Explore the vast range of titles available.

Evidence from genetic disorders of CNP signalling suggests that plasma concentrations of CNP are subject to feedback regulation. In subjects with Achondroplasia (Ach), CNP intracellular activity is suppressed and plasma concentrations are raised but the therapeutic impact of exogenous CNP agonists on endogenous CNP is unknown. In this exploratory dose finding and extension study of 28 Ach children receiving Vosoritide over a 5 year period of treatment, endogenous CNP production was assessed using measurements of plasma aminoterminal proCNP (NTproCNP) adjusted for age and sex and normalised as standard deviation score (SDS), and then related to skeletal growth. Before treatment NTproCNP SDS was raised. Within the first 3 months of accelerating growth, levels were significantly reduced. Across the 5 years of sustained growth, levels varied widely and were markedly increased in some subjects during adolescence. Plasma NTproCNP was suppressed at 4 h post-injection in proportion to the prevailing level of hormone resistance as reflected by SDS before injection. We conclude CNP remains subject to regulation during growth promoting doses of Vosoritide. Fall in CNP during accelerating growth is consistent with an indirect feedback whereas the fall at 4 h is likely to be a direct effect from removal of intra cellular CNP resistance.

In this phase 3 trial, crinecerfont was superior to placebo in reducing elevated androstenedione levels and lowering glucocorticoid doses in pediatric participants with classic congenital adrenal hyperplasia.

Vosoritide is a biologic analogue of C-type natriuretic peptide, a stimulator of endochondral ossification, which is disordered in achondroplasia. In this phase 2 dose-finding study and extension study involving children with achondroplasia, once-daily administration of vosoritide resulted in a sustained increase in the annualized growth velocity.

Abstract Context Crinecerfont, a corticotropin-releasing factor type 1 receptor antagonist, has been shown to reduce elevated adrenal androgens and precursors in adults with congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21OHD), a rare autosomal recessive disorder characterized by cortisol deficiency and androgen excess due to elevated adrenocorticotropin. Objective To evaluate the safety, tolerability, and efficacy of crinecerfont in adolescents with 21OHD CAH. Methods This was an open-label, phase 2 study (NCT04045145) at 4 centers in the United States. Participants were males and females, 14 to 17 years of age, with classic 21OHD CAH. Crinecerfont was administered orally (50 mg twice daily) for 14 consecutive days with morning and evening meals. The main outcomes were change from baseline to day 14 in circulating concentrations of ACTH, 17-hydroxyprogesterone (17OHP), androstenedione, and testosterone. Results 8 participants (3 males, 5 females) were enrolled; median age was 15 years and 88% were Caucasian/White. After 14 days of crinecerfont, median percent reductions from baseline to day 14 were as follows: ACTH, −57%; 17OHP, −69%; and androstenedione, −58%. In female participants, 60% (3/5) had ≥50% reduction from baseline in testosterone. Conclusion Adolescents with classic 21OHD CAH had substantial reductions in adrenal androgens and androgen precursors after 14 days of oral crinecerfont administration. These results are consistent with a study of crinecerfont in adults with classic 21OHD CAH.

Context: Crinecerfont, a corticotropin-releasing factor type 1 receptor antagonist, has been shown to reduce elevated adrenal androgens and precursors in adults with congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21OHD), a rare autosomal recessive disorder characterized by cortisol deficiency and androgen excess due to elevated adrenocorticotropin. Objective: To evaluate the safety, tolerability, and efficacy of crinecerfont in adolescents with 21OHD CAH. Methods: This was an open-label, phase 2 study (NCT04045145) at 4 centers in the United States. Participants were males and females, 14 to 17 years of age, with classic 21OHD CAH. Crinecerfont was administered orally (50 mg twice daily) for 14 consecutive days with morning and evening meals. The main outcomes were change from baseline to day 14 in circulating concentrations of ACTH, 17-hydroxyprogesterone (17OHP), androstenedione, and testosterone. Results: 8 participants (3 males, 5 females) were enrolled; median age was 15 years and 88% were Caucasian/White. After 14 days of crinecerfont, median percent reductions from baseline to day 14 were as follows: ACTH, -57%; 17OHP, -69%; and androstenedione, -58%. In female participants, 60% (3/5) had [greater than or equal to] 50% reduction from baseline in testosterone. Conclusion: Adolescents with classic 21OHD CAH had substantial reductions in adrenal androgens and androgen precursors after 14 days of oral crinecerfont administration. These results are consistent with a study of crinecerfont in adults with classic 21OHD CAH. Key Words: congenital adrenal hyperplasia, 21-hydroxylase deficiency, crinecerfont, CRF type 1 receptor antagonist, adolescents, pediatric

Describe the clinical and molecular findings of patients with Kabuki syndrome (KS) who present with hypoglycemia due to congenital hyperinsulinism (HI), and assess the incidence of KS in patients with HI. We documented the clinical features and molecular diagnoses of 10 infants with persistent HI and KS via a combination of sequencing and copy-number profiling methodologies. Subsequently, we retrospectively evaluated 100 infants with HI lacking a genetic diagnosis, for causative variants in KS genes. Molecular diagnoses of KS were established by identification of pathogenic variants in KMT2D (n = 5) and KDM6A (n = 5). Among the 100 infants with HI of unknown genetic etiology, a KS diagnosis was uncovered in one patient. The incidence of HI among patients with KS may be higher than previously reported, and KS may account for as much as 1% of patients diagnosed with HI. As the recognition of dysmorphic features associated with KS is challenging in the neonatal period, we propose KS should be considered in the differential diagnosis of HI. Since HI in patients with KS is well managed medically, a timely recognition of hyperinsulinemic episodes will improve outcomes, and prevent aggravation of the preexisting mild to moderate intellectual disability in KS.

Continuous Glucose Monitoring and the Reality of Metabolic Control in Preschool Children With Type 1 Diabetes George S. Jeha , MD 1 2 , Lefkothea P. Karaviti , MD, PHD 1 2 , Barbara Anderson , PHD 1 , E. O’Brian Smith , PHD 1 , Susan Donaldson , RN 2 , Toniean S. McGirk , RN 2 and Morey W. Haymond , MD 1 2 1 Section of Pediatric Endocrinology and Metabolism, Baylor College of Medicine, Houston, Texas 2 Section of Pediatric Endocrinology and Metabolism, Texas Children’s Hospital, Houston, Texas Address correspondence and reprint requests to George Jeha, MD, Texas Children’s Hospital, Clinical Care Center, Suite 1020, 6621 Fannin St., CC 1020.05, Houston, TX 77030. E-mail: gsjeha{at}texaschildrenshospital.org Abstract OBJECTIVE —To determine using the MiniMed continuous glucose monitoring system (CGMS) 1 ) whether twice-daily insulin injection therapy achieves adequate control in preschool children with type 1 diabetes and 2 ) whether the CGMS is more informative than self-monitoring of blood glucose (SMBG) regarding glucose control and well tolerated by preschool children and their families. RESEARCH DESIGN AND METHODS —Ten children <6 years of age with type 1 diabetes were monitored twice using the CGMS. The distribution of glucose values was analyzed, particularly the frequency, duration, and distribution of hypoglycemia. We analyzed the accuracy of the CGMS in detecting hypoglycemia as well as the clinical relevance of the difference between CGMS and SMBG values. RESULTS —Although hypoglycemia was more frequent during the night (0.8 nighttime episodes · subject –1 · 24 h –1 vs. 0.3 daytime episodes · subject –1 · 24 h –1 ), the difference did not reach statistical significance ( P = 0.07). However, nighttime episodes lasted longer than daytime episodes (1.2 vs. 0.2 h · subject –1 · 24 h –1 , P = 0.006). Hypoglycemia accounted for 7% and normoglycemia for 24%, while hyperglycemia occurred 64% of the time, with postprandial hyperglycemia being an almost universal feature (94 ± 7% of all postmeal values). The CGMS correlated well with SMBG without significant clinical discrepancy. The CGMS sensitivity to detect hypoglycemia was 70% with a specificity of 99%; however, the CGMS detected twice as many total episodes as SMBG (82 vs. 40). CONCLUSIONS —Twice-daily insulin injection rarely achieves control in preschool children with type 1 diabetes. The CGMS is well tolerated by patients and has the advantage of revealing daily glucose trends missed by SMBG. CGMS, continuous glucose monitoring system SMBG, self-monitoring of blood glucose Footnotes A table elsewhere in this issue shows conventional and Système International (SI) units and conversion factors for many substances. Accepted August 31, 2004. Received May 7, 2004. DIABETES CARE

The author Diva D. De Leon was incorrectly listed as instead of Diva D. De Leó-Critchlow in the original version of this paper.The author Diva D. De Leon was incorrectly listed as instead of Diva D. De Leó-Critchlow in the original version of this paper.

Abstract Disclosure: N. Nokoff: Consultant for Neurocrine Biosciences and expert panel member for World Athletics. M. Vogiatzi: Research support and consultingfor Neurocrine, Spruce, Crinetics and Adrenas. M.T. Dattani: Lecturing fees from Meck Serono, Pfizer, Novo Nordisk, Sandoz, Advisory Boards for Pfizer, Novo Nordisk, Consultant for Sandoz, Pfizer, Besins. G.S. Jeha: Full-time employee of Neurocrine Biosciences, Inc. G.B. Rosales: Full-time employee of Neurocrine Biosciences, Inc. J.L. Chan: Full-time employee of Neurocrine Biosciences, Inc. Background: In patients with classic congenital adrenal hyperplasia (CAH), chronic glucocorticoid (GC) treatment often leads to weight gain or obesity. Crinecerfont, a corticotropin releasing factor type 1 receptor antagonist, is a first-in-class medication that is FDA-approved for adjunctive treatment to GC replacement to control androgens in patients with CAH. In CAHtalyst™ Pediatric (NCT04806451), least-squares mean (LSM) percent changes in GC dose at Week 28 (end of double-blind placebo-controlled [DBPC] period) indicated a significant reduction with crinecerfont (-18.0% vs +5.6% for placebo; LSM difference [LSMD] -23.5%, P<0.0001) while androstenedione was maintained or improved relative to Day 1 baseline (BL). At Week 52 (end of open-label [OL] period), mean percent decreases from BL in GC dose were -17.3% in participants continuing crinecerfont (CFT/CFT) and -6.1% in those switched from placebo (PBO/CFT). Objective: To evaluate weight-related outcomes in pediatric patients with CAH who received up to 1 year of crinecerfont. Methods: Mean changes from BL in body mass index (BMI) standard deviation score (SDS) were analyzed at Weeks 28 and 52. In participants who were overweight or obese at BL (BMI ≥85th percentile), analyses included achievement of ≥0.15 reduction in BMI SDS and achievement of normal BMI. These responder analyses, assessed at Weeks 28 and 52, are presented as percentage (n/N) of participants, with n=number of responders and N=number with available data. Results: Mean BMI SDS at BL was 1.20 (crinecerfont) and 1.12 (placebo), and >50% of participants were overweight or obese (58.0% [40/69] crinecerfont, 58.8% [20/34] placebo). At Week 28, LS mean BMI SDS was reduced from BL with crinecerfont compared to an increase with placebo (-0.09 vs +0.04; LSMD: -0.13, P=0.0493). At Week 52, mean reductions from BL in BMI SDS were maintained with crinecerfont (-0.09 CFT/CFT, -0.02 PBO/CFT). Among participants who were overweight or obese at BL, a higher percentage achieved ≥0.15 reduction from BL in BMI SDS at Week 28 with crinecerfont (17.5% [7/40]) versus placebo (10.5% [2/19]). At Week 52, 32.4% (12/37) and 26.3% (5/19) achieved this threshold in the CFT/CFT and PBO/CFT groups, respectively. Achievement of normal BMI at Week 28 was also higher with crinecerfont (12.5% [5/40]) than placebo (5.3% [1/19]. At Week 52, 13.5% (5/37) and 10.5% (2/19) achieved normal BMI in the CFT/CFT and PBO/CFT groups, respectively. Conclusion: Children and adolescents with CAH who received up to 1 year of crinecerfont showed reductions in BMI SDS. Moreover, one-third of participants who were overweight or obese at baseline achieved a ≥0.15 reduction in BMI SDS with crinecerfont, and 13% achieved normal BMI. These analyses indicate that the GC dose reductions enabled by crinecerfont can allow for improvements in the weight-related effects associated with chronic supraphysiologic GC exposure. Presentation: Monday, July 14, 2025

Abstract Disclosure: R.S. Newfield: Clinical trial investigator for Neurocrine Biosciences, Inc. and Spruce Biosciences; consultant for Spruce Biosciences. M.E. Geffner: Research support from Ascendis, Diurnal, Neurocrine Biosciences, Novo Nordisk, Pfizer, and Spruce Biosciences; serves on advisory boards or as a consultant for Adrenas Therapeutics, As. Y. Hsu: Consultant for Neurocrine. M.T. Dattani: Lecturing fees: Meck Serono, Pfizer, Novo Nordisk, Sandoz. Advisory Boards: Pfizer, Novo Nordisk. Consultancy: Sandoz, Pfizer, Besins.. M. Bettendorf: None. R.H. Farber: Full-time employee of Neurocrine Biosciences, Inc. G.B. Rosales: Full-time employee of Neurocrine Biosciences, Inc. G.S. Jeha: Full-time employee of Neurocrine Biosciences, Inc. J.L. Chan: Full-time employee of Neurocrine Biosciences, Inc.. Background: Crinecerfont, a corticotropin-releasing factor type 1 receptor (CRF1) antagonist, is a first-in-class medication that is FDA-approved for adjunctive treatment to glucocorticoid (GC) replacement to control androgens in patients with classic congenital adrenal hyperplasia (CAH). In two phase 3 trials, crinecerfont significantly reduced excess androgens, enabling subsequent reductions in GC doses in pediatric and adult patients with CAH. Objective: To evaluate changes in androstenedione (A4) levels and GC doses in pediatric patients with CAH who received up to 1 year of crinecerfont. Methods: Participants from the 28-week double-blind placebo-controlled (DBPC) period of CAHtalystTM Pediatric (NCT04806451) continued crinecerfont (25, 50, or 100 mg BID based on weight) (CFT/CFT) or were switched from placebo (PBO/CFT) in the 24-week open-label (OL) period. In both periods, GC doses were kept stable for the first 4 weeks and then decreased to a target dose of 8-10 mg/m2/d while maintaining or improving A4 relative to Day 1 baseline (BL). Changes in serum A4 levels (before morning GC dose) were analyzed after stable GC dosing (Weeks 4 and 32) and end of DBPC and OL treatment (Weeks 28 and 52). Changes in GC dose were analyzed at end of DBPC and OL treatment. Decreases in GC dose were set to zero if A4 was not maintained or improved relative to BL. For predefined endpoints in the DBPC period, results are presented as least squares (LS) mean changes with LS mean difference (LSMD) and p-value. Results: At BL, mean A4 was 431 ng/dL; mean GC dose was 16.4 mg/m2/d. In the DBPC period, A4 decreased from BL at Week 4 with crinecerfont and increased with placebo (-197 vs. +71 ng/dL; LSMD: -268 ng/dL, P=0.0002) and Week 28 (-94 vs. +147 ng/dL). A4 reduction with crinecerfont enabled a subsequent percentage decrease in GC dose from BL at Week 28, compared to an increase with placebo (-18% vs. +5.6%; LSMD: -23.5%, P<0.0001). In the OL period, mean A4 decreased to below BL at Week 32 (CFT/CFT, -121 ng/dL; PBO/CFT, -174 ng/dL) and after GC dose reduction at Week 52 (CFT/CFT, -13.8 ng/dL; PBO/CFT, -60.9 ng/dL). Mean changes and mean percentage changes in GC dose at Week 52 were as follows: CFT/CFT (-3.0 mg/m2/d, -17.3%); PBO/CFT (-1.1 mg/m2/d, -6.1%). Moreover, 33.8% and 17.2% of participants achieved a GC dose ≤11 mg/m2/d while maintaining or improving A4 in the CFT/CFT and PBO/CFT groups, respectively. Conclusion: In children and adolescents with CAH, reductions in excess A4 and GC doses observed with crinecerfont during the DBPC period were maintained during the OL period. By the end of OL treatment, mean A4 was maintained below BL levels despite a significant reduction in GC dosing to lower, more physiologic doses. Thus, not only can crinecerfont reduce androgen excess, but by enabling GC doses to be lowered, crinecerfont may also reduce the adverse effects of chronic exposure to supraphysiologic GCs over a lifetime of treatment. Presentation: Saturday, July 12, 2025