RARE DISEASE
Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency
Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency
Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency
Synonyms: Classic 21-OHD CAH
Synonyms: Classic 21-OHD CAH
Synonyms: Classic 21-OHD CAH
Drug discovery
3
drugs
With orphan designations
Overview
Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency is an autosomal recessive disorder causing impaired cortisol/aldosterone synthesis, leading to adrenal insufficiency and androgen excess. Symptoms include ambiguous genitalia in 46,XX newborns, salt-wasting crises, accelerated growth with premature epiphyseal closure, and metabolic complications. Diagnosis involves elevated 17-OH-progesterone levels and CYP21A2 gene mutations [1][4][8]. Treatment focuses on glucocorticoid/mineralocorticoid replacement and androgen suppression [1][2][12].
Burden
Mortality: 20% lifetime risk of adrenal crisis-related death, with average 7-year life expectancy reduction [3][7]
Comorbidities: 2.8× increased diabetes risk, 2.4× dyslipidemia, 1.6× cardiovascular events [7][15]
Healthcare utilization: 171 lifetime sick-day rule implementations and 11 adrenal crisis hospitalizations per patient [3][19]
Therapies
Lifelong replacement: Hydrocortisone (10-20 mg/m²/day) + fludrocortisone (0.05-0.2 mg/day) [1][2][6]
Emergency protocols: Stress-dose glucocorticoids during illness/surgery to prevent adrenal crises [3][16]
Emerging approaches: Modified-release hydrocortisone (Chronocort®), CRH antagonists, and AAV-based gene therapy trials [14][18]
Categories: rare developmental anomalies during embryogenesis, rare endocrine diseases, rare genetic diseases, rare gynecological and obstetric diseases, rare infertility disorders, rare urogenital diseases
Research Papers
195 drug discovery papers about Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency, with 2 first-in-class and 1 next-in-class emerging drug candidate forecasted to outperform the average preclinical success rate. Recent publications:
195 drug discovery papers about Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency, with 2 first-in-class and 1 next-in-class emerging drug candidate forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-08-21 | Biochemical control in young women with congenital adrenal hyperplasia taking oral contraceptives: a prospective observational study.
Androgen excess in 21-hydroxylase deficiency (21OHD) remains difficult to manage in adolescent females. Combined oral contraceptive(s) (OC) containing ethinylestradiol and progestin modulate ovarian and adrenal steroidogenesis, but their specific impact on 21OHD has not been systematically evaluated. We therefore examined how combined OCs influence the steroid metabolome in young women with classic 21OHD. Prospective observational study. Young women aged 11-24 years with classic 21OHD who planned to initiate combined OC were enrolled. The study comprised 3 visits and included blood sampling and 24-hour urine collection: Visit 1 before OC initiation, Visit 2 during the third OC cycle, and Visit 3 during the sixth OC cycle. Plasma steroids were quantified by liquid chromatography-mass spectrometry and urinary metabolites by gas chromatography-mass spectrometry. Differences in steroid and metabolite levels across visits were assessed using the Friedman test. Of the 20 participants recruited, 17 (median age 16.8 years, range 11-24) completed the study. Compared with baseline, plasma concentrations of 17α-hydroxyprogesterone, androstenedione, dehydroepiandrosterone, and testosterone decreased significantly (all P < .005), while cortisol increased (P < .001). Urinary 24-hour excretion of androgen metabolites, including 11-oxo-etiocholanolone, declined. Between visits 1 and 3, 8 participants (47%) reduced their hydrocortisone dose in response to biochemical changes. Combined OCs were observed to modify steroid metabolism and lower androgen levels in women with classic 21OHD. OC therapy may serve as a useful adjunct in the management of androgen excess in this population, particularly when conventional glucocorticoid therapy alone does not achieve satisfactory biochemical control.
2026-08-06 | Congenital adrenal hyperplasia in children: a comprehensive review of clinical spectrum, diagnostic strategies, and management approaches
INTRODUCTION: Congenital adrenal hyperplasia (CAH) comprises a group of rare autosomal recessive disorders and is a leading cause of primary adrenal insufficiency in children. Most cases are due to classic 21-hydroxylase deficiency. Earlier diagnosis has been made possible with newborn screening, which has also reduced the risk of adrenal crises. This review is based on a search of PubMed, Embase, Scopus, and Medline for articles published from 2000 to 2025, using the terms "congenital adrenal hyperplasia", "21-hydroxylase deficiency", "primary adrenal insufficiency", and "steroidogenesis" with a focus on paediatric studies, clinical trials, systematic reviews, and consensus guidelines. CONTENT: The aims of clinical management are appropriate glucocorticoid and mineralocorticoid replacement, prevention of adrenal crises, monitoring of growth, puberty, and metabolic health. The main challenges include balancing androgen suppression with minimising glucocorticoid overexposure and monitoring for long-term complications such as early bone maturation and testicular adrenal rest tumours. Diagnostic accuracy and genotype-phenotype correlations have improved through advances in biochemical testing and molecular genetics. Newer and adjunctive therapies, including modified-release hydrocortisone, CRF1 receptor antagonists, adrenal-targeted drugs, and experimental gene therapies, may further improve disease management and simplify treatment. SUMMARY AND OUTLOOK: Effective management of CAH in children requires balancing optimal hormonal control with minimising treatment-related adverse effects. Newer and future therapies are expected to improve physiological management and long-term outcomes. Further research is needed to enhance individualised care and support transition to adult services.
2026-08-06 | Genetic characteristics and clinical features of pediatric congenital adrenal hyperplasia in Korea.
Despite the clinical importance of congenital adrenal hyperplasia (CAH), comprehensive data on subtype distribution, genetic characteristics, and the impact of newborn screening in Korea are limited. We analyzed the genetic profiles and clinical characteristics at diagnosis in 368 patients with CAH diagnosed before 19 years of age from the Multicenter Networks for Ideal Outcomes of Pediatric Rare Endocrine and Metabolic Diseases in Korea (OUTSPREAD) cohort. 21-hydroxylase deficiency (21-OHD) was the most prevalent CAH subtype (299 cases, 85.7%; 208 genetically confirmed and 91 clinically diagnosed), followed by lipoid congenital adrenal hyperplasia (LCAH; 9.5%) and 17α-hydroxylase deficiency (17α-OHD; 3.7%), accounting for 98.8% of cases. Frequent variants included c.293-13 C > G and p.Ile173Asn in 21-OHD, whereas p.Gln258Ter and p.His373Leu predominated in LCAH and 17α-OHD, consistent with East Asian population databases. Genotype-phenotype correlation analysis in 21-OHD demonstrated high positive predictive value, with genotypes characterized by minimal or absent residual enzyme activity associated with classic CAH in over 95% of cases. Among patients with salt-wasting 21-OHD, diagnosis occurred significantly earlier after newborn screening introduction, regardless of karyotype (46,XX: median 18.3 vs. 9.1 days, P = 0.031; 46,XY: 29.1 vs. 18.3 days, P = 0.019), along with a significant reduction in salt-wasting-related symptoms at diagnosis (46,XX: 33.3% vs. 10.5%, P = 0.031; 46,XY: 87.5% vs. 21.6%, P < 0.001). This national multicenter cohort study provides comprehensive genetic and clinical characterization of pediatric CAH in Korea, particularly in delineating CAH subtype distribution and the impact of newborn screening.
2026-08-01 | P29 - ECE_2951 - Modified release hydrocortisone, a new treatment for congenital adrenal hyperplasia due to 21-hydroxylase deficiency: one-year outcomes from a “real-world evidence” study
Abstract Management of congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21OHD) involves chronic glucocorticoid (GC) replacement in patients with adrenal insufficiency while controlling androgen excess. Treatment with conventional GCs is characterized by regimens with unphysiological peaks and troughs, often associated with GC overexposure and/or poor androgen control. In this scenario, the recently approved twice daily modified-release hydrocortisone (MR-HC) represents a useful tool for a more accurate reproduction of physiological cortisol circadian rhythm, particularly mimicking overnight cortisol increase for better control morning surge of adrenocorticotropic hormone (ACTH) and androgens.The current study aimed at investigating the impact of the switch from conventional GCs to MR-HC on disease control, GC daily dose, hormonal and biochemical profiles in 61 CAH patients treated for 12 months with MR-HC. Thirty-nine (63.9%) females and 22 (36.1%) males, 45 with classic-form [29 (47.5%) with salt-wasting and 16 (26.2%) with simple-virilizing] and 16 (26.2%) with non-classic form, with a median age of 30.9 ± 9.4 yrs, were enrolled. Patients were switched from conventional GC regimens [immediate or dual-release hydrocortisone (IR/DR-HC) or cortisone acetate (CA)] (25.43 ± 8.9 mg/day HC equivalents) to MR-HC (24, 91 ± 8,1 mg/day). The primary outcome was the change from baseline to 12 months of MR-HC in the percentage of patients with good disease control, defined as a morning 17OH-progesterone (17OHP) <12 ng/ml and androstenedione within the reference ranges, according to the phase 3 study. Secondary outcomes included changes in GC total daily dose, hormonal and biochemical parameters. At month 12, the percentage of patients with controlled disease significantly increased: controlled patients were 59% vs 32.8% at baseline (P = .006). Particularly, a significant decrease in 17OHP [6.33 ± 11.36 vs 12.77 ± 15.93 ULN at baseline (P = .002)] and androstenedione [0.87 ± 1.33 vs 0.95 ± 0.76 ULN at baseline (P = .025)] was observed at month 12. Furthermore, a reduction in morning ACTH [10.85 ± 10.3 vs 156 ± 180 pg/mL at baseline (P = .001)] was observed at month 12, while morning cortisol increased [10.14 ± 15.35 vs 84.3 ± 49 ng/ml at baseline (P = .001)] compared to baseline. Lastly, baseline MR-HC dose was reduced by 4.8% [23.27 ± 8.1 mg/day vs 24.91 ± 8,13 mg/day at baseline (P = .005)] at month 12. Data from the current real-world experience showed that MR-HC significantly improved disease control while reducing GC daily dose in 21OHD CAH patients.
2026-08-01 | S12.3 - Management of CAH across the life span
Abstract Management of congenital adrenal hyperplasia (CAH) requires a lifelong, multidisciplinary approach that adapts to the evolving physiological and psychosocial needs of each patient. 21-hydroxylase deficiency accounts for 95%-99% of all CAH. Classic CAH due to 21-hydroxylase deficiency typically presents in infancy, necessitating early diagnosis through newborn screening and prompt initiation of glucocorticoid and mineralocorticoid therapy to prevent adrenal crises. During childhood, management centers on optimizing growth and development while avoiding both undertreatment—associated with hyperandrogenism—and overtreatment, which risks iatrogenic Cushingoid features and impaired growth potential. Regular monitoring of hormones, growth velocity, and bone age is essential, alongside careful titration of therapy. The transition to adolescence introduces new challenges, including puberty induction or modulation, fertility considerations, metabolic risk, and gender identity or body image concerns. A structured transition program supports the shift toward autonomous disease management and ensures continuity of care. In adulthood, treatment goals broaden to include preservation of fertility, cardiometabolic health, bone density, and psychological well-being. Women may face issues related to menstrual function, polycystic ovarian morphology, or sexual health, whereas men may develop testicular adrenal rest tumors requiring surveillance. Adrenal crisis is most common during childhood but can occur at any age and is the most common cause of death in CAH and is therefore of utmost importance to prevent. Throughout life, emerging therapies—including modified-release hydrocortisone, CRF1 antagonists, and gene-based approaches—offer potential to reduce androgen excess and glucocorticoid exposure. Comprehensive care should integrate endocrinologists, surgeons, psychologists, reproductive specialists, and genetic counsellors. Effective lifelong management of CAH requires individualized therapy, anticipatory guidance through key developmental stages, and ongoing evaluation of both clinical outcomes and quality of life.
antibodies
2025-10-01 | SAT-455 A Phase 2, Open-Label Trial Evaluating the Efficacy and Safety of Anti-ACTH Antibody Lu AG13909 in Adults With Classic Congenital Adrenal Hyperplasia: Trial Design
Abstract Disclosure: U. Srirangalingam: Crinetics Pharmaceuticals Inc, Diurnal, Lundbeck. A. Prete: Spruce, Diurnal, Recordati, Lundbeck. T. Frederiksen: None. M.M. Binderup: None. M. Folden Flensburg: None. J. Luthman: None. R.J. Auchus: Neurocrine Biosciences/Neurocrine UK, LTD, Spruce Biosciences, Corcept Therapeutics, Crinetics Pharamceuticals, Recordati Rare Diseases, Adrenas Therapeutics, Mineralys Pharmaceuticals, Quest Diagnostics, Xeris Pharmaceuticals, Novo Nordisk, Sparrow Pharmaceuticals, Astellas Pharmaceuticals, Acerand Therapeutics, Lundbeck. Introduction: Classic congenital adrenal hyperplasia (CAH) caused by 21-hydroxylase deficiency is a rare autosomal recessive disorder. The defect in cortisol biosynthesis leads to impaired negative feedback on the hypothalamus-pituitary-adrenal axis, elevated adrenocorticotropic hormone (ACTH), and consequent hyperandrogenemia. Supraphysiologic glucocorticoid (GC) dosing, often required to manage hyperandrogenemia, is associated with adverse long-term health outcomes. Lu AG13909 is a novel, high-affinity, anti-ACTH monoclonal antibody that inhibits ACTH-induced signaling. A phase 1 trial (NCT05669950) in adults with classic CAH demonstrated that Lu AG13909 is well-tolerated and can reduce 17-hydroxyprogesterone (17-OHP) and androstenedione (A4) concentrations. Here, we describe the phase 2 trial design, evaluating the efficacy and safety of Lu AG13909 in adults with classic CAH. Methods: The open-label phase 1 trial was amended to contain a phase 2 component in an adaptive design. The phase 2 trial will enroll men and women, aged ≥18 to ≤70 years with classic CAH, under stable GC dosing. Participants are divided into 2 cohorts: cohort C1, including up to 18 participants with hyperandrogenemia, and cohort C2, including up to 12 participants with normal androgen concentrations but treated with supraphysiologic GC doses. There are 2 treatment periods: Period 1 (maintenance of stable baseline daily GC dose) and Period 2 (down-titration of daily GC dose using a predefined schedule). In Period 1, participants will receive 6 (cohort C1) or 2 (cohort C2) intravenous (IV) administrations of Lu AG13909 at 4- to 5-week intervals. The shorter treatment duration in cohort C2 is due to normal A4 baseline concentration. Cohort C1 is divided into 3 treatment groups receiving either a low, medium, or high Lu AG13909 dose. Cohort C2 all receive the medium dose of Lu AG13909. All participants with normalized A4 concentrations enter Period 2 and receive 3 IV administrations of Lu AG13909 at 4- to 5-week intervals, with GC dose down-titrated over 12 weeks. Participants may enter an optional open-label extension, where they receive 12 IV administrations of Lu AG13909 at 4- to 5-week intervals, with daily GC dose optimization based on individual androgen concentrations. Outcomes: The primary endpoint is biochemical response, defined as morning concentrations of A4 <upper limit of normal (pre-daily GC dosing) after 24 weeks of treatment in cohort C1. Other endpoints include relative reduction from baseline in morning concentrations of A4 and 17-OHP; relative reduction from baseline in GC daily dose; and the safety, tolerability, and PK profile of Lu AG13909. Conclusions: This trial will evaluate the efficacy and safety of Lu AG13909 for lowering androgen concentrations, and GC dosing in adults with classic CAH, reinforcing the development of Lu AG13909 as a novel anti-ACTH treatment strategy. Presentation: Saturday, July 12, 2025
2024-10-01 | 12484 Safety And Pharmacokinetics Of Anti-ACTH Antibody Lu AG13909 In Patients With Classic Congenital Adrenal Hyperplasia: Phase 1 Open-label, Multiple-Ascending-Dose Trial Protocol
Abstract Disclosure: U. Srirangalingam: Advisory Board Member; Self; Lundbeck. Consulting Fee; Self; Diurnal. Research Investigator; Self; Neurocrine. A. Velusamy: Consulting Fee; Self; Novo Nordisk. M. Binderup: Employee; Self; H. Lundbeck A/S. B. Baker: Employee; Self; H. Lundbeck A/S. M. Folden Flensburg: Employee; Self; H. Lundbeck A/S. L. Pickering Boserup: Employee; Self; H. Lundbeck A/S. J. Luthman: Employee; Self; H. Lundbeck A/S. H. Benecke: Employee; Self; H. Lundbeck A/S. R.J. Auchus: Consulting Fee; Self; Neurocrine Biosciences, Diurnal, Corcept Therapeutics, Recordati Rare Diseases, Crinetics Pharmaceuticals, Quest Diagnostics, Xeris Pharmaceuticals, Novo Nordisk, H. Lundbeck A/S, Sparrow Pharmaceuticals. Research Investigator; Self; Adrenas Therapeutics, Spruce Biosciences, Neurocrine Biosciences, Diurnal, Corcept Therapeutics, Recordati Rare Diseases, Crinetics Pharmaceuticals. Introduction: Classic congenital adrenal hyperplasia (CAH) is a rare, autosomal recessive disorder characterized by cortisol and aldosterone deficiency, elevated adrenocorticotropic hormone (ACTH) and subsequent hyperandrogenemia, most commonly due to 21-hydroxylase deficiency. Balancing physiological glucocorticoid replacement and control of hyperandrogenism remains a challenge with the risk of long-term consequences of glucocorticoid overtreatment. Lu AG13909 is a novel, high-affinity, anti-ACTH monoclonal antibody that neutralizes ACTH-induced signaling. In preclinical models, Lu AG13909 dose-dependently and persistently reduced plasma corticosterone and cortisol concentrations. No adverse effects were observed after 6 months of intravenous dosing every 2 weeks in cynomolgus monkeys. Here, we describe the ongoing first-in-human trial of Lu AG13909, investigating the safety, tolerability, pharmacokinetic (PK) properties, and pharmacodynamic (PD) effects of Lu AG13909 in adults with classic CAH. Methods: This is a Phase 1, open-label, multiple-ascending-dose trial with intra-participant dose escalation (EUCT #2023-503711-15-00). The trial enrolls men and women with classic CAH aged between ≥18 and ≤70 years under stable glucocorticoid and mineralocorticoid dosing, with morning 17-hydroxyprogesterone >4 times the upper limit of normal. Each participant receives up to 6 doses of Lu AG13909 every 28-35 days at increasing dose levels. The trial consists of 2 parts: Part A has a 3+3 design, in which 3 participants are given a certain dose, and escalation to the next dose is based on a 28-day safety observation period. Part B explores the pharmacologically relevant Lu AG13909 doses identified in Part A in a larger number of participants. The aim is for a total of 12 participants to receive each of the dose levels identified as relevant. Outcomes The primary safety and tolerability endpoints include adverse events and clinical safety tests. PK endpoints include maximum observed exposure and area under the Lu AG13909 concentration-time curve in a dosing interval. The PD endpoints are the relative reductions in morning 17-hydroxyprogesterone, androstenedione, and unbound ACTH, from baseline to the day after each Lu AG13909 dose. Conclusions This innovative, multi-dose, intra-participant dose escalation trial design was developed specifically for the rare classic CAH population, who have a high unmet medical need due to the challenges with current glucocorticoid treatment. The aim of the trial is to gather safety, PK, and PD data while minimizing participant risk and burden. Data from this trial will reinforce the development of Lu AG13909 as a novel treatment strategy in conditions characterized by increased levels of ACTH, such as classic CAH and Cushing disease. Presentation: 6/3/2024
gene therapies
2026-09-01 | Clinical and genetic spectrum of classic congenital adrenal hyperplasia due to CYP21A2 mutations in a Taiwanese cohort.
Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21-OHD) is the most common inherited adrenal disorder in children. Clinical severity is determined by residual CYP21A2 enzyme activity. This study aimed to characterize the clinical and genetic spectrum of classic CAH and to evaluate genotype-phenotype correlations in a Taiwanese cohort. We retrospectively reviewed 53 patients with classic CAH (31 salt-wasting [SW], 22 simple virilizing [SV]) followed at Linkou Chang Gung Memorial Hospital between 1987 and 2023. Clinical characteristics, biochemical profiles, electrolyte disturbances, and CYP21A2 genotypes were analyzed. Virilization in females was graded using the Prader scale. Statistical analyses were performed using nonparametric methods. Patients with SW CAH were diagnosed significantly earlier than those with SV CAH (median 16.4 days vs. 6.1 years, p < 0.0001) and exhibited more pronounced electrolyte abnormalities, including lower sodium (p = 0.0004) and higher potassium levels (p = 0.0061). Among 35 patients who underwent genetic testing (70 alleles), the most common variants were c.293-13A > G and p.Ile173Asn (c.518T > A), which were predominantly associated with SW and SV phenotypes, respectively. Female patients with SW CAH demonstrated more severe virilization (Prader stages 3-5 in 82.4%) compared with those with SV CAH (p = 0.0012). Overall genotype-phenotype concordance was high, although a minority of cases showed discordance between predicted enzymatic activity and clinical severity. Salt-wasting CAH was the predominant form in this Taiwanese cohort, and the CYP21A2 mutation spectrum was consistent with global reports. The severity of virilization correlated with underlying enzymatic activity, supporting the clinical utility of genotyping for disease prediction and counseling. However, discordant cases highlight the potential role of modifying factors and underscore the need for individualized clinical management.
small molecules
2026-08-21 | Biochemical control in young women with congenital adrenal hyperplasia taking oral contraceptives: a prospective observational study.
Androgen excess in 21-hydroxylase deficiency (21OHD) remains difficult to manage in adolescent females. Combined oral contraceptive(s) (OC) containing ethinylestradiol and progestin modulate ovarian and adrenal steroidogenesis, but their specific impact on 21OHD has not been systematically evaluated. We therefore examined how combined OCs influence the steroid metabolome in young women with classic 21OHD. Prospective observational study. Young women aged 11-24 years with classic 21OHD who planned to initiate combined OC were enrolled. The study comprised 3 visits and included blood sampling and 24-hour urine collection: Visit 1 before OC initiation, Visit 2 during the third OC cycle, and Visit 3 during the sixth OC cycle. Plasma steroids were quantified by liquid chromatography-mass spectrometry and urinary metabolites by gas chromatography-mass spectrometry. Differences in steroid and metabolite levels across visits were assessed using the Friedman test. Of the 20 participants recruited, 17 (median age 16.8 years, range 11-24) completed the study. Compared with baseline, plasma concentrations of 17α-hydroxyprogesterone, androstenedione, dehydroepiandrosterone, and testosterone decreased significantly (all P < .005), while cortisol increased (P < .001). Urinary 24-hour excretion of androgen metabolites, including 11-oxo-etiocholanolone, declined. Between visits 1 and 3, 8 participants (47%) reduced their hydrocortisone dose in response to biochemical changes. Combined OCs were observed to modify steroid metabolism and lower androgen levels in women with classic 21OHD. OC therapy may serve as a useful adjunct in the management of androgen excess in this population, particularly when conventional glucocorticoid therapy alone does not achieve satisfactory biochemical control.
2026-08-06 | Congenital adrenal hyperplasia in children: a comprehensive review of clinical spectrum, diagnostic strategies, and management approaches
INTRODUCTION: Congenital adrenal hyperplasia (CAH) comprises a group of rare autosomal recessive disorders and is a leading cause of primary adrenal insufficiency in children. Most cases are due to classic 21-hydroxylase deficiency. Earlier diagnosis has been made possible with newborn screening, which has also reduced the risk of adrenal crises. This review is based on a search of PubMed, Embase, Scopus, and Medline for articles published from 2000 to 2025, using the terms "congenital adrenal hyperplasia", "21-hydroxylase deficiency", "primary adrenal insufficiency", and "steroidogenesis" with a focus on paediatric studies, clinical trials, systematic reviews, and consensus guidelines. CONTENT: The aims of clinical management are appropriate glucocorticoid and mineralocorticoid replacement, prevention of adrenal crises, monitoring of growth, puberty, and metabolic health. The main challenges include balancing androgen suppression with minimising glucocorticoid overexposure and monitoring for long-term complications such as early bone maturation and testicular adrenal rest tumours. Diagnostic accuracy and genotype-phenotype correlations have improved through advances in biochemical testing and molecular genetics. Newer and adjunctive therapies, including modified-release hydrocortisone, CRF1 receptor antagonists, adrenal-targeted drugs, and experimental gene therapies, may further improve disease management and simplify treatment. SUMMARY AND OUTLOOK: Effective management of CAH in children requires balancing optimal hormonal control with minimising treatment-related adverse effects. Newer and future therapies are expected to improve physiological management and long-term outcomes. Further research is needed to enhance individualised care and support transition to adult services.
2026-08-06 | Genetic characteristics and clinical features of pediatric congenital adrenal hyperplasia in Korea.
Despite the clinical importance of congenital adrenal hyperplasia (CAH), comprehensive data on subtype distribution, genetic characteristics, and the impact of newborn screening in Korea are limited. We analyzed the genetic profiles and clinical characteristics at diagnosis in 368 patients with CAH diagnosed before 19 years of age from the Multicenter Networks for Ideal Outcomes of Pediatric Rare Endocrine and Metabolic Diseases in Korea (OUTSPREAD) cohort. 21-hydroxylase deficiency (21-OHD) was the most prevalent CAH subtype (299 cases, 85.7%; 208 genetically confirmed and 91 clinically diagnosed), followed by lipoid congenital adrenal hyperplasia (LCAH; 9.5%) and 17α-hydroxylase deficiency (17α-OHD; 3.7%), accounting for 98.8% of cases. Frequent variants included c.293-13 C > G and p.Ile173Asn in 21-OHD, whereas p.Gln258Ter and p.His373Leu predominated in LCAH and 17α-OHD, consistent with East Asian population databases. Genotype-phenotype correlation analysis in 21-OHD demonstrated high positive predictive value, with genotypes characterized by minimal or absent residual enzyme activity associated with classic CAH in over 95% of cases. Among patients with salt-wasting 21-OHD, diagnosis occurred significantly earlier after newborn screening introduction, regardless of karyotype (46,XX: median 18.3 vs. 9.1 days, P = 0.031; 46,XY: 29.1 vs. 18.3 days, P = 0.019), along with a significant reduction in salt-wasting-related symptoms at diagnosis (46,XX: 33.3% vs. 10.5%, P = 0.031; 46,XY: 87.5% vs. 21.6%, P < 0.001). This national multicenter cohort study provides comprehensive genetic and clinical characterization of pediatric CAH in Korea, particularly in delineating CAH subtype distribution and the impact of newborn screening.
2026-08-01 | P29 - ECE_2951 - Modified release hydrocortisone, a new treatment for congenital adrenal hyperplasia due to 21-hydroxylase deficiency: one-year outcomes from a “real-world evidence” study
Abstract Management of congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21OHD) involves chronic glucocorticoid (GC) replacement in patients with adrenal insufficiency while controlling androgen excess. Treatment with conventional GCs is characterized by regimens with unphysiological peaks and troughs, often associated with GC overexposure and/or poor androgen control. In this scenario, the recently approved twice daily modified-release hydrocortisone (MR-HC) represents a useful tool for a more accurate reproduction of physiological cortisol circadian rhythm, particularly mimicking overnight cortisol increase for better control morning surge of adrenocorticotropic hormone (ACTH) and androgens.The current study aimed at investigating the impact of the switch from conventional GCs to MR-HC on disease control, GC daily dose, hormonal and biochemical profiles in 61 CAH patients treated for 12 months with MR-HC. Thirty-nine (63.9%) females and 22 (36.1%) males, 45 with classic-form [29 (47.5%) with salt-wasting and 16 (26.2%) with simple-virilizing] and 16 (26.2%) with non-classic form, with a median age of 30.9 ± 9.4 yrs, were enrolled. Patients were switched from conventional GC regimens [immediate or dual-release hydrocortisone (IR/DR-HC) or cortisone acetate (CA)] (25.43 ± 8.9 mg/day HC equivalents) to MR-HC (24, 91 ± 8,1 mg/day). The primary outcome was the change from baseline to 12 months of MR-HC in the percentage of patients with good disease control, defined as a morning 17OH-progesterone (17OHP) <12 ng/ml and androstenedione within the reference ranges, according to the phase 3 study. Secondary outcomes included changes in GC total daily dose, hormonal and biochemical parameters. At month 12, the percentage of patients with controlled disease significantly increased: controlled patients were 59% vs 32.8% at baseline (P = .006). Particularly, a significant decrease in 17OHP [6.33 ± 11.36 vs 12.77 ± 15.93 ULN at baseline (P = .002)] and androstenedione [0.87 ± 1.33 vs 0.95 ± 0.76 ULN at baseline (P = .025)] was observed at month 12. Furthermore, a reduction in morning ACTH [10.85 ± 10.3 vs 156 ± 180 pg/mL at baseline (P = .001)] was observed at month 12, while morning cortisol increased [10.14 ± 15.35 vs 84.3 ± 49 ng/ml at baseline (P = .001)] compared to baseline. Lastly, baseline MR-HC dose was reduced by 4.8% [23.27 ± 8.1 mg/day vs 24.91 ± 8,13 mg/day at baseline (P = .005)] at month 12. Data from the current real-world experience showed that MR-HC significantly improved disease control while reducing GC daily dose in 21OHD CAH patients.
2026-08-01 | S12.3 - Management of CAH across the life span
Abstract Management of congenital adrenal hyperplasia (CAH) requires a lifelong, multidisciplinary approach that adapts to the evolving physiological and psychosocial needs of each patient. 21-hydroxylase deficiency accounts for 95%-99% of all CAH. Classic CAH due to 21-hydroxylase deficiency typically presents in infancy, necessitating early diagnosis through newborn screening and prompt initiation of glucocorticoid and mineralocorticoid therapy to prevent adrenal crises. During childhood, management centers on optimizing growth and development while avoiding both undertreatment—associated with hyperandrogenism—and overtreatment, which risks iatrogenic Cushingoid features and impaired growth potential. Regular monitoring of hormones, growth velocity, and bone age is essential, alongside careful titration of therapy. The transition to adolescence introduces new challenges, including puberty induction or modulation, fertility considerations, metabolic risk, and gender identity or body image concerns. A structured transition program supports the shift toward autonomous disease management and ensures continuity of care. In adulthood, treatment goals broaden to include preservation of fertility, cardiometabolic health, bone density, and psychological well-being. Women may face issues related to menstrual function, polycystic ovarian morphology, or sexual health, whereas men may develop testicular adrenal rest tumors requiring surveillance. Adrenal crisis is most common during childhood but can occur at any age and is the most common cause of death in CAH and is therefore of utmost importance to prevent. Throughout life, emerging therapies—including modified-release hydrocortisone, CRF1 antagonists, and gene-based approaches—offer potential to reduce androgen excess and glucocorticoid exposure. Comprehensive care should integrate endocrinologists, surgeons, psychologists, reproductive specialists, and genetic counsellors. Effective lifelong management of CAH requires individualized therapy, anticipatory guidance through key developmental stages, and ongoing evaluation of both clinical outcomes and quality of life.
antibodies
2025-10-01 | SAT-455 A Phase 2, Open-Label Trial Evaluating the Efficacy and Safety of Anti-ACTH Antibody Lu AG13909 in Adults With Classic Congenital Adrenal Hyperplasia: Trial Design
Abstract Disclosure: U. Srirangalingam: Crinetics Pharmaceuticals Inc, Diurnal, Lundbeck. A. Prete: Spruce, Diurnal, Recordati, Lundbeck. T. Frederiksen: None. M.M. Binderup: None. M. Folden Flensburg: None. J. Luthman: None. R.J. Auchus: Neurocrine Biosciences/Neurocrine UK, LTD, Spruce Biosciences, Corcept Therapeutics, Crinetics Pharamceuticals, Recordati Rare Diseases, Adrenas Therapeutics, Mineralys Pharmaceuticals, Quest Diagnostics, Xeris Pharmaceuticals, Novo Nordisk, Sparrow Pharmaceuticals, Astellas Pharmaceuticals, Acerand Therapeutics, Lundbeck. Introduction: Classic congenital adrenal hyperplasia (CAH) caused by 21-hydroxylase deficiency is a rare autosomal recessive disorder. The defect in cortisol biosynthesis leads to impaired negative feedback on the hypothalamus-pituitary-adrenal axis, elevated adrenocorticotropic hormone (ACTH), and consequent hyperandrogenemia. Supraphysiologic glucocorticoid (GC) dosing, often required to manage hyperandrogenemia, is associated with adverse long-term health outcomes. Lu AG13909 is a novel, high-affinity, anti-ACTH monoclonal antibody that inhibits ACTH-induced signaling. A phase 1 trial (NCT05669950) in adults with classic CAH demonstrated that Lu AG13909 is well-tolerated and can reduce 17-hydroxyprogesterone (17-OHP) and androstenedione (A4) concentrations. Here, we describe the phase 2 trial design, evaluating the efficacy and safety of Lu AG13909 in adults with classic CAH. Methods: The open-label phase 1 trial was amended to contain a phase 2 component in an adaptive design. The phase 2 trial will enroll men and women, aged ≥18 to ≤70 years with classic CAH, under stable GC dosing. Participants are divided into 2 cohorts: cohort C1, including up to 18 participants with hyperandrogenemia, and cohort C2, including up to 12 participants with normal androgen concentrations but treated with supraphysiologic GC doses. There are 2 treatment periods: Period 1 (maintenance of stable baseline daily GC dose) and Period 2 (down-titration of daily GC dose using a predefined schedule). In Period 1, participants will receive 6 (cohort C1) or 2 (cohort C2) intravenous (IV) administrations of Lu AG13909 at 4- to 5-week intervals. The shorter treatment duration in cohort C2 is due to normal A4 baseline concentration. Cohort C1 is divided into 3 treatment groups receiving either a low, medium, or high Lu AG13909 dose. Cohort C2 all receive the medium dose of Lu AG13909. All participants with normalized A4 concentrations enter Period 2 and receive 3 IV administrations of Lu AG13909 at 4- to 5-week intervals, with GC dose down-titrated over 12 weeks. Participants may enter an optional open-label extension, where they receive 12 IV administrations of Lu AG13909 at 4- to 5-week intervals, with daily GC dose optimization based on individual androgen concentrations. Outcomes: The primary endpoint is biochemical response, defined as morning concentrations of A4 <upper limit of normal (pre-daily GC dosing) after 24 weeks of treatment in cohort C1. Other endpoints include relative reduction from baseline in morning concentrations of A4 and 17-OHP; relative reduction from baseline in GC daily dose; and the safety, tolerability, and PK profile of Lu AG13909. Conclusions: This trial will evaluate the efficacy and safety of Lu AG13909 for lowering androgen concentrations, and GC dosing in adults with classic CAH, reinforcing the development of Lu AG13909 as a novel anti-ACTH treatment strategy. Presentation: Saturday, July 12, 2025
2024-10-01 | 12484 Safety And Pharmacokinetics Of Anti-ACTH Antibody Lu AG13909 In Patients With Classic Congenital Adrenal Hyperplasia: Phase 1 Open-label, Multiple-Ascending-Dose Trial Protocol
Abstract Disclosure: U. Srirangalingam: Advisory Board Member; Self; Lundbeck. Consulting Fee; Self; Diurnal. Research Investigator; Self; Neurocrine. A. Velusamy: Consulting Fee; Self; Novo Nordisk. M. Binderup: Employee; Self; H. Lundbeck A/S. B. Baker: Employee; Self; H. Lundbeck A/S. M. Folden Flensburg: Employee; Self; H. Lundbeck A/S. L. Pickering Boserup: Employee; Self; H. Lundbeck A/S. J. Luthman: Employee; Self; H. Lundbeck A/S. H. Benecke: Employee; Self; H. Lundbeck A/S. R.J. Auchus: Consulting Fee; Self; Neurocrine Biosciences, Diurnal, Corcept Therapeutics, Recordati Rare Diseases, Crinetics Pharmaceuticals, Quest Diagnostics, Xeris Pharmaceuticals, Novo Nordisk, H. Lundbeck A/S, Sparrow Pharmaceuticals. Research Investigator; Self; Adrenas Therapeutics, Spruce Biosciences, Neurocrine Biosciences, Diurnal, Corcept Therapeutics, Recordati Rare Diseases, Crinetics Pharmaceuticals. Introduction: Classic congenital adrenal hyperplasia (CAH) is a rare, autosomal recessive disorder characterized by cortisol and aldosterone deficiency, elevated adrenocorticotropic hormone (ACTH) and subsequent hyperandrogenemia, most commonly due to 21-hydroxylase deficiency. Balancing physiological glucocorticoid replacement and control of hyperandrogenism remains a challenge with the risk of long-term consequences of glucocorticoid overtreatment. Lu AG13909 is a novel, high-affinity, anti-ACTH monoclonal antibody that neutralizes ACTH-induced signaling. In preclinical models, Lu AG13909 dose-dependently and persistently reduced plasma corticosterone and cortisol concentrations. No adverse effects were observed after 6 months of intravenous dosing every 2 weeks in cynomolgus monkeys. Here, we describe the ongoing first-in-human trial of Lu AG13909, investigating the safety, tolerability, pharmacokinetic (PK) properties, and pharmacodynamic (PD) effects of Lu AG13909 in adults with classic CAH. Methods: This is a Phase 1, open-label, multiple-ascending-dose trial with intra-participant dose escalation (EUCT #2023-503711-15-00). The trial enrolls men and women with classic CAH aged between ≥18 and ≤70 years under stable glucocorticoid and mineralocorticoid dosing, with morning 17-hydroxyprogesterone >4 times the upper limit of normal. Each participant receives up to 6 doses of Lu AG13909 every 28-35 days at increasing dose levels. The trial consists of 2 parts: Part A has a 3+3 design, in which 3 participants are given a certain dose, and escalation to the next dose is based on a 28-day safety observation period. Part B explores the pharmacologically relevant Lu AG13909 doses identified in Part A in a larger number of participants. The aim is for a total of 12 participants to receive each of the dose levels identified as relevant. Outcomes The primary safety and tolerability endpoints include adverse events and clinical safety tests. PK endpoints include maximum observed exposure and area under the Lu AG13909 concentration-time curve in a dosing interval. The PD endpoints are the relative reductions in morning 17-hydroxyprogesterone, androstenedione, and unbound ACTH, from baseline to the day after each Lu AG13909 dose. Conclusions This innovative, multi-dose, intra-participant dose escalation trial design was developed specifically for the rare classic CAH population, who have a high unmet medical need due to the challenges with current glucocorticoid treatment. The aim of the trial is to gather safety, PK, and PD data while minimizing participant risk and burden. Data from this trial will reinforce the development of Lu AG13909 as a novel treatment strategy in conditions characterized by increased levels of ACTH, such as classic CAH and Cushing disease. Presentation: 6/3/2024
gene therapies
2026-09-01 | Clinical and genetic spectrum of classic congenital adrenal hyperplasia due to CYP21A2 mutations in a Taiwanese cohort.
Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21-OHD) is the most common inherited adrenal disorder in children. Clinical severity is determined by residual CYP21A2 enzyme activity. This study aimed to characterize the clinical and genetic spectrum of classic CAH and to evaluate genotype-phenotype correlations in a Taiwanese cohort. We retrospectively reviewed 53 patients with classic CAH (31 salt-wasting [SW], 22 simple virilizing [SV]) followed at Linkou Chang Gung Memorial Hospital between 1987 and 2023. Clinical characteristics, biochemical profiles, electrolyte disturbances, and CYP21A2 genotypes were analyzed. Virilization in females was graded using the Prader scale. Statistical analyses were performed using nonparametric methods. Patients with SW CAH were diagnosed significantly earlier than those with SV CAH (median 16.4 days vs. 6.1 years, p < 0.0001) and exhibited more pronounced electrolyte abnormalities, including lower sodium (p = 0.0004) and higher potassium levels (p = 0.0061). Among 35 patients who underwent genetic testing (70 alleles), the most common variants were c.293-13A > G and p.Ile173Asn (c.518T > A), which were predominantly associated with SW and SV phenotypes, respectively. Female patients with SW CAH demonstrated more severe virilization (Prader stages 3-5 in 82.4%) compared with those with SV CAH (p = 0.0012). Overall genotype-phenotype concordance was high, although a minority of cases showed discordance between predicted enzymatic activity and clinical severity. Salt-wasting CAH was the predominant form in this Taiwanese cohort, and the CYP21A2 mutation spectrum was consistent with global reports. The severity of virilization correlated with underlying enzymatic activity, supporting the clinical utility of genotyping for disease prediction and counseling. However, discordant cases highlight the potential role of modifying factors and underscore the need for individualized clinical management.
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Drug Discovery Landscape
3 orphan drug designations for Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency.
3 orphan drug designations for Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
adeno-associated virus vector expressing human 21-hydroxylase | gene therapies | FDA | Adrenas Therapeutics Inc | |
chromium picolinate and chromium histidinate | — | FDA | — | JDS Therapeutics, LLC |
metformin | — | FDA | EffRx Pharmaceuticals SA |
“Terminated” – programs with discontinued clinical trials, or with no updates reported for 5 years after completion or 12 years after the last trial started.
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