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

Abstract: For children with growth hormone deficiency (GHD), treatment burden with daily somatropin injections [human growth hormone (hGH)] is high, which may lead to poor adherence and suboptimal overall treatment outcomes. Lonapegsomatropin (TransCon hGH) is an investigational long-acting, once-weekly prodrug for the treatment of GHD. Objective The objective of this study was to evaluate the efficacy and safety of once-weekly lonapegsomatropin vs daily somatropin. Design The heiGHt trial was a randomized, open-label, active-controlled, 52-week Phase 3 trial (NCT02781727). Setting This trial took place at 73 sites across 15 countries. Patients This trial enrolled and dosed 161 treatment-naïve, prepubertal patients with GHD. Interventions Patients were randomized 2:1 to receive lonapegsomatropin 0.24 mg hGH/kg/week or an equivalent weekly dose of somatropin delivered daily. Main Outcome Measure The primary end point was annualized height velocity (AHV) at week 52. Secondary efficacy end points included change from baseline in height SD scores (SDS). Results Least squares (LS) mean (SE) AHV at 52 weeks was 11.2 (0.2) cm/year for lonapegsomatropin vs 10.3 (0.3) cm/year for daily somatropin (P = 0.009), with lonapegsomatropin demonstrating both noninferiority and superiority over daily somatropin. LS mean (SE) height SDS increased from baseline to week 52 by 1.10 (0.04) vs 0.96 (0.05) in the weekly lonapegsomatropin vs daily somatropin groups (P = 0.01). Bone age/chronological age ratio, adverse events, tolerability, and immunogenicity were similar between groups. Conclusions The trial met its primary objective of noninferiority in AHV and further showed superiority of lonapegsomatropin compared to daily somatropin, with similar safety, in treatment-naïve children with GHD.

Abstract: The positive predictive value of newborn screening for congenital adrenal hyperplasia (CAH) in New Zealand is approximately 10%. The use of a second tier liquid chromatography-tandem mass spectrometry bloodspot steroid profile test with birth weight– or gestational age–adjusted screening cutoffs may result in further screening improvements. Methods Three years of newborn screening data with additional second-tier steroid metabolites was evaluated (n = 167 672 births). Data from babies with a negative screening test and confirmed CAH cases were compared. First- and second-tier steroid measurements were correlated with both birth weight and gestational age. Analysis of variance was used to determine birth weight and gestational age groups. Screening cutoffs were determined and applied retrospectively to model screening performance. Results First-tier immunoassay data correlated better with gestational age than with birth weight, but there was no difference with second-tier steroid measurements. Four distinct birth weight and gestational age groups were established for 17-hydroxyprogesterone and a steroid ratio measurement. Application of 97.5th percentile second-tier birth weight– or gestational age–adjusted cutoffs would result in 10 positive tests over the period of the study with 8 true-positive screens and 2 false-positive tests. The positive predictive value of screening would be increased from 10.8% to 80%. Conclusions The use of either birth weight– or gestational age–adjusted cutoffs for second-tier screening tests can significantly reduce the false positive rate of newborn screening for CAH in New Zealand without loss in screening sensitivity.

Abstract: It is unclear whether newborns with mild thyrotropin elevation (mTSHe) are at risk of neurocognitive impairment. We assessed whether mTSHe at birth persists during childhood and compared neurocognitive functioning to siblings. Methods This study encompassed children born in the Auckland region (New Zealand) with a newborn screen TSH level of 8 to 14 mIU/L blood, age 6.9 to 12.6 years at assessment, and their siblings. Thyroid function tests (serum TSH and free thyroxine) and neurocognitive assessments were performed, including IQ via the Wechsler Intelligence Scale for Children, fourth edition. Results Ninety-six mTSHe individuals were studied, including 67 children recruited with 75 sibling controls. Mean mTSHe newborn TSH level was 10.1 mIU/L blood and 2.4 mIU/L at assessment (range, 0.8-7.0 mIU/L, serum). Although higher newborn TSH levels in the mTSHe group correlated with lower full-scale IQ scores (r = 0.25; P = .040), they were not associated with the magnitude of the IQ difference within sibling pairs (P = .56). Cognitive scores were similar for mTSHe and controls (full-scale IQ 107 vs 109; P = .36), with a minor isolated difference in motor coordination scores. Conclusions Our data do not suggest long-term negative effects of neonatal mild TSH elevation. TSH elevation below the screen threshold appears largely transient, and midchildhood neurocognitive performance of these children was similar to their siblings. We propose that associations between neonatal mild TSH elevation and IQ are due to familial confounders. We caution against the practice of reducing screening CH cutoffs to levels at which the diagnosis may not offer long-term benefit for those detected.

Abstract: Hysterosalpingography (HSG) with oil-soluble contrast medium (OSCM) improves pregnancy rates. However, OSCM has high iodine content and long half-life, leading to potential iodine excess. Objective This work aimed to determine the pattern of iodine excess after OSCM HSG and the effect on thyroid function. Methods A prospective cohort study was conducted of 196 consecutive consenting eligible women without overt hypothyroidism or hyperthyroidism. All completed the study with compliance greater than 95%. Participants underwent OSCM HSG (Auckland, 2019-2021) with serial monitoring of thyrotropin (TSH), free thyroxine (FT4), and urine iodine concentration (UIC) for 24 weeks. The main outcome measure was the development of subclinical hypothyroidism (SCH), defined as a nonpregnant TSH greater than 4 mIU/L with normal FT4 (11-22 pmol/L) in those with normal baseline thyroid function. Results Iodine excess (UIC ≥ 300 μg/L) was almost universal (98%) with UIC peaking usually by 4 weeks. There was marked iodine excess, with 90% and 17% of participants having UIC greater than or equal to 1000 μg/L and greater than 10 000 μg/L, respectively. Iodine excess was prolonged with 67% having a UIC greater than or equal to 1000 μg/L for at least 3 months. SCH developed in 38%; the majority (96%) were mild (TSH 4-10 mIU/L) and most developed SCH by week 4 (75%). Three participants met the current treatment guidelines (TSH & gt; 10 mIU/L). Thyroxine treatment of mild SCH tended to improve pregnancy success (P = .063). Hyperthyroidism (TSH & lt; 0.3 mIU/L) occurred in 9 participants (5%). Conclusion OSCM HSG resulted in marked and prolonged iodine excess. SCH occurred frequently with late-onset hyperthyroidism occasionally. Regular thyroid function tests are required for 6 months following this procedure.

Abstract: Prader–Willi syndrome (PWS) is characterized by lack of appetite control and hyperphagia, leading to obesity. Pharmacological options for weight management are needed. Objective To determine whether liraglutide treatment for weight management is superior to placebo/no treatment in pediatric individuals with PWS. Methods This was a multicenter, 52-week, placebo-controlled trial with a 16-week double-blinded period. Adolescents (n = 31, aged 12-17 years; Tanner stage 2-5) and children (n = 24, aged 6-11 years; Tanner stage & lt;2) with PWS and obesity were included. Patients were randomized 2:1 to liraglutide 3.0 mg (or maximum-tolerated dose) or placebo for 16 weeks, after which placebo was stopped. Liraglutide was continued for 52 weeks. All patients followed a structured diet and exercise program throughout the trial. The coprimary endpoints were change in body mass index (BMI) standard deviation score (SDS) from baseline to 16 and 52 weeks. Secondary endpoints included other weight-related parameters, hyperphagia, and safety. Results Change in BMI SDS from baseline to weeks 16 and 52 was not significantly different between treatments in adolescents (estimated treatment difference: −0.07 at week 16 and −0.14 at week 52) and children (−0.06 and −0.07, respectively). Changes in other weight-related parameters between treatments were not significant. At week 52, hyperphagia total and drive scores were lower in adolescents treated with liraglutide vs no treatment. The most common adverse events with liraglutide were gastrointestinal disorders. Conclusion Although the coprimary endpoints were not met, changes in hyperphagia total and drive scores in adolescents warrant further studies on liraglutide in this population.

Abstract: Disclosure: R. Savarirayan: Advisory Board Member; Self; Biomarin, Ascendis. Consulting Fee; Self; BridgeBio. C. McDonnell: Advisory Board Member; Self; Pfizer. Research Investigator; Self; Ascendis, KyowaKirin. Other; Self; Honoraria: Biomarin, Pfizer; Travel, Accommodations, and Expenses: Pfizer. D.G. Hoernschemeyer: Consulting Fee; Self; Orthopediatrics. Grant Recipient; Self; Zimvie. Research Investigator; Self; Zimvie, Biomarin. Speaker; Self; Zimvie. Stock Owner; Self; Orthopediatrics. Other; Self; Travel, Accommodations, Expenses: Orthopediatrics; Honoraria: Biomarin; Patents, Royalties, Other IP: Orthopediatrics; Other relationship: Orthopediatrics, Zimvie. H.B. Hove: Advisory Board Member; Self; Pfizer. Consulting Fee; Self; Pfizer, Ascendis Pharma. Y.A. Zarate: None. M.B. Bober: Advisory Board Member; Self; Biomarin, Ultragenyx. Consulting Fee; Self; Biomarin, QED, Ascendis. Grant Recipient; Self; Biomarin. Research Investigator; Self; Biomarin, Pfizer/Therachon, QED, Ascendis, Takeda, Ultragenyx, MedLife, Sobi. Speaker; Self; Alexion. Other; Self; Honoraria: Novo Nordisk. C.A. Bacino: Consulting Fee; Self; Best Doctors, Inc (Teladoc). Grant Recipient; Self; Ascendis, Roche, Ionis, BioMarin. Other; Self; Patents, Royalties, Other IP: UpToDate. J.M. Legare: Grant Recipient; Self; BioMarin. Research Investigator; Self; BioMarin. Speaker; Self; BioMarin. Other; Self; Honoraria (Self): BioMarin. W. Högler: Advisory Board Member; Self; Biomarin, Alexion. Consulting Fee; Self; Alexion, Pfizer. Grant Recipient; Self; Novo Nordisk. Research Investigator; Self; Alexion, Kyowa Kirin, Amgen. Other; Self; Honorara (Self): Alexion; Travel, Accommodations, Expenses: Alexion, Kyowa Kirin. T. Quattrin: Consulting Fee; Self; ProventionBio, Ascendis, Merck, Janssen. Research Investigator; Self; Ascendis, Janssen, Merck, Pfizer, ProventionBio. M. Abuzzahab: Advisory Board Member; Self; Pfizer, NovoNordisk, Ascendis, Rhythm. Consulting Fee; Self; Ascendis, Rhythm. Research Investigator; Self; Ascendis, NovoNordisk, Rhythm, Lumos, Soleno, Saniona, Levo, Affreza, Medtronic. P.L. Hofman: Other; Self; Honoraria (Self): Novo Nordisk and Eli-Lilly. K.K. White: Research Investigator; Self; Biomarin, Ascendis, Pfizer, Ultragenyx. Other; Self; Honorara (Self): Biomarin; Patents, Royalties, Other IP: UpToDate.com. N. Ma: Research Investigator; Self; Ascendis Pharma (site-PI), Ultragenyx (Sub-I), Amgen (site-PI). Other; Self; Patents, Royalties, Other IP (Self): UpToDate peer reviewer royalties, Co-Editor of Pediatrics section of Current Osteoporosis Reports. D. Schnabel: Advisory Board Member; Self; Biomarin, Novo Nordisk, Sandoz, Kyowa Kirin. Consulting Fee; Self; Kyowa Kirin. Other; Self; Honoraria: Kyowa Kirin, Sandoz; Travel, Accommodations, Expenses: Kyowa Kirin. S.B. Sousa: Advisory Board Member; Self; Biomarin, Ascendis. Other; Self; Honoraria (Self): Biomarin, Ascendis, Kiowa Kirin; Travel, Accomodations, Expenses: Biomarin. X. Fan: Employee; Self; Ascendis Pharma Inc. M. Chakraborty: Employee; Self; Ascendis Pharma Inc. A. Giwa: Employee; Self; Ascendis Pharma Inc. S.E. Smith: Employee; Self; Ascendis Pharma Inc. B. Volck: Employee; Self; Ascendis Pharma A/S. A.D. Shu: Employee; Self; Ascendis Pharma, Inc. Background: Achondroplasia (ACH) is the most common form of hereditary disproportionate short stature and is associated with complications that can diminish functional capacity and quality of life. ACH is caused by a pathogenic variant in the FGFR3 gene resulting in fibroblast growth factor 3 pathway overactivation leading to impaired endochondral ossification. C-type natriuretic peptide (CNP) promotes chondrocyte development by inhibiting the FGFR3 pathway. TransCon CNP is an investigational prodrug of CNP, designed to provide sustained release of CNP supporting continuous CNP exposure and a once-weekly dosing regimen. The ACcomplisH trial assessed TransCon CNP for the treatment of children with ACH aged 2 to 10 years. Methods: ACcomplisH is a phase 2, multicenter, double-blind, randomized, placebo-controlled, dose-escalation trial of once-weekly TransCon CNP in prepubertal children aged 2-10 years with ACH. Participants were randomized to TransCon CNP dosed at 6, 20, 50 and 100 μg CNP/kg/week across 4 cohorts or placebo in a 3:1 ratio. The primary objectives were safety and annualized height velocity (AHV) at 52 weeks. Results: 57 participants were enrolled; 42 received TransCon CNP: 6 μg CNP/kg/week (n=10), 20 μg CNP/kg/week (n=11), 50 μg CNP/kg/week (n=10), or 100 μg CNP/kg/week (n=11 of which 55% female, 73% ≥5 years); or pooled placebo (n=15; 33% female, 47% ≥5 years). TransCon CNP was well tolerated with no treatment discontinuations. No serious treatment-emergent adverse events (TEAEs) were reported as related to TransCon CNP. Most TEAEs were mild (grade 1) with no grade 3 or 4 TEAEs reported. There was a low frequency of injection site reactions (ISRs). In & gt;2,000 TransCon CNP injections, only 11 ISRs in 8 participants over 52 weeks were reported. There were no reports of symptomatic hypotension and no trends to suggest worsening of disproportionality. TransCon CNP 100 μg CNP/kg/week resulted in significantly higher AHV vs placebo at 52 weeks (least square [LS] mean 5.42 vs 4.35 cm/year; p=0.022) resulting in improved ACH-specific height SDS from baseline vs placebo (LS mean 0.22 vs -0.08; p=0.028). There was a dose-dependent treatment effect on AHV of 4.09 cm/year (6 μg CNP/kg/week) to 5.42 cm/year (100 μg CNP/kg/week; p=0.003). All participants completed blinded treatment and continued in the 2-year open-label extension (OLE), receiving 100 μg CNP/kg/week of TransCon CNP. Preliminary OLE data suggest sustained efficacy and safety. Conclusion: Once-weekly TransCon CNP dosed up to 100 μg CNP/kg/week was generally safe and well tolerated with mild TEAEs, few ISRs, and no discontinuations. TransCon CNP at 100 μg CNP/kg/week provided statistically significant improvement in AHV vs placebo. These results support continued investigation of TransCon CNP for children with ACH in the ongoing Phase 2b ApproaCH trial (NCT05598320) including treatment impact on ACH-related complications. Presentation: Thursday, June 15, 2023

Abstract: Age of pubertal onset has been decreasing in many countries but there have been no data on pubertal development in Chinese children over the last decade. Objective The primary objective of the study was to evaluate the current status of sexual maturation in Chinese children and adolescents. Secondary objectives were to examine socioeconomic, lifestyle, and auxological associations with pubertal onset. Methods In this national, cross-sectional, community-based health survey, a multistage, stratified cluster random sampling method was used to select a nationally representative sample, consisting of 231 575 children and adolescents (123 232 boys and 108 343 girls) between 2017 and 2019. Growth parameters and pubertal staging were assessed by physical examination. Results Compared to 10 years previously, the median age of Tanner 2 breast development and menarche were similar at 9.65 years and 12.39 years respectively. However, male puberty occurred earlier with a median age of testicular volume ≥4 mL of 10.65 years. Pubertal onset did occur earlier at the extremes, with 3.3% of the girls with breast development at 6.5-6.99 years old, increasing to 5.8% by 7.5-7.99 years old. Early pubertal onset was also noted in boys, with a testicular volume ≥ 4 mL noted in 1.5% at 7.5-7.99 years, increasing to 3.5% at 8.5-8.99 years old. Obesity and overweight increased risk of developing earlier puberty relative to normal weight in both boys and girls. Conclusion Over the past decade, pubertal development is occurring earlier in Chinese children. While the cause is multifactorial, overweight and obesity are associated with earlier puberty onset. The currently used normative pubertal data of precocious puberty may not be applicable to diagnose precocious puberty.