INTRODUCTION:Somatrogon is a once-weekly, long-acting growth hormone approved to treat children with growth hormone deficiency (GHD). This study evaluated the long-term efficacy and safety of once-weekly somatrogon in children with GHD following up to 3 years of treatment. METHODS:During the 12-month main study, patients were randomized 1:1 to once-weekly somatrogon (0.66 mg/kg/week) or once-daily somatropin (0.24 mg/kg/week). Patients could then enter an open-label extension (OLE), wherein somatrogon-treated patients continued receiving somatrogon and somatropin-treated patients switched to somatrogon (0.66 mg/kg/week). Data to the end of the second year of the OLE (OLE year [Y] 2) are reported. Of the 222 patients who completed the main study, 212 entered OLE Y1 and 177 entered OLE Y2. RESULTS:Mean (SD) height velocity (HV) was 8.11 (1.84) and 7.91 (1.84) cm/year at OLE Y1 and Y2, respectively. Mean (SD) height SD score (SDS) was -1.42 (0.90) and -0.95 (0.84) in OLE Y1 and Y2, respectively. In OLE Y1 and Y2, mean change in height SDS (ΔHSDS) was 1.36 and 1.61, respectively, and mean insulin-like growth factor I (IGF-I) SDS remained >1, confirming the efficacy of the treatment. Patients who switched from somatropin to somatrogon had similar HV, height SDS, and ΔHSDS to those who received somatrogon continuously. The incidence of adverse events (all causality) was 71.7% and 72.3% in OLE Y1 and Y2, respectively; most were mild or moderate in severity. Injection site pain and injection site erythema were the most commonly reported treatment-related adverse events in the OLE period. In OLE Y1 and Y2, up to one quarter of patients had IGF-I SDS >2 at two consecutive assessments, meeting protocol criteria for dose reduction. CONCLUSION:Following up to 3 years of somatrogon treatment, children with GHD showed a persistent increase in linear growth velocity compared to baseline. Somatrogon was well tolerated, with no new safety signals identified.

Objectives:Somatrogon is a long-acting growth hormone utilized for treatment of pediatric patients with growth hormone deficiency (GHD). This matched cohort analysis compared the first 3 years of height outcomes for somatrogon-treated patients from a Phase 3 somatrogon study (NCT02968004) with historical data from somatropin-treated patients in the Kabi/Pfizer International Growth Study (KIGS). Methods:In the somatrogon study, patients with GHD were randomized to once-weekly somatrogon (0.66 mg/kg/week) or once-daily somatropin (0.24 mg/kg/week) for 12 months, followed by an open-label extension, during which all patients received somatrogon (0.66 mg/kg/week or lower dose as per protocol). Patients in the somatrogon study (somatrogon cohort) were matched with patients with GHD from KIGS (KIGS cohort) who had received somatropin (0.20-0.30 mg/kg/week), using propensity score matching according to baseline characteristics of geographic region, gender, age, peak GH, and height standard deviation score (HtSDS) (ie, peak GH and HtSDS at study entry). Results:155 patients in the somatrogon study were matched to 155 somatropin-treated patients from KIGS. The somatrogon and KIGS cohorts had similar mean annualized height velocity through Years (Y) 1 to 3 of treatment (Y1: 10.03 vs 9.57; Y2: 7.70 vs 7.33; Y3: 7.15 vs 6.56). Mean changes in HtSDS (from baseline) through Y1-3 were comparable between both cohorts, though the somatrogon cohort appeared to have larger changes in Y2-3. Conclusion:Somatrogon-treated patients in the Phase 3 study had similar height outcomes compared with matched somatropin-treated patients in KIGS, strengthening the expectation that once-weekly somatrogon will have comparable efficacy to somatropin in real-world treatment of pediatric patients with GHD.

INTRODUCTION:Studies of gonadotropin-releasing hormone analogues (intramuscular [IM] leuprolide acetate [LA] and triptorelin) for treatment monitoring of central precocious puberty (CPP) demonstrate this approach is effective for confirming pubertal hormone suppression. Herein, we provide new data using subcutaneous LA (SC LA), suggesting similar efficacy for treatment monitoring. METHODS:PubMed, Embase, and CINAHL were searched for studies of GnRHa used to monitor treatment of CPP. The titles and the abstracts were reviewed; 5 studies were selected. Additionally, new unpublished data for SC LA from the original phase 3 trial (primary data published by Klein et al.) were evaluated. Serum luteinizing hormone (LH) and leuprolide levels at screening, 1, 4, and 6 h after the first dose SC LA were analyzed and plotted. RESULTS:Data from 162 children (155 girls) were evaluated. SC and IM LA produced overlapping median LH concentration curves and peak LH concentrations after the first dose. For IM LA, subsequent doses yielded suppressed peak LH levels (2.7 IU/L [mean]). For SC LA, subsequent doses also resulted in significant suppressed peak LH levels (0.2 ± 0.02 IU/L) and achieved sex-steroid hormone suppression of >98%. CONCLUSIONS:Compared to IM LA and triptorelin, long-acting SC LA shows similar burst kinetics and rapid LH rise after the first dose, followed by similar suppression of LH and sex steroids after subsequent doses. Since IM LA and triptorelin have demonstrated usefulness that is comparable to that of traditional GnRH stimulation testing for monitoring CPP, we presume that SC LA may be similarly employed.

• The efficacy of weekly somatrogon injections was no different from that of daily somatropin injections to treat children who don’t make enough growth hormone to grow adequately. ○ Efficacy refers to how well a drug works in a clinical trial. ○ Children treated with weekly somatrogon had an increased growth rate, similar to that of children treated with daily somatropin . • The safety of weekly somatrogon injections was similar to that of daily somatropin injections. The original scientific article on which this summary is based was published in The Journal of Clinical Endocrinology & Metabolism and can be accessed for free at: https://academic.oup.com/jcem/article/107/7/e2717/6566444 . The details of the original article are as follows: Cheri L. Deal, Joel Steelman, Elpis Vlachopapadopoulou, Renata Stawerska, Lawrence A Silverman, Moshe Phillip, Ho-Seong Kim, CheolWoo Ko, Oleg Malievskiy, Jose F. Cara, Carl L. Roland, Carrie Turich Taylor, Srinivas Rao Valluri, Michael P. Wajnrajch, Aleksandra Pastrak, and Bradley S. Miller. Efficacy and safety of weekly somatrogon vs daily somatropin in children with growth hormone deficiency: a phase 3 study. J Clin Endocrinol Metab 2022; 107(7): e2717–e2728. The purpose of this plain language summary is to help you to understand the findings from recent research. • Somatrogon is used to treat growth hormone deficiency (the condition under study that is discussed in this summary). Approval varies by country; please check with your local healthcare provider for more details. • The results of this study may differ from those of other studies. Physicians/providers should make treatment decisions based on all available evidence and not on the results of a single study.

A thorough history and physical examination including Tanner staging and growth assessments can guide differential diagnosis and aid in the evaluation of precocious puberty. Basal luteinizing hormone levels measured using a highly sensitive assay can be helpful in diagnosing central precocious puberty (CPP). Brain MRI is indicated with males diagnosed with CPP and females under the age of 6 with CPP. As more information becomes available regarding the genetic etiologies of CPP, genetic testing may preclude the need for imaging studies and other hormonal testing, especially in familial cases.

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 &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 <.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<.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

Abstract Disclosure: B.S. Miller: Consulting Fee; Self; Abbvie, Ascendis Pharma, Bristol Myers Squibb, BioMarin, Endo Pharmaceuticals, EMD Serono, Novo Nordisk, Pfizer, Tolmar Pharmaceuticals. Research Investigator; Self; Alexion, Abbvie, Aeterna Zentaris, Amicus, Lumos Pharma, Lysogene, Novo Nordisk, OPKO Health, Pfizer, Prevail Therapeutics, Sangamo Therapeutics. D. Boldt-Houle: Employee; Self; Tolmar Pharmaceuticals, Inc. S.N. Atkinson: Employee; Self; Tolmar Pharmaceuticals, Inc. Background: Childhood obesity is associated with an increased risk of central precocious puberty (CPP).1 Thus, data on whether weight status affects the treatment of children with CPP would be valuable to help clinicians ensure correct management. We present secondary analyses of hormone and height velocity (HV) data from the pivotal trial of the first small-volume, long-acting, subcutaneously administered gonadotropin-releasing hormone agonists (GnRHa) for CPP, with the goal of assessing if the study drug adequately suppresses hormones in overweight and obese children. Methods: 62 children with treatment-naïve CPP received 2 doses of 45 mg subcutaneous leuprolide acetate at 24-week intervals over the 48-week study period. The BMI percentile for children was calculated based on the Center for Disease Control growth charts, accounting for height, weight, age, and gender. Luteinizing hormone (LH) concentrations were assessed using a validated central Cobas ECLIA assay with a lower limit of detection of 0.100 IU/L. Estradiol (E2) concentrations were assessed using liquid chromatography-tandem mass spectrometry/mass spectrometry (LC-MS/MS) with a lower limit of detection of 10 pg/mL. HV was calculated as the change in height between visits/((number of weeks between visits)/52). Results: Mean GnRH-stimulated LH concentrations at screening, week 24, and week 48 were 24.5, 2.1, and 2.5 IU/L in non-overweight children, 10.5, 3.2, and 2.2 IU/L in overweight children, and 31.5, 4.8, and 1.9 IU/L in obese children, respectively. In these same groups, mean E2 concentrations at screening, week 24, and week 48 were 28.2, 10.5, and 10.3 pg/mL in non-overweight children, 17.8, 10.4, and 10.4 pg/mL in overweight children, and 25.9, 11.0, and 11.1 pg/mL in obese children, respectively. Mean HV at week 4, week 24, and week 48 was 10.2, 5.6, and 5.7 cm/year in non-overweight children, 7.7, 5.5, and 6.2 cm/year in overweight children, and 8.2, 4.9, and 6.6 cm/year in obese children, respectively. Conclusions: Subcutaneous leuprolide acetate effectively treated all overweight children without any requirement for weight-based dosing. This is consistent with results from previous studies of GnRHa efficacy in obese and normal-weight children with CPP.2 Clinicians should consider providing counseling and interventions that support healthy diets and lifestyles to children with above-normal BMI and their caregivers. References Cited 1.Liu G, Guo J, Zhang X, Lu Y, Miao J, Xue H. Obesity is a risk factor for central precocious puberty: a case-control study. BMC Pediatr. 2021;21(1):509.2. Chen M, Eugster EA. Central precocious puberty: update on diagnosis and treatment. Paediatr Drugs. 2015;17(4):273-281. Presentation: Thursday, June 15, 2023