Pfizer, Inc. Stock Owner; Self; Pfizer, Inc. Introduction: Somatrogon, a long-acting recombinant human growth hormone (LAGH), is approved in multiple countries as a once-weekly treatment for pediatric growth hormone deficiency (GHD). A global Phase 3 study in pediatric subjects with GHD compared the efficacy and safety of once-weekly somatrogon (0.66 mg/kg/wk) vs once-daily Genotropin® (0.24 mg/kg/wk) in a 12-mo main study, followed by an open-label extension (OLE) where all subjects received somatrogon (0.66 mg/kg/wk). Results: Subjects #1 (male; 6 y) and #2 (female; 9 y) are siblings from India randomized in the main study to somatrogon and Genotropin, respectively. Both had severe growth and weight attenuation at baseline, with peak GH levels (GH stimulation test) of 0.1 ng/ml; their IGF-1 standard deviation scores (SDS) were -3.96 and -3.94, respectively. At main study Mo 12, subject #1 had an annual height velocity (HV) of 11.77 cm/year (height SDS improved from -7.48 to -6.4) and IGF-I SDS increased to -1.84. After a 116-day drug holiday (started at the end of main study Mo 12), he continued into the OLE; at OLE Mo 9, his HV decreased to 3.08 cm/y, there was no additional improvement in height SDS (-6.76) and his IGF-1 SDS was -2.31. A test for anti-drug antibodies (ADAs) to somatrogon was positive at main study Mo 6; tests for ADAs, and neutralizing antibodies (NAbs) were positive at Mo 12. At OLE ∼Mo 1 and 3, tests were ADA+ and NAb-; at OLE Mo 6 and 9, tests were ADA-. At main study Mo 12, subject #2 had an annual HV of 11.87 cm/year (height SDS improved from -9.93 to -7.36); IGF-I SDS increased to -2.97. After a 123-day drug holiday, she switched to somatrogon during the OLE (per protocol) and had an HV of 10.01 cm/y and IGF-1 SDS of -1.83 at OLE Mo 9. Low titer ADAs to human GH were detected during the drug holidays. In the OLE, anti-GH ADAs were still detected, but at very low titers and tests were NAb−. Whole exome sequencing revealed a homozygous whole gene deletion of the GH1 gene in both siblings. Both completed the main study and OLE without any serious adverse events or dose reductions. Conclusions: Both siblings have classic congenital isolated GHD due to a homozygous GH1 deletion. Development of anti-GH ADAs and growth attenuation during GH therapy are likely due to lack of exposure to GH during fetal life followed by exposure to exogenous GH. The variability in antibody production and heterogeneity in clinical responsiveness to GH replacement has been well described, even in siblings,1 and if encountered in clinical practice, should prompt clinicians to consider the possibility of a GH1 deletion. To our knowledge, this is the first description of GH1 deletions in LAGH-treated subjects and the study findings are wholly consistent with those for daily GH products. Clinicaltrials.gov: NCT02968004 Reference: Ghosh et al. J Clin Res Pediatr Endocrinol 2021;13:456-60. Acknowledgements: The authors wish to thank all the investigators involved in this study. Presentation: Thursday, June 15, 2023

Evaluation of Adult Height in Patients with Non-Permanent Idiopathic GH Deficiency

Background: Several studies have evaluated the role of IGF-1 in the diagnosis of growth hormone deficiency (GHD). According to a recent study, an IGF-1 concentration of a −1.5 standard deviation score (SDS) appeared to be the best cut-off for distinguishing between children with GHD and normal children. This value should always be interpreted in conjunction with other clinical and biochemical parameters for the diagnosis of GHD, since both stimulation tests and IGF-1 assays have poor diagnostic accuracy by themselves. Our study was designed to evaluate the adult height (AH) in children with short stature and baseline IGF-1 concentration ≤ −1.5 SDS. Design: This retrospective analysis included 52 children and adolescents evaluated over the last 30 years for short stature and/or deceleration of the growth rate who underwent diagnostic procedures to evaluate a possible GHD. Only the patients who had baseline IGF-1 values ≤−1.5 SDS at the time of the first test were included in the study. Patients with genetic/organic GHD or underlying diseases were not included. Method: The case group consisted of 24 patients (13 boys and 11 girls) with non-permanent, idiopathic, and isolated GHD (peak GH < 10 μg/L after two provocative tests with arginine (Arg), insulin tolerance test (ITT), and clonidine (Clo), or <20 μg/L after GHRH + Arginine (GHRH+Arg); normal MRI; normal GH; and/or normal IGF-1 concentrations at near-AH). These patients were treated with GH (25–35 μg/kg/die) until near-AH. The control group consisted of 28 patients (23 boys and 5 girls) with idiopathic short stature (ISS, normal peak GH after provocative testing, no evidence of other causes for their shortness). Both groups had basal IGF-1 ≤−1.5 SDS. Results: AH and height gain in both groups were comparable. In the group of cases, mean IGF-1 SDS at the time of diagnosis was significantly lower than the levels found at the time of retesting. Conclusions: In this study, both treated patients with idiopathic GHD and untreated patients with ISS reached similar near-AHs (within target height) and showed similar increases in SDS for their height. Thus, the efficacy of treatment with rhGH in these patients may be questionable. This could be due to the fact that children with ISS are frequently misdiagnosed with GHD.

RF26 | PMON332 Safety and Efficacy of Treatment with Lonapegsomatropin in Children with Growth Hormone Deficiency at Week 130 in the enliGHten Trial

Abstract Background Once-weekly lonapegsomatropin (TransCon hGH) is a long-acting prodrug of somatropin, recently approved for the treatment of pediatric growth hormone deficiency (GHD) by the US FDA. In the pivotal 52-week phase 3 heiGHt trial and the 26-week fliGHt trial, lonapegsomatropin demonstrated safety and efficacy in both treatment-naïve and treatment-experienced children with GHD. Methods Results are reported from Week 130 (data snapshot date: September 01, 2021) from the open-label extension trial enliGHten. Upon entry into enliGHten, all participants received lonapegsomatropin via vial/syringe, with subsequent switch to TransCon hGH Auto-Injector when available. Results A total of 298 participants (98% of parent trials) continued from the heiGHt or fliGHt trials into enliGHten. At Week 130, 36 participants had completed the trial and 248 participants remain enrolled. The height standard deviation score (SDS) mean (standard deviation [SD]) at Week 130 was -0.64 (0.85) compared with baseline value of -1.56 (0.88) at the start of enliGHten. Participants continued to approach the average parental height SDS mean (SD) of -0.39 (0.77). The annualized height velocity mean (SD) at Week 130 was 9.32 cm/year (0.45). Average IGF-1 SDS mean (SD) at Week 130 was 1.46 (1.18) compared with 0.52 (1.58) at enliGHten baseline. For the 36 participants who had completed the trial, 14 had reached bone age of >14 years (girls) or >16 years (boys), and 24 had completed the study based on investigator judgement that treatment for growth hormone deficiency was no longer necessary. The difference between mean (SD) height SDS at last visit and average parental height SDS was -0.05 (0.75) for the 36 completers, and 61.1% of these participants had met or exceeded the average parental height SDS. The mean (SD) total duration of hGH treatment for participants who completed the trial (including daily treatment and lonapegsomatropin) was 3.53 (0.88) years, and the mean (SD) duration of treatment with lonapegsomatropin was 2.20 (0.66). With continued lonapegsomatropin treatment, the AE profile remained consistent with what was observed in the parent trials, with no new safety signals. Conclusions Children and adolescents treated with lonapegsomatropin showed continued improvement of height SDS through their 3rd year of therapy. Lonapegsomatropin continued to demonstrate a safety profile comparable to that of daily somatropin therapy. Presentation: Monday, June 13, 2022 12:30 p.m. - 12:35 p.m., Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.

Insulin-Like Growth Factor-I Might be a Predictor for Severe Non-Alcoholic Fatty Liver Disease in Morbidly Obese Patients.

The aim of the study was to compare the IGF-1 levels, metabolic and clinical parameters among the ultrasonographically classified non-alcoholic fatty liver disease (NAFLD) groups and determine the factors that may predict the NAFLD severity in patients with morbid obesity. This study was conducted on 316 morbidly obese patients (250 F/66 M). The data of patients before and 1st-year after bariatric surgery were recorded. According to the ultrasonographically NAFLD screening, patients with normal hepatic features were classified as Group 1(n=57), with mild and moderate NAFLD were classified as Group 2(n=219), and with severe NAFLD were classified as Group 3(n=40). IGF-1 standard deviation scores (SDSIGF1) were calculated according to age and gender. Parameters that could predict the presence and severity of NAFLD were evaluated. IGF-1 levels were significantly associated with Group 3 than Group 1(p=0.037), and the significance remained between the same groups when IGF-1 levels were standardized as SDSIGF1(p=0.036). Decreased levels of SDSIGF1 explained 5% of severe NAFLD than the normal group (p=0.036). Liver Diameter, FPG, ALT, AST, and GGT were also found as significant predictors for severe NAFLD. There were significant differences between pre-and postop values in all groups (p<0.001). This study showed that IGF-1 might be considered a sgnificant predictor of severe NAFLD in morbidly obese patients. It is crucial in clinical practice to determine predictive factors of NAFLD that could support the diagnosis accompanied by non-invasive imaging methods.

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.

Relationship between hemoglobin and insulin-like growth factor-1 in children and adolescents with idiopathic short stature

BackgroundThe growth hormone/insulin-like growth factor-1 (GH/IGF-1) axis is critical for the regulation of children’s growth and development. Serum IGF-1 concentrations are usually low in individuals with idiopathic short stature (ISS) despite normal endogenous GH levels, and the associated underlying factors are unknown. This study aimed to explore the relationship between IGF-1 and hemoglobin (Hb) in children with ISS.MethodsA cross-sectional analysis was performed including 178 children and adolescents with ISS who were enrolled from March 2013 to February 2019. The related clinical and biochemical parameters were evaluated for each patient. Univariate analysis, smooth curve fitting and multivariate piecewise linear regression were performed.ResultThe mean levels of IGF-1 standard deviation scores (SDS) and Hb were − 0.99 (− 1.60 - -0.09) and 131.81 ± 9.36 g/L, respectively. Univariate analysis displayed a significant positive association between Hb and IGF-1 SDS (P < 0.001). After adjusting for potential confounding factors, the positive relationship between Hb and IGF-1 SDS remained (P = 0.001). Furthermore, there was an inflection point for Hb in the curve. In a multivariate piecewise linear regression model, IGF-1 SDS was significantly positively associated with Hb when Hb concentrations were lower than 145 g/L (B 0.05; 95% CI 0.02, 0.07; P < 0.001). However, IGF-1 SDS decreased with increasing Hb levels when Hb concentrations were greater than 145 g/L (B -0.15; 95% CI -0.23, − 0.06; P = 0.001).ConclusionThis study demonstrated that Hb is associated with IGF-1 in Chinese children and adolescents with ISS. The levels of IGF-1 increased with the elevation of Hb, but when the concentration of Hb exceeded a certain range, with the increase of Hb, IGF-1 decreased instead.

SAT-LB16 Maintenance of Favorable Treatment Effect of Once-Weekly TransCon hGH for Children With Growth Hormone Deficiency: Interim Analysis From the Enlighten Long-Term Extension Trial

Background Once-weekly TransCon hGH is an investigational long-acting prodrug for growth hormone deficiency (GHD) that consists of 3 components: unmodified growth hormone (hGH; somatropin), an inert carrier that protects it, and a linker that temporarily binds the two. In the randomized phase 3 heiGHt Trial evaluating treatment-naïve children with GHD, TransCon hGH demonstrated superior annualized height velocity and ∆ height standard deviation score (SDS) compared to Genotropin and had a similar safety and tolerability profile. Methods Results are reported from an interim analysis of subjects from heiGHt who continued in the ongoing enliGHten long-term extension trial for 26 weeks. In the 52-week heiGHt Trial, treatment-naïve, prepubertal subjects with GHD were randomized 2:1 to receive once-weekly TransCon hGH 0.24 mg hGH/kg/week or an equivalent weekly dose of daily Genotropin. Subjects completing heiGHt could enroll in enliGHten, where all subjects received TransCon hGH. Two groups were analyzed: Group A (TransCon hGH in both heiGHt and enliGHten) and Group B (Genotropin in heiGHt, followed by TransCon hGH in enliGHten). Safety and growth outcomes were evaluated approximately every 13 weeks in heiGHt and enliGHten. IGF-1 was sampled on postdose Day 5 (±1 day) in enliGHten. A by-visit ANCOVA model was used to analyze numeric efficacy endpoints.ResultsAll but one subject who completed heiGHt continued into enliGHten (A: N=103, B: N=55). Baseline characteristics at the start of heiGHt were balanced between groups. The statistically significant treatment difference in ∆ height SDS (Group A vs B) at the end of heiGHt (Week 52, N=159; 1.10 vs 0.96, P=0.0149) was sustained through Week 78 (N=154; 1.39 vs 1.24, P=0.0436), demonstrating persistence of catch-up growth for both groups and maintenance of superior treatment effect for subjects treated with TransCon hGH in the first year of therapy. At Week 78, least-squares mean (SE) IGF-1 SDS on postdose Day 5 (N=153) was 0.52 (0.15) for Group A and 0.59 (0.19) for Group B. Adverse events (AEs) were comparable between groups during heiGHt. During enliGHten, 48.7% (76/156) and 1.9% (3/156) of subjects experienced AEs and serious AEs, respectively; the AE profile was consistent with what was previously observed in heiGHt. A low titer of anti-hGH binding antibodies were detected in 10/156 (6.4%) subjects during treatment with TransCon hGH in heiGHt and enliGHten; no neutralizing antibodies were detected. Lab parameters (HbA1c, cortisol, free thyroxine) were stable and generally remained within the normal range throughout the trials. Mean (SD) BMI SDS was 0.0 (0.8) for Group A and 0.1 (0.9) for Group B at Week 78.Conclusions Children treated with TransCon hGH showed continued improvement of height SDS beyond the first year. Treatment with TransCon hGH through 78 weeks demonstrated an AE and immunogenicity profile comparable to that of a daily hGH therapy.

MON-113 The Effect of Body Mass Index on the Peak Growth Hormone Level After Growth Hormone Stimulation Test in Children with Short Stature

Objective: The aim of this study is to evaluate the effect of body mass index (BMI) on peak growth hormone (GH) response after GH stimulation test in children with short stature.Methods: Data was obtained from retrospective review of medical records who visited the pediatric endocrinology at St. Vincent hospital of catholic university for short stature from January 2010 to June 2019. We studied 115 children (aged 3-17 years old) whose height was less than 3percentile for one’s age and sex and who underwent GH stimulation test {GH deficiency (GHD) = 47, Idiopathic short stature (ISS) = 68)}. Peak GH response was stimulated by dopamine (n=111), clonidine (n=7), glucagon (n=19), insulin (n=56) and arginine (n=32). Birth weight, parental height, chronologic age, bone age, height SDS (standard deviation score), weight SDS, BMI SDS hemoglobin, fT4, T3 TSH, cortisol, ACTH, GH, IGF-1 SDS, IGF-BP3 SDS and peak stimulated GH were analyzed.Results: In the characteristics of subject, weight SDS and BMI SDS in GHD group were increased than ISS group (p<0.000, p=0.000). Free T4 was decreased in GHD group than ISS group (p=0.012). In total group, BMI SDS was associated negatively with peak GH level stimulated by dopamine (r=-0.419, p<0.000), insulin (r=-0.271, p=0.044) and arginine (r=-0.368, p=0.038), but did not showed correlation with peak GH level stimulated by glucagon. In GHD group, BMI SDS showed negative correlation with peak GH level using dopamine (r=-0.356, p=0.015) and arginine (r=-0.509, p=0.022). In ISS group, BMI SDS was correlated negatively with peak GH using dopamine (r=-0.330, p=0.007). In multivariate regression analysis of GHD group, weight SDS and BMI SDS were the only two significant predictors of peak GH response in stimulation test stimulated by dopamine (ß=-0.576, p=0.015) and arginine (ß=-0.097, p=0.022). In ISS group, only mother’s height (ß=0.474, p=0.000) and TSH (ß=-2.251, p<0.000) were demonstrated statistically significant predictors of peak GH stimulated by dopamine in multivariate regression analysis. In case of using insulin as a stimulant in ISS group, there is nothing which has statistical significance as a predictor of peak GH response in multivariate regression analysis.Conclusion: BMI was associated negatively with peak GH response after GH stimulation test in children with short stature, especially in GHD group.

SAT-094 Evaluation of IGF-1 as a Biomarker to Inform Phase 3 Clinical Trial Design and Dose Selection in Patients Born Small for Gestational Age Who Fail to Demonstrate Catch-Up Growth by Age 2–4 Years

Insulin-like growth factor-1 (IGF-1) is a key hormone in mediating the physiological response to endogenous and exogenous growth hormone (GH). Current clinical guidelines suggest use of IGF-1 for dose titration in adults with GH deficiency and for safety monitoring in adults and pediatric patients. Several GH drug development programs for pediatric indications have collected IGF-1, height standard deviation score (HSDS), and height velocity (HV), to support dose selection in Phase 3 clinical trials. In this analysis, patients born small for gestational age (SGA) who fail to demonstrate catch-up growth by age 2–4 years from different growth hormone product development programs were included. A total of 663 patients from 8 clinical trials were included in this analysis, with 7 placebo arms and 15 growth hormone treated arms. The growth hormone dosing regimen ranged from 33 ug/kg/day to 100 ug/kg/day. Both boys and girls throughout a wide range of ages (3 to 7 years old on average) were represented in this analysis. The average patient was 3 to 4 standard deviations below the age- and sex- adjusted mean height at baseline. IGF-1 was collected and standardized according to age and sex, so called the IGF-1 standard deviation score (IGF-1 SDS). At baseline, the average patient had normal IGF-1 (-1 to 0 on average). Based on preliminary findings, IGF-1 SDS change from baseline (CFB) at 6 months was correlated with HSDS CFB at 12 months. HSDS CFB at 3 months and 6 months were also correlated with HSDS CFB at 12 months, respectively. These findings were consistent across the three GH products included in the analysis, as well as age and gender. However, IGF-1 SDS CFB had much larger variability than HSDS CFB. Both HSDS CFB at 3 months and 6 months precisely and accurately predicted HSDS CFB at 12 months. IGF-1 SDS was more variable and did not add any further contribution in the prediction of HSDS at 12 months and therefore IGF-1 may not be sufficient in informing Phase 3 dose selection in such trials. Reference: 1. Shoshana Yakar, Clifford J. Rosen, Wesley G. Beamer, et al. Circulating levels of IGF-1 directly regulate bone growth and density. J Clin Invest. 2002 Sep 15; 110(6): 771–781. 2. Locatelli V, Bianchi VE. Effect of GH/IGF-1 on Bone Metabolism and Osteoporosis. Int J Endocrinol. 2014;2014:235060 Nothing to Disclose: TL, JP, BC, MZ, JV, CS

OR17-4 Transcon Growth Hormone In The Treatment Of Pediatric Growth Hormone Deficiency: Results Of The Phase 3 Height Trial

TransCon Growth Hormone in the Treatment of Pediatric Growth Hormone Deficiency: Results of the Phase 3 heiGHt Trial Background TransCon Growth Hormone is a sustained-release recombinant human growth hormone (hGH; somatropin) prodrug in development as a long-acting GH (LAGH) for children with growth hormone deficiency (GHD). In its prodrug form, TransCon hGH is inactive with hGH transiently bound to a TransCon carrier via a TransCon linker. Upon injection and triggered by physiological pH and temperature, unmodified recombinant hGH is sustainably released and thus designed to maintain the same mode-of-action and distribution as daily hGH replacement therapy but with once-weekly dosing. In a 6-month phase 2 trial of TransCon hGH vs. a daily hGH in children with GHD, mean annualized height velocity (AHV) for TransCon hGH was 12.9 cm/y compared to 11.6 cm/y for a daily hGH at an equivalent hGH dose (0.21 mg/kg/wk). The subsequent pivotal phase 3 global heiGHt Trial (ClinicalTrials.gov: NCT02781727) was designed to investigate the safety, tolerability, and efficacy of weekly TransCon hGH versus daily hGH over 52 weeks in treatment-naive prepubertal children with GHD. Methods Subjects were randomized in a 2:1 ratio and received either once-weekly TransCon hGH 0.24 mg hGH/kg/wk or dose-equivalent once-daily Genotropin over 52 weeks. Key baseline demographics variables included age, gender, height standard deviation score (SDS), IGF-1 SDS, peak stimulated GH, and bone age delay. Study endpoints included AHV, IGF-1 response, immunogenicity, and safety. Results At baseline, the mean age of study participants, of whom 82% were male, was 8.5 years. Mean height SDS was -2.93, and mean IGF-1 SDS was -2.04. Mean peak stimulated GH was 5.77 µg/L, and mean bone delay was 2.63 years. The final sample size (n=161) was larger than planned (n=150) which strengthens the study power for noninferiority. Top-line results, including AHV, change in height SDS, serum IGF-1 levels, change in bone age, and adverse events, will be available for presentation at ENDO 2019. Conclusion Only LAGHs based on unmodified hGH have obtained approval in Europe or the United States. By February 2019, all subjects will have completed their participation in this pivotal trial of a LAGH designed to release unmodified hGH, with top-line analyses available in March. The heiGHt Trial was well-powered to demonstrate noninferiority between TransCon hGH and a daily hGH, with baseline demographic variables in the range of recent GH trials.

Postoperative use of somatostatin analogs and mortality in patients with acromegaly.

Objective To assess the effect of somatostatin analogs (SSAs) on mortality in relation to disease control of acromegaly after pituitary surgery. Design A retrospective study in two large tertiary referral centers in The Netherlands. Methods Overall, 319 patients with acromegaly in whom pituitary surgery was performed as primary therapy between January 1980 and July 2017 were included. Postoperative treatment with SSA was prescribed to 174 (55%) patients because of persistent or recurrent disease. Disease control at last visit was assessed by IGF1 standard deviation score (SDS). Adequate disease control was defined as IGF1 SDS ≤2. Univariate determinants of mortality and standardized mortality ratios (SMRs) were calculated for groups with and without SSA at any moment postoperatively and at last visit. Results In total, 27 deaths were observed. In univariate analysis, determinants of mortality were inadequate disease control (relative risk (RR): 3.41, P = 0.005), surgery by craniotomy (RR: 3.53, P = 0.013) and glucocorticoid substitution (RR: 2.11, P = 0.047). There was a strong trend toward increased mortality for patients who used SSA (RR: 2.01, P = 0.067) and/or dopamine agonists (RR: 2.54, P = 0.052) at last visit. The SMR of patients with adequate disease control who used SSA at any moment postoperatively (1.07, P = 0.785) and at last visit (1.19; P = 0.600) was not increased. Insufficiently controlled patients had a significantly raised SMR (3.92, P = 0.006). Conclusions Postoperative use of SSA is not associated with increased mortality in patients with acromegaly who attain adequate disease control. In contrast, inadequate disease control, primary surgery by craniotomy and glucocorticoid substitution are associated with increased mortality.

Comparison of effectiveness of growth hormone therapy according to disease-causing genes in children with Noonan syndrome.

PurposeTo analyze the growth response to growth hormone (GH) therapy in prepubertal patients with Noonan syndrome (NS) harboring different genetic mutations.MethodsTwenty-three patients with prepubertal NS treated at Pusan National University Children’s Hospital between March 2009 and July 2017 were enrolled. According to the disease-causing genes identified, the patients with NS were divided into 4 groups. Three groups were positive for mutations of the PTPN11, RAF1, and SOS1 genes. The five genes undetected (FGU) group was negative for PTPN11, RAF1, SOS1, KRAS, and BRAF gene mutations. The influence of genotype was retrospectively analyzed by comparing the growth parameters after GH therapy.ResultsThe mean chronological age at the start of GH treatment was 5.85±2.67 years. At the beginning of the GH treatment, the height standard deviation score (SDS), growth velocity (GV), and lower levels of insulin-like growth factor-1 (IGF)-1 levels were not statistically different among the groups. All the 23 NS patients had significantly increased height SDS and serum IGF-1 level during the 3 years of treatment. GV was highest during the first year of treatment. During the 3 years of GH therapy, the PTPN11, RAF1, and SOS1 groups showed less improvement in height SDS, IGF-1 SDS, and GV, and less increase in bone age-to-chronological age ratio than the FGU group.ConclusionThe 3-year GH therapy in the 23 prepubertal patients with NS was effective in improving height SDS, GV, and serum IGF-1 levels. The FGU group showed a better response to recombinant human GH therapy than the PTPN11, RAF1, and SOS1 groups.

The association of insulin-like growth factor-1 standard deviation score and height in Chinese children with type 1 diabetes mellitus

Assessing the relationship between IGF-1 and height in type 1 diabetes children. Seventy-two type 1 diabetes children and 190 controls were recruited. The height standard deviation score of type 1 diabetes children was significantly higher than controls. The height standard deviation score was higher than the target height standard deviation score in both type 1 diabetes and controls. Serum IGF-1 levels and the IGF-1 standard deviation score were significantly lower in type 1 diabetes patients compared with controls. There was a significant difference in IGF-1 standard deviation score between the good glycemic control group and control group. The height standard deviation score was significantly correlated with C-peptide and IGF-1 levels. Furthermore, the IGF-1 standard deviation score was significantly correlated with glycemic control and C-peptide. The growth hormone/IGF-1 axis is impaired in type 1 diabetes, but height with good or poor glycemic control is not impaired.

Factors affecting height velocity in normal prepubertal children.

PurposeTo analyze the effects of clinical and laboratory factors, including insulin-like growth factor (IGF) levels, on the height velocity of normal prepubertal children.MethodsNinety-five healthy prepubertal children (33 boys, 62 girls) were enrolled. The mean chronological age was 6.3±1.4 years, with a height standard deviation score (SDS) of -0.88±0.70. IGF-1, IGF binding protein-3 (IGFBP-3), SDS for anthropometric measurements, and changes in SDS for anthropometric measurements were analyzed for 1 year, and their associations with 1-year height velocity were investigated.ResultsThe group of children with a 1-year height velocity of ≥6 cm were chronologically younger than the group with a 1-year height velocity of <6 cm (5.9±1.3 years vs. 6.7±1.3 years, P=0.004), with a lesser increase of SDS for body mass index (BMI) over 1 year (-0.18±0.68 vs. 0.13±0.53, P=0.014). There were no differences between the 2 groups in IGF-1 SDS and IGFBP-3 SDS. Multiple linear regression showed that baseline chronological age (r=0.243, P=0.026) and height SDS (r=0.236, P=0.030) were positively associated with IGF-1 SDS. Binomial logistic regression showed that an older chronologic age at referral (odds ratio [OR], 0.68; 95% confidence interval [CI], 0.47–0.99) and an increase of BMI SDS over 1 year (OR, 0.41; 95% CI, 0.18–0.89) were associated with a decreased growth possibility of an above-average height velocity (≥6 cm/yr).ConclusionsHeight velocity of normal prepubertal children is affected by an increase of BMI SDS and chronological age. Prepubertal IGF-1 SDS reflects height SDS at the time of measurement but is not associated with subsequent height velocity.

Etiology of short stature in Indian children and an assessment of the growth hormone-insulin-like growth factor axis in children with idiopathic short stature.

Background Our objectives were to evaluate the etiology of short stature, assess the prevalence of idiopathic short stature (ISS) and assess the growth hormone (GH)-insulin-like growth factor (IGF) axis in children with ISS. Methods A stepwise diagnostic evaluation was done in 394 children aged 4-16 years with short stature. Children with no definitive etiology were labeled as ISS. In these children, baseline IGF-1, IGF binding protein-3 (IGFBP-3) and stimulated IGF-1 after administration of GH for 4 days were measured. Results Hypothyroidism (in 18.1%) and ISS (in 15.5%) were the commonest causes of short stature. In children with ISS (n=61), the mean baseline and stimulated IGF-1 standard deviation scores (SDSs) were -1.2±1.0 and -0.3±1.4, respectively, with levels below -2 SDS in 13 (21%) and six (10%) children, respectively. In 33 (54%) of the ISS patients, response to GH was suboptimal (increment in the IGF-1 level <40%). There was no difference in the mean peak GH, IGFBP-3 and baseline and stimulated IGF-1 levels between children with familial and non-familial ISS. A significant positive correlation of height SDS with baseline IGF-1 SDS (r=0.28, p=0.026), stimulated IGF-1 SDS (r=0.32, p=0.010) and ΔIGF-1 SDS (r=0.26, p=0.036) was observed in children with ISS. Conclusions Hypothyroidism and ISS were the commonest etiologies for short stature. The baseline IGF-1 was below -2 SDS in 21% and the increment after GH stimulation was suboptimal in 54% of children, indicating that a substantial proportion of children with ISS had an impaired GH-IGF axis.

IGF1R Gene Alterations in Small for Gestational Age (SGA) Children.

BACKGROUND:Small for gestational age children (SGA) is born on term with BW and or BL of -2.0 standard deviation score (SDS). SGA children have an increased risk of being short, developing DM, and cardiovascular and cerebrovascular disease. Often defects of IGF1R are the cause of SGA. Most frequently affected part of the IGF1R gene is the exon 2.AIM:To investigate whether the exon 2 of the IGF1R gene is affected in the SGA children.PATIENTS AND METHODS:A cohort of 100 SGA children born in term was evaluated for alterations in IG1R gene. Their anthropometric parameters, IGF1 serum concentrations and IGF1 SDS values were analysed. The molecular analysis of IGF1R gene was performed by PCR restriction-site analysis and followed by direct sequencing of conspicuous fragments.RESULTS:Within our cohort, 64 SGA children were with short stature (height SDS -3.25 ± 0.90 SDS), and 36 were with normal height for their age and sex, (H SDS was 0.20 ± 1.1 SDS). None of these children had microcephaly (occipitofrontal circumference -0.70 ± 1.01 SDS vs 0.06 ± 0.56 SDS in SGA children with normal height) or dysmorphic features. The IGF1 serum concentrations and IGF1 SDS values of all children were within normal range. Only one child had lower normal serum IGF1 concentration. No alterations in exon 2 of IGF1R gene were detected.CONCLUSIONS:The genetic analysis of the exon 2 of the IGF1R gene did not detect any gene defects in the analysed patients. The putative genetic defect in those children affects other parts of the IGF1R gene or another gene (s), or yet unidentified factors.

The Relationship between the Growth Hormone/Insulin-like Growth Factor System and the Histological Features of Nonalcoholic Fatty Liver Disease.

Objective Growth hormone (GH) deficiency has recently been reported as a cause of nonalcoholic fatty liver disease (NAFLD), and GH supplementation has been shown to improve the histology of NAFLD. The aim of the present study was to clarify the relationship between the histological severity of NAFLD and production of the GH/insulin-like growth factor 1 (IGF-1) axis. Methods A total of 222 Japanese patients with liver biopsy-confirmed NAFLD and 55 patients with hepatitis C virus (HCV)-related chronic liver disease (CLD) were enrolled in the present study. The serum levels of GH, IGF-1, and IGF-binding protein 3 (IGFBP-3) were measured and their relationships with the histological severity of liver disease were assessed. To exclude age- and sex-related differences, the IGF-1 standard deviation score (IGF-1:SDS) was determined for each patient. Results With respect to the stage of fibrosis in patients with NAFLD, the serum GH levels were higher and the serum IGFBP-3 levels and IGF-1:SDSs were lower in patients with cirrhosis (grade F4 fibrosis) than in patients grade F1-F3 fibrosis; moreover, these differences were statistically significant (all p<0.01). The GH, IGF-1, and IGFBP-3 levels were not correlated with fibrosis in patients with HCV-related CLD. Furthermore, the GH levels were lower and the IGFBP-3 levels were significantly higher in patients with severe steatosis (S3) than in patients with mild to moderate steatosis (S1-S2) (p<0.05). Conclusion Increased GH levels and decreased IGF-1 and IGFBP-3 levels might contribute to the progression of NAFLD. The GH/IGF-1 axis may be important in the development of NAFLD, but not in patients with HCV-related CLD.

Adiposity in Children Born Small for Gestational Age Is Associated With β-Cell Function, Genetic Variants for Insulin Resistance, and Response to Growth Hormone Treatment

Genetic susceptibility to insulin resistance is associated with lower adiposity in adults. Insulin resistance, and therefore adiposity, may alter sensitivity to GH. We aimed to determine the relationship between adiposity, genetic susceptibility to insulin resistance or insulin secretion, and response to GH treatment in short children born small for gestational age (SGA). In 89 short prepubertal SGA children (age, 6.2 ± 1.6 y; 55 boys) treated with GH for 1 year in a multicenter study, body fat percentage was estimated at baseline and 1 year using dual-energy x-ray absorptiometry. The main outcome measures were treatment-related changes in height, IGF-1 standard deviation score, insulin sensitivity, insulin secretion, and disposition index. Combined multiallele gene scores based on single nucleotide polymorphisms with known associations with lower insulin sensitivity (gene scores for insulin resistance [GS-InRes]) and insulin secretion (gene scores for insulin secretion [GS-InSec]) were analyzed for their relationships with adiposity. Mean percentage body fat at baseline was low compared to normative data (P = .045) and decreased even further on GH treatment (baseline vs 1-year z-scores, -0.26 ± 1.2 vs -1.23 ± 1.54; P < .0001). Baseline percentage body fat was positively associated with IGF-1 responses (p-trends = .042), first-year height gains (B [95% confidence interval], 0.61 cm/y [0.28,0.95]; P < .0001), insulin secretion at baseline (p-trends = .020) and 1 year (p-trends = .004), and disposition index at 1 year (p-trends = .024). GS-InRes was inversely associated with body mass index (-0.13 SD score per allele [-0.26, -0.01]; P = .040), body fat (-0.49% per allele [-0.97, -0.007]; P = .047), and limb fat (-0.81% per allele [-1.62, 0.00]; P = .049) at baseline. During GH treatment, GS-InRes was related to a lesser decline in trunk fat (0.38% per allele [0.16, 0.59]; P = .001) and a higher trunk-limb fat ratio at 1 year (0.04 per allele [0.01, 0.08]; P = .008). GS-InSec was positively associated with truncal fat (0.36% per allele [0.09, 0.63]; P = .009). Adiposity in SGA children has favorable effects on GH sensitivity and glucose metabolism. The associations with multiallele scores support a causal role of insulin resistance in linking lesser body fat to reduced sensitivity to exogenous GH.

The Exon 3-Deleted/Full-Length Growth Hormone Receptor Polymorphism and Response to Growth Hormone Therapy in Growth Hormone Deficiency and Turner Syndrome: A Multicenter Study

Background/Aim: The exon 3-deleted/full-length (d3/fl) growth hormone (GH) receptor (GHR) polymorphism has been associated with responsiveness to GH therapy in some diagnostic groups. However, there are still controversies on this issue. To evaluate the effect of the GHR exon 3 polymorphism on growth after 1 and 2 years of GH therapy in Turkish patients with GH deficiency (GHD) and Turner’s syndrome (TS) and the distribution of GHR exon 3 isoforms. Materials and Methods: 218 patients with GHD (125 males/93 females) and 43 patients with TS were included in the study. The control group included 477 healthy adults aged from 18 to 57 years (54 females/423 males). Anthropometric parameters and insulin-like growth factor (IGF)-1 and IGF binding protein (IGFBP)-3 were evaluated annually. GHR isoforms were studied using simple multiplex PCR. Height and body mass index were expressed as standard deviation score (SDS). Results: There were no differences among TS, GHD and healthy adults regarding the distribution of GHR exon 3 isoforms (fl/fl, fl/d3 and d3/d3). There was a significant increase in height SDS in both diagnostic groups on GH therapy; however, there were neither differences in height SDS and Δheight velocity between fl/fl, fl/d3 and d3/d3 groups nor a correlation between the distribution of GHR exon 3 isoforms and change in IGF-1 SDS and IGFBP-3 SDS levels on GH therapy in either of the diagnostic groups. There was also no gender difference in GHR isoforms in healthy adults. Conclusion: The results suggest that responsiveness to GH therapy does not depend on the exon 3 GHR genotypes in GHD and TS patients.