Treatment Of Growth Hormone Deficiency Research Articles

Diagnosis and treatment of growth hormone deficiency in children on the ketogenic diet: A case series.

The ketogenic diet (KD) can have a negative impact on the linear growth and body composition of children. The aims of this study were to review two centers' experience with children who developed height deceleration on the KD and determine if the height deceleration was secondary to growth hormone deficiency (GHD), and if growth hormone therapy (GHT) would be effective and safe (not altering ketosis or seizure frequency). Retrospective chart reviews were performed on patients with KD referred to Endocrinology between 2013 and 2018. Seventeen children were identified. Data reviewed included: demographics, growth velocity, KD ratio, protein/calorie intake, lab results, GH dosage, Tanner stage, and seizure frequency, and endocrine recommendations. Descriptive statistics were performed. Of the 17 children referred to the Endocrine Division, seven children were growth hormone deficient and began GHT. Data were provided for six patients (2 males, 4 females; age 2-7 years at the start of KD) on the KD for >6 years and on GHT for >4 years. Growth for all patients stabilized or increased. IGF-1 z-scores normalized. GHT did not affect seizure frequency or ketosis. GHT in those with GHD can be an appropriate option allowing better growth while still maintaining ketogenic therapy and seizure control. PLAIN LANGUAGE SUMMARY: The KD can be an effective treatment for difficult-to-control epilepsy and some disorders of carbohydrate metabolism. The KD can adversely affect the linear growth (height) of children. This case series reviewed six patients who had slow linear growth. It was found that all six children had growth hormone deficiency, grew better with growth hormone treatments, and that their seizures and ketone levels were not affected.

Long-acting growth hormone in the treatment of growth hormone deficiency in children: a systematic literature review and network meta-analysis

The purpose of this study is to compare the relative efficacy and safety of long-acting growth hormone (LAGH) as a growth hormone replacement therapy in prepubertal children with growth hormone deficiency (GHD). We searched the PubMed, Embase, CNKI, and Wanfang databases from inception to July 2023 and identified eleven relevant studies. PEG-LAGH showed better effect on height velocity (mean difference [MD]: − 0.031, 95% credibility interval [CrI]: − 0.278, 0.215) than somatrogon (MD: 0.105, 95% CrI: − 0.419, 0.636), somapacitan (MD: 0.802, 95% CrI: − 0.451, 2.068) and lonapegsomatropin (MD: 1.335, 95% CrI: − 0.3, 2.989) when compared with daily growth hormone (DGH). Furthermore, in terms of height standard deviation score, PEG-LAGH demonstrated better improvement (MD: − 0.15, 95% CrI: − 1.1, 0.66) than somatrogon (MD: − 0.055, 95% CrI: − 1.3, 0.51) and somapacitan (MD: 0.22, 95% CrI: − 0.91, 1.3). PEG-LAGH (risk ratio [RR]: 1.00, 95% CrI: 0.82, 1.2) reduced the risk of adverse events compared with other LAGH (somatrogon, RR: 1.1, 95% CrI: 0.98, 1.2; somapacitan, RR: 1.1, 95% CrI: 0.96, 1.4; lonapegsomatropin, RR, 1.1, 95% CrI: 0.91, 1.3) and was comparable with DGH. This is the first study to indirectly compare the LAGH thorough a network meta-analysis and provide evidence of the optimal efficacy of various LAGH specifically PEG-LAGH and acceptable safety profile in prepubertal children with GHD.

Tackling access and payer barriers for growth hormone therapy in Saudi Arabia: a consensus statement for the Saudi Working Group for Pediatric Endocrinology.

Prompt diagnosis and early treatment are key goals to optimize the outcomes of children with growth hormone deficiency (GHD) and attain the genetically expected adult height. Nonetheless, several barriers can hinder prompt diagnosis and treatment of GHD, including payer-related issues. In Saudi Arabia, moderate-to-severe short stature was reported in 13.1 and 11.7 % of healthy boys and girls, respectively. Several access and payer barriers can face pediatric endocrinologists during the diagnosis and treatment of GHD in Saudi Arabia. Insurance coverage policies can restrict access to diagnostic tests for GHD and recombinant human growth hormone (rhGH) due to their high costs and lack of gold-standard criteria. Some insurance policies may limit the duration of treatment with rhGH or the amount of medication covered per month. This consensus article gathered the insights of pediatric endocrinologists from Saudi Arabia to reflect the access and payer barriers to the diagnostic tests and treatment options of children with short stature. We also discussed the current payer-related challenges endocrinologists face during the investigations of children with short stature. The consensus identified potential strategies to overcome these challenges and optimize patient management.

A Superlong-Acting Growth Hormone-Polypeptide Fusion for Growth Hormone Deficiency Treatment.

Recombinant human growth hormone (rhGH) is clinically used to treat growth hormone deficiency (GHD). However, daily administration of rhGH is required due to its poor stability and short blood circulation, which causes pains and burdens as well as inconvenience to patients. In this study, a method for genetically fusing rhGH to a thermosensitive polymer of elastin-like polypeptide (ELP) is reported, using which the rhGH-ELP thermosensitive fusion protein can be purified by the thermosensitivity of ELP instead of chromatography. The ELP fusion not only drastically improves the stability of rhGH, but also enables the in situ formation of a sustained-release depot of rhGH-ELP upon subcutaneous (SC)injection, which exhibits gentle release with a platform-to-trough fluctuation in blood and a very long circulatory half-life of 594.6h. In contrast, rhGH exhibits a peak-to-trough fluctuation in blood with a very short circulatory half-life of 0.7h. As a result, a single subcutaneous injection of rhGH-ELP can consecutively promote the linear growth of rats and the development of major tissues and organs over 3weeks without obvious side effects, whereas rhGH is required to be injected daily to achieve similar therapeutic results.

Drivers of patient and caregiver preferences for growth hormone deficiency treatments in France: a discrete choice experiment.

To identify drivers of preference for growth hormone deficiency (GHD) treatment in French children, and their caregivers, and to quantify the relative importance of different aspects of treatment modalities using a discrete choice experiment (DCE). Attributes characterizing GHD treatment modalities were identified through a literature review, qualitative interviews and focus groups with children, adolescents, and caregivers. A DCE questionnaire of 12 choice tasks was administered online to four groups of participants: autonomous adolescents (12 to 18 years), non-autonomous adolescent / caregiver dyads, caregivers of non-autonomous children (3 to 11 years) and autonomous children / caregiver dyads. The survey was pilot tested. A multinomial logit model with random effects was used to estimate preference weights for all attribute levels. Frequency of administration, injection pain, dose setting, type of device, storage and device reusability were selected as DCE attributes following the qualitative research phase and a pilot study. A total of 105 patients were represented in the DCE survey. Frequency of administration and injection pain were the attributes with the greatest influence on respondents' preferences and had similar importance. Weekly administration was significantly preferred over daily administration by all groups of participants. Respondents' choices were also significantly influenced by the type of device, dose setting and device reusability. Children with GHD and their caregivers prefer a less frequent injection schedule and lower injection pain. Both aspects of treatment modalities are important to consider in treatment decisions to alleviate the daily burden for GHD patients and their families and potentially enhance treatment adherence.

Effects of different doses of long-acting growth hormone in treating children with growth hormone deficiency.

With the improvement of economy and living standards, the attention paid to short stature in children has been increasingly highlighted. Numerous causes can lead to short stature in children, among which growth hormone deficiency (GHD) is a significant factor. To investigate the long-term efficacy and safety of different doses of long-acting polyethylene glycol recombinant human growth hormone (PEG-rhGH) in the treatment of GHD in children. We selected 44 pediatric patients diagnosed with GHD who were treated at Wuhu First People's Hospital from 2014 to 2018. Total 23 patients were administered a high dose of long-acting PEG-rhGH at 0.2 mg/kg subcutaneously each week, forming the high-dose group. Meanwhile, 21 patients were given a lower dose of long-acting PEG-rhGH at 0.14 mg/kg subcutaneously each week, establishing the low-dose Group. The total treatment period was 2 years, during which we monitored the patients' height, annual growth velocity (GV), height standard deviation score (HtSDS), chronological age (CA), bone age (BA), and serum levels of insulin-like growth factor-1 (IGF-1) and insulin-like growth factor-binding protein-3 (IGFBP-3) before treatment and at 6 mo, 1 year, and 2 years after treatment initiation. We also monitored thyroid function, fasting plasma glucose, fasting insulin, and other side effects. Furthermore, we calculated the homeostatic model assessment for insulin resistance. After 1 year of treatment, the GV, HtSDS, IGF-1, BA, and IGFBP-3 in both groups significantly improved compared to the pre-treatment levels (P < 0.05). Moreover, when comparing GV, HtSDS, IGF-1, BA, and IGFBP-3 between the two groups, there were no statistically significant differences either before or after the treatment (P > 0.05). During the treatment intervals of 0-1.0 years and 1.0-2.0 years, both patient groups experienced a slowdown in GV and a decline in HtSDS improvement (P < 0.05). The use of PEG-rhGH in treating GHD patients was confirmed to be effective, with similar outcomes observed in both the high-dose group and low-dose groups, and no significant differences in the main side effects.

THU162 Impact On Visual Function And Optic Nerve Morphology In Early Stages Of Growth Hormone Treatment

Abstract Disclosure: D.G. Braslavsky: None. A.C. Keselman: None. M.G. Ballerini: None. S. Rosenbrock: None. N. Cappa: None. G. Negrete: None. G. Dech: None. M.G. Ropelato: None. S. Gamio: None. I. Bergada: None. Background Current safety of recombinant human growth hormone (rhGH) treatment arises mainly from postmarketing surveillance. Headache is a relatively frequent symptom in children under rhGH. Secondary intracranial hypertension (SIH), is an adverse effect (AE), usually occurring within the first 12 weeks of treatment associated to headaches. Permanent visual defects are the most feared complication. Scarce information exists regarding incidence and natural history of visual impairment under rhGH. Aim To evaluate visual impairment and/or optic nerve affection in children throughout early rhGH treatment. Materials and Methods Prospective interventional study conducted from February 2018 to January 2020. Children ≥4 yr who received rhGH treatment for growth hormone deficiency (GHD), 0.16-0.25 mg/kg/w; Turner syndrome (TS), small for gestational age (SGA), 0.33 mg/kg/w and Prader Willy Syndrome (PWS) 1 mg/m2/d. Patients were assessed at basal, 1, 3, and 6 months of treatment. Each visit included clinical variables (adherence, auxology, AE, presence of headache), serum IGF1, IGFBP3, glucose, insulin, aldosterone, plasma renin activity, electrolytes and ophthalmologic evaluation [fundoscopy, optical coherence tomography (OCT), retinal nerve fiber layer (RNFL), ganglionic eye complex, ocular ultrasound, intraocular pressure (IOP), autorefractometry, biomicroscopy]. Results Sixty patients were enrolled, 12 GHD, 11 ST, 31 SGA, 3 PWS, 3 TBI (23 females), with a median age of 8.08 yrs (ranged 4.24-15). Median height was -2.25 ± 1.05 SDS. Baseline ophthalmologic evaluation was normal. Abnormal ophthalmological findings were observed in 15/60 (25%). Twelve patients showed changes in OCT, spontaneous recovery occurred in 8, whereas persistence or worsening of RNFL thickening lead to an MRI assessment and lumbar puncture (LP) in 4 patients (1 GHD, 2 SGA, 1 ST); only one referred headache. LP revealed opening pressure of 19, 21, 22 and 30 mmHg, respectively, the latter assumed as SIH at the 1st month of treatment. In these four patients, during the findings of ocular abnormalities, they presented a mean IGF1 1.12 ± 1.04 SDS and IGFBP3 -0.02 ± 2.34 SDS. ΔBMI -0.45 ± 0.71 SDS. Prevalence of SIH was 1.6%. All four patients received acetazolamide; median time for RNFL improvement took 4 months (range 4-8). One patient developed post-dural puncture headache. Three had elevated IOP. Along the protocol 19/60 referred headache (26 events). Three of these patients with headaches had abnormal ophthalmological findings (2 mild changes in OCT; 1 elevated IOP). Conclusion We have demonstrated a marked prevalence of abnormal ophthalmological findings upon early rhGH treatment. These observations occurred in the absence of suggestive clinical symptoms, and conversely, headache did not predict SIH. The prevalence of SIH due to rhGH is higher than previously reported. Presentation: Thursday, June 15, 2023

THU004 Impact Of Continuous Medical Education At Improving Knowledge And Confidence Related To New And Emerging Pediatric Growth Hormone Deficiency Treatment Options

Abstract Disclosure: A. Larkin: None. C. Capparelli: None. B.S. Miller: Advisory Board Member; Self; Abbvie, Vertice, Ascendis, Bristol-Myers Squibb, Biomarin, Tolmar, Novo Nordisk, Pfizer, Inc. Research Investigator; Self; Abbvie, Amicus, Aeterna Zentaris, Amgen Inc, OPKO, Alexion Pharmaceuticals, Inc., Lumos, Novo Nordisk, Lysogene, Pfizer, Inc. M.E. Geffner: Consulting Fee; Self; Ferring Pharmaceuticals, Adrenas, Neurocrine Biosciences, Novo Nordisk, Eton, Pfizer, Inc., Nutritional Growth Solutions, Nutritional Growth Solutions. Research Investigator; Self; Novo Nordisk. L.A. Silverman: Consulting Fee; Self; Novo Nordisk, Ascendis, Pfizer, Inc., OPKO Health, Tolmar. Research Investigator; Self; Novo Nordisk, Lumos, Pfizer, Inc. Speaker; Self; Pfizer, Inc. Stock Owner; Self; Johnson &amp;Johnson. Introduction: We sought to determine if an online continuing medical education (CME) activity could improve knowledge and confidence of endocrinologists related to new/emerging treatment options for pediatric growth hormone deficiency (GHD). Methods: The CME intervention comprised a 30-min online video-based roundtable discussion among 3 expert faculty with downloadable slides. The effects of education were assessed for learners completing all 3 knowledge pre- and post-assessment questions using a matched pre-/post-assessment design, with participants serving as their own controls. A paired samples t-test was conducted for significance testing on overall average number of correct responses and for confidence rating, and a McNemar test was conducted at the question level (5% significance level, P &amp;lt;.05). Confidence was assessed in a 4th question using a 5-point Likert scale. The activity posted September 29, 2022, and data were collected through November 20, 2022. Results: Within the 2 months of data collection, 176 endocrinologists participated in the activity, with 36 completing all questions. (To date, 182 endocrinologists have participated as of December 12, 2022) Overall, 22% of endocrinologist learners improved their knowledge and 31% more answered ALL questions correctly after education. On a question-level: 8% of endocrinologists demonstrated improvement and 56% demonstrated reinforcement at recognizing gaps with once-daily pediatric GHD treatment options; 8% of endocrinologists demonstrated improvement and 58% demonstrated reinforcement at identifying efficacy comparisons between current daily and new/emerging once-weekly treatment options; 8% of endocrinologists demonstrated improvement and 56% demonstrated reinforcement at selecting the best strategies for team-based care to improve education and adherence in pediatric patients with GHD; Confidence: Overall, 28% of endocrinologists self-reported increased confidence in understanding the mechanism of once-weekly GHD treatment options, for an average confidence shift of +100% in those who increased confidence (P&amp;lt;.05). Continued educational gaps: 36% of endocrinologists need additional education to appreciate gaps with once-daily pediatric GHD treatments; 33% of endocrinologists need additional education to understand efficacy of once-weekly GHD treatment options; 17% of endocrinologists need additional education regarding team-based care of pediatric patients with GHD. Conclusion: This study demonstrates the success of an interactive, 30-min online CME on improving knowledge confidence of endocrinologists regarding once-weekly GHD treatment options, with gaps identified for future education. Presentation: Thursday, June 15, 2023

OR21-01 Pre-treatment Blood Transcriptome Predicts First-year Growth And IGF-I Response To Somapacitan Treatment In Children With GH Deficiency

Abstract Disclosure: T. Garner: Grant Recipient; Self; Novo Nordisk. P.E. Clayton: Grant Recipient; Self; Novo Nordisk. M. Hojby: Employee; Self; Novo Nordisk. Stock Owner; Self; Novo Nordisk. P. Murray: Grant Recipient; Self; Novo Nordisk. A. Stevens: Grant Recipient; Self; Novo Nordisk. Background: Growth hormone (GH) replacement therapy often requires daily subcutaneous injections that can be burdensome for patients and their caregivers. Somapacitan is a long-acting, once-weekly GH derivative in development for treating GH deficiency (GHD) in children. Somapacitan reduces treatment burden and shows a similar efficacy and safety profile as daily GH in children with GHD. Here, we investigate the prediction of first-year growth and insulin-like growth factor-I (IGF-I) response based on baseline blood transcriptome in children with GHD treated with somapacitan or daily GH. Methods: 200 treatment-naïve prepubertal children with GHD were enrolled into REAL4, a randomised, multinational, open-labelled, and active-controlled phase 3 trial. 128 consented to a baseline blood transcriptome profile. Children were treated with once-weekly somapacitan (n=81) or daily GH (n=47) for 52 weeks and categorised based on treatment response: the upper quartile of height velocity (HV; cm/year) was defined as good responders, and the lower quartile as poor responders. We split the somapacitan group into training (70%) and testing (30%) sets for prediction validation of HV and the GH response marker: ΔIGF-I standard deviation score (SDS). Gene expression was assessed between the target quartile and the remaining quartiles for both HV and ΔIGF-I SDS to identify the top 100 differentially expressed genes by adjusted p-value. Classes were balanced using a synthetic minority oversampling technique and Boruta, a feature selection algorithm, was used to refine gene lists. We performed random forest and calculated “out of box” (OOB) area under the curve (AUC) and OOB error rate (ER), measures of predictive accuracy and robustness, respectively. Results: HV prediction from the transcriptome was excellent for both treatments (AUC range: 0.95-0.99). It was more robust for identifying good responders (ER: 7.0-7.5%) than poor responders (ER: 13.2-17.5%). Genes previously identified as predictive of growth response for daily GH (Stevens et al., 2021. The Pharmacogenomics J., 21:594-607) were demonstrated to have high predictive value for once-weekly somapacitan and daily GH treatment in this study (AUC range: 0.84-0.97, ER &amp;lt;22%). Using the somapacitan group for validation, HV prediction (AUC range: 0.78-0.81) was stronger than ΔIGF-I SDS prediction (AUC range: 0.63-0.72). Conclusions: We demonstrate pre-treatment blood transcriptome predicts first-year growth response for somapacitan. This represents an independent validation of earlier observations and shows that genes predictive of growth response for daily GH treatment in children with GHD are also predictive for once-weekly somapacitan. Further, we demonstrate that the pre-treatment blood transcriptome predicts growth response better than it predicts IGF-I SDS response. Presentation: Saturday, June 17, 2023

Evaluating the Usefulness and Ease of Use of a Next-Generation-Connected Drug Delivery Device for Growth Hormone Therapy: Qualitative Study of Health Care Professionals' Perceptions.

Digital solutions targeting children's health have become an increasingly important element in the provision of integrated health care. For the treatment of growth hormone deficiency (GHD), a unique connected device is available to facilitate the delivery of recombinant human growth hormone (r-hGH) by automating the daily injection process and collecting injection data such that accurate adherence information is available to health care professionals (HCPs), caregivers, and patients. The adoption of such digital solutions requires a good understanding of the perspectives of HCPs as key stakeholders because they leverage data collection and prescribe these solutions to their patients. This study aimed to evaluate the third generation of the easypod device (EP3) for the delivery of r-hGH treatment from the HCP perspective, with a focus on perceived usefulness and ease of use. A qualitative study was conducted, based on a participatory workshop conducted in Zaragoza, Spain, with 10 HCPs experienced in the management of pediatric GHD from 7 reference hospitals in Spain. Several activities were designed to promote discussion among participants about predefined topics based on the Technology Acceptance Model and the Unified Theory of Acceptance and Use of Technology to provide their perceptions about the new device. Participants reported 2 key advantages of EP3 over previous easypod generations: the touch screen interface and the real-time data transmission functionality. All participants (10/10, 100%) agreed that the new device should be part of a digital health ecosystem that provides complementary functionalities including data analysis. This study explored the perceived value of the EP3 autoinjector device for the treatment of GHD by HCPs. HCPs rated the new capabilities of the device as having substantial improvements and concluded that it was highly recommendable for clinical practice. EP3 will enhance decision-making and allow for more personalized care of patients receiving r-hGH.

PCR3 Pain-Free Injections for Growth Hormone Deficiency (GHD) Improve Quality of Life: A Time Trade-Off (TTO) Study in the UK and Canada

Growth hormone deficiency (GHD) in children causes decreased growth and markedly reduced adult height. The treatment for GHD has been given as daily subcutaneous injections. However, new GH formulations can be given weekly. Injections are a burden for children and caregivers, but to our knowledge, the impact on quality of life (QoL) has not been investigated using time trade-off (TTO) methodology. This study evaluates the impact of type of injections on QoL using a TTO survey.

Relationship between 25-hydroxyvitamin D and IGF1: a cross-sectional study of the Third National Health and Nutrition Examination Survey participants

Background25-Hydroxyvitamin D (25OHD) and insulin-like growth factor 1 (IGF1) are crucial for bone health. Some studies have shown that they interact, whereas others have indicated no association. However, it remains inconclusive whether the interaction between the two is dose dependent. Herein, we explored the relationship between 25OHD and IGF1 by conducting a cross-sectional study.MethodsThis study involved 6,046 individuals from the Third National Health and Nutrition Examination Survey (NHANES III). The dependent and independent variables were IGF1 and 25OHD levels, respectively. The covariates included age, sex, race, BMI, exercise, smoking behavior, alcohol intake, diabetes, and serum calcium level. Multiple linear regression and generalized additive model were employed to analyze the relationship between 25OHD and IGF1. Interaction and hierarchical analyses were also performed.ResultsThe 25OHD and IGF1 levels positively correlated after adjusting for covariates (β = 0.16, 95% CI: 0.04–0.29, P = 0.0103). Smooth curve fitting demonstrated a curvilinear relationship. When the 25OHD level was < 75 nmol/L, a positive correlation (β = 0.43, 95% CI: 0.25–0.62, P < 0.0001) was observed. When the 25OHD level was > 75 nmol/L, a negative correlation was observed (β = −0.53, 95% CI: −0.90 to −0.15, P = 0.0057).ConclusionThis study demonstrated a nonlinear relationship between 25OHD and IGF1. It suggests that keeping the 25OHD level within a specific range may be more conducive to bone health. Additionally, when IGF1 is used to evaluate the efficacy and safety of recombinant human growth hormone (rhGH) in growth hormone deficiency treatment, the effect of 25OHD on the actual IGF1 level should be taken into account.

Actively separated microneedle patch for sustained-release of growth hormone to treat growth hormone deficiency

Growth hormone deficiency (GHD) has become a serious healthcare burden, and presents a huge impact on the physical and mental health of patients. Here, we developed an actively separated microneedle patch (PAA/NaHCO3-Silk MN) based on silk protein for sustained release of recombinant human growth hormone (rhGH). Silk protein, as a friendly carrier material for proteins, could be constructed in mild full-water conditions and ensure the activity of rhGH. After manually pressing PAA/NaHCO3-Silk MN patch to skin for 1min, active separation is achieved by absorbing the interstitial fluid (ISF) to trigger HCO3 ‒ in the active backing layer to produce carbon dioxide gas (CO2). In rats, the MN patch could maintain the sustained release of rhGH for more than 7 days, and produce similar effects as daily subcutaneous (S.C.) injections of rhGH in promoting height and weight with well tolerated. Moreover, the PAA/NaHCO3-Silk MN patch with the potential of painless self-administration, does not require cold chain transportation and storage possess great economic benefits. Overall, the PAA/NaHCO3-Silk MN patch can significantly improve patient compliance and increase the availability of drugs, meet current unmet clinical needs, improve clinical treatment effects of GHD patients.

Clinical application of artificial intelligence in longitudinal image analysis of bone age among GHD patients.

This study aims to explore the clinical value of artificial intelligence (AI)-assisted bone age assessment (BAA) among children with growth hormone deficiency (GHD). A total of 290 bone age (BA) radiographs were collected from 52 children who participated in the study at Sun Yat-sen Memorial Hospital between January 2016 and August 2017. Senior pediatric endocrinologists independently evaluated BA according to the China 05 (CH05) method, and their consistent results were regarded as the gold standard (GS). Meanwhile, two junior pediatric endocrinologists were asked to assessed BA both with and without assistance from the AI-based BA evaluation system. Six months later, around 20% of the images assessed by the junior pediatric endocrinologists were randomly selected to be re-evaluated with the same procedure half a year later. Root mean square error (RMSE), mean absolute error (MAE), accuracy, and Bland-Altman plots were used to compare differences in BA. The intra-class correlation coefficient (ICC) and one-way repeated ANOVA were used to assess inter- and intra-observer variabilities in BAA. A boxplot of BA evaluated by different raters during the course of treatment and a mixed linear model were used to illustrate inter-rater effect over time. A total of 52 children with GHD were included, with mean chronological age and BA by GS of 6.64 ± 2.49 and 5.85 ± 2.30 years at baseline, respectively. After incorporating AI assistance, the performance of the junior pediatric endocrinologists improved (P < 0.001), with MAE and RMSE both decreased by more than 1.65 years (Rater 1: ΔMAE = 1.780, ΔRMSE = 1.655; Rater 2: ΔMAE = 1.794, ΔRMSE = 1.719), and accuracy increasing from approximately 10% to over 91%. The ICC also increased from 0.951 to 0.990. During GHD treatment (at baseline, 6-, 12-, 18-, and 24-months), the difference decreased sharply when AI was applied. Furthermore, a significant inter-rater effect (P = 0.002) also vanished upon AI involvement. AI-assisted interpretation of BA can improve accuracy and decrease variability in results among junior pediatric endocrinologists in longitudinal cohort studies, which shows potential for further clinical application.

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 &amp;gt;14 years (girls) or &amp;gt;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.

RF26 | PMON334 Once-Weekly Somapacitan in Growth Hormone Deficiency: 4-Year Efficacy and Safety Results from REAL 3, a Randomised Controlled Phase 2 Trial

Abstract The current treatment for growth hormone deficiency (GHD) requires daily subcutaneous injections, which can be burdensome. Somapacitan is a long-acting growth hormone (GH) derivative in development for once-weekly use in children with GHD. REAL 3 (NCT02616562) is an ongoing, phase 2, multinational, randomised, open-label, controlled trial designed to investigate the efficacy and safety of somapacitan compared with daily GH (Norditropin®). Prepubertal children with GHD who were naïve to GH treatment received 0.04 (n=16), 0.08 (n=15) or 0.16 mg/kg/week (n=14) somapacitan, or daily GH 0.034 mg/kg/day (equivalent to 0.238 mg/kg/week; n=14) for 1 year. This was followed by a 2-year safety extension, in which all patients on somapacitan (n=45) received 0.16 mg/kg/week, while patients receiving daily GH remained on daily GH. In a further, ongoing 4-year long-term safety extension, patients treated with somapacitan remained on somapacitan (somapacitan/somapacitan, n=39) and all patients on daily GH switched to somapacitan 0.16 mg/kg/week (daily GH/somapacitan, n=11). Here, we present efficacy and safety results from the first year of the 4-year long-term safety extension. At year 4, the mean (SD) height velocity (HV) was 7.4 (1.6) cm/year for the somapacitan/somapacitan group and 6.6 (1.6) cm/year for the daily GH/somapacitan group, compared with 8.3 (1.7) and 7.6 (2.0) cm/year for the somapacitan/somapacitan and daily GH groups, respectively, at year 3. The mean (SD) HV standard deviation score (SDS) was 1.55 (1.70) for the somapacitan/somapacitan group and 0.88 (1.61) for the daily GH/somapacitan group, and the mean (SD) change in height SDS from baseline was 2.85 (1.25) and 2.28 (0.97), respectively. The mean (SD) insulin-like growth factor-I SDS at year 4 was 1.29 (1.23) and 0.94 (1.60) for the somapacitan/somapacitan and daily GH/somapacitan groups, respectively. During year 4, 20 patients (51.3%) experienced 84 adverse events (AEs) in the somapacitan/somapacitan group, and eight patients (72.7%) experienced 12 AEs in the daily GH/somapacitan group. The most common AE was nasopharyngitis, occurring in four patients (10.3%) in the somapacitan/somapacitan group and one patient (9.1%) in the daily GH/somapacitan group; all other AEs occurred in &amp;lt;10% of patients in either group. Most AEs were mild or moderate and unlikely related to GH treatment. One severe AE (surgery for elbow fracture) occurred in the somapacitan/somapacitan group. No serious AEs were reported in year 4. Since previously reported in year 3, one patient in the somapacitan/somapacitan group experienced five injection-site reactions; none occurred in the daily GH/somapacitan group. In conclusion, these year 4 data support the efficacy and safety results of somapacitan observed in the previous 3 years of the trial. In year 4, height-related outcomes were similar for patients who continued treatment with somapacitan and those who switched from daily GH to somapacitan. Somapacitan was well tolerated, and no safety signals were identified. Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m., Monday, June 13, 2022 12:44 p.m. - 12:49 p.m.

PMON336 Pfizer Registry of Outcomes in Growth hormone RESearch (PROGRES): A multi-country, non-interventional, prospective, cohort study of patients receiving human growth hormone treatments under routine clinical care

Abstract Background Children with growth hormone deficiency (GHD) are treated with recombinant human growth hormone (rhGH), usually administered as a daily subcutaneous injection. Long-acting hGH (LAGH) treatments (approved and in development) have the potential to improve adherence and treatment outcomes. Somatrogon is a LAGH currently being developed as a once-weekly injectable treatment for GHD. The Pfizer Registry of Outcomes in Growth hormone RESearch (PROGRES) study was initiated to assess the long-term safety and effectiveness of Genotropin and other hGH formulations to treat GHD under routine clinical care. Goals &amp; aims: The overall goal of the registry is to increase our understanding of hGH treatments as used in a real-world setting. Enrolling children treated with different daily hGH brands as well as somatrogon (if approved in a given geography) will enable comparison between daily and LAGH, and across daily hGH brands. The primary objectives of the study are to describe and compare the safety and effectiveness of daily and LAGH treatments in children. Secondary objectives include evaluating adherence to hGH treatments and the health-related quality of life (HRQoL) and treatment experience of patients receiving hGH treatments. Methods For this non-interventional, prospective, phase 4 cohort study, eligible patients (male or female at any age) from &amp;gt;20 countries are planned for inclusion, with the aim of targeting 667 patients across the daily hGH brands in each of the three geographic regions. Patients will be enrolled from September 2021 to October 2029, with data collection planned until October 2030. Study inclusion criteria include prescription of daily Genotropin or other approved hGH treatments for GHD and the provision of informed consent/assent. If somatrogon is approved by regulatory agencies, somatrogon-treated patients will also be eligible for inclusion. Patients participating in any interventional clinical trials at the time of enrollment will be excluded from the study. Patients will be followed until the end of the study, withdrawal of consent, death, switch to an excluded hGH, or loss to follow-up, whichever occurs first. In addition to demographic and clinical characteristics, information on hGH treatment brand, dose and start/end dates will be collected, along with reasons for switching or discontinuing treatment. Primary safety outcomes include adverse events (AEs), serious AEs, and AEs of special interest. Primary effectiveness outcomes include annual height velocity (HV) and change in HV standard deviation scores. Treatment adherence, compliance outcomes, HRQoL, and patient treatment experience will be assessed. Conclusions The findings from the PROGRES study will provide valuable insights into the use of somatrogon, Genotropin and other approved hGH treatments in real-world clinical practice, specifically with regard to the long-term safety and effectiveness of these treatments as well as treatment compliance and patient HRQoL. Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.

Population pharmacokinetic/pharmacodynamic analysis of PEG-rhGH enhances confidence in exploring dosing schemes with longer intervals

Background and objectivesPEG-rhGH (Jintrolong®, 0.2 mg/kg/week) is approved in China for the treatment of growth hormone deficiency (GHD) in children. Although 0.2 mg/kg/2 weeks PEG-rhGH failed the non-inferiority threshold of 20% compared with 0.2 mg/kg/week PEG-rhGH, it notably increases serum IGF-1 levels and height velocity in a phase IV trial. In the absence of investigation on the relationship between pharmacokinetics and pharmacodynamics, this analysis aimed to build a population pharmacokinetic/pharmacodynamic (PopPK/PD) model to characterize the relationship between serum PEG-rhGH concentration and serum insulin-like growth factor-1 (IGF-1) levels after subcutaneously administration of PEG-rhGH and to explore the possibility of flexible dosing schemes and improve the clinical monitor practice of IGF-1 levels. MethodsA total of 41 subjects were included for the PopPK analysis, consisting of 30 healthy adults (single dose of 0.1–0.4 mg/kg) and 11 GHD children (multiple doses of 0.2 mg/kg/2 weeks for 26 consecutive weeks). Only GHD children were included for the PopPK/PD analysis. The time courses of serum PEG-rhGH concentrations in healthy adults and GHD children and those of serum IGF-1 levels stimulated by serum PEG-rhGH were well developed with non-linear mixed-effects modeling. ResultsSerum PEG-rhGH pharmacokinetics after subcutaneous administration were adequately described by a one-compartment model with a zero-order input into the absorption compartment followed by first-order absorption dictating absorption into the central compartment, with a dual elimination process consisting of a capacity limited process and a non-capacity limited process. Body weight was a significant covariate. The drug effects on IGF-1 levels were adequately described by a turnover model with saturable effect relationship. IGF-1 responses at the various dosing scheme scenarios were simulated, and illustrated that dosing schemes with intervals longer than the approved one week could be promising, which may provide comparable peaks and average IGF-1 levels and IGF-1 SDS to dosing schemes that have been clinically proven to be tolerated and effective. An accurate prediction of the time course of the effect of various dosing schemes may assist the clinical monitoring practice. ConclusionsThis pharmacokinetic/pharmacodynamic analysis suggested that longer intervals or higher dosing strengths (e.g., 0.3 mg/kg/10 days) in children with GHD are promising compared with the approved dosing scheme (0.2 mg/kg/week). Our simulation may assist the clinical monitoring of the PEG-rhGH therapy.

Somapacitan: a long-acting growth hormone derivative for treatment of growth hormone deficiency

Growth hormone deficiency (GHD) is characterized by inadequate HG production from the anterior pituitary gland. Adult patients with GHD have increased fat mass, an abnormal lipid profile, decreased lean body mass and bone mineral density, decreased muscle strength and exercise endurance, and a diminished quality of life. Adult GHD (AGHD) has been treated with GH replacement therapy by daily subcutaneous injections. However, the administration of daily injections can be burdensome for some patients and affect treatment adherence. Somapacitan is a new long-acting human GH (hGH) analogue that is administered once a week by subcutaneous injection. It was first approved by the U.S. Food and Drug Administration (FDA) as GH replacement therapy for adults with GHD, becoming the first hGH therapy for AGHD administered by once-weekly injection, compared with other approved hGH therapies for AGHD administered by daily injection. This article reviews the pharmacokinetic, clinical and safety data that led to the approval of somapacitan as the first long-acting GH therapy for adults with GHD.

Spotlight on Lonapegsomatropin Once-Weekly Injection and Its Potential in the Treatment of Growth Hormone Deficiency in Pediatric Patients.

Lonapegsomatropin, a long-acting GH therapy (LAGH), was approved by the United States Food and Drug Administration in August 2021 for the treatment of pediatric growth hormone deficiency (GHD). Lonapegsomatropin is a prodrug consisting of unmodified GH transiently conjugated to methoxypolyethylene glycol which enables time-release of GH with a half-life of ~25 hours allowing for once-weekly administration. Clinical trials of lonapegsomatropin have demonstrated positive efficacy results in children (phase 2 and 3) and adults (phase 2) with GHD. The phase 3 trial in children with GHD established non-inferiority and statistical superiority of height velocity with lonapegsomatropin (11.2 cm/yr) compared to daily GH (10.3 cm/yr), with no concerning side effects with lonapegsomatropin. Similar growth responses have been reported in other LAGH products in phase 2 (somapacitan) and phase 3 (somatrogon) trials. Lonapegsomatropin is distributed in temperature-stable, prefilled cartridges at 9 different doses that can be prescribed based upon specific weight brackets designed to deliver approximately 0.24 mg/kg/wk. An electronic delivery device is required to combine the powdered medication with the diluent and deliver the medication subcutaneously through a small gauge needle to the recipient. The pharmacodynamic data from the clinical trials of lonapegsomatropin has been used to develop models to estimate an average IGF-1 value drawn at any time during the weekly injection interval. This average IGF-1 value may be used to for safety monitoring and/or to guide dose adjustment. New LAGH products, including lonapegsomatropin, may potentially improve patient adherence, quality of life and clinical outcomes, particularly in patients with poor adherence to daily GH injections in the future. With the availability of new LAGH products, clinicians will need to identify the best candidates for LAGH therapy and understand how to monitor and adjust therapy. Long-term surveillance studies are needed to demonstrate adherence, efficacy, cost-effectiveness and safety of LAGH preparations.