Review
BibTex RIS Cite

21-HİDROKSİLAZ EKSİKLİĞİNE BAĞLI KONJENİTAL ADRENAL HİPERPLAZİ TEDAVİSİNDEKİ YENİLİKLER

Year 2025, Volume: 88 Issue: 2, 155 - 163, 28.04.2025

Ecesu Çetin , Mehmet Furkan Burak

https://doi.org/10.26650/IUITFD.1626109

Abstract

Konjenital adrenal hiperplazi (KAH), adrenal bezlerde glukokor tikoid (GC) ve mineralokortikoid (MC) sentezinin bozulmasıyla karakterize bir grup kalıtsal hastalığı ifade eder. Vakaların büyük çoğunluğu, kortizol ve aldosteron seviyelerinin azalmasına yol açan, buna bağlı olarak adrenokortikotropik hormon (ACTH) düzeylerinde reaktif bir artışla adrenal androjen üretiminin faz laca artmasına neden olan 21-hidroksilaz (21-OH) enziminin ek sikliğinden kaynaklanır. KAH, genellikle ACTH’yi ve buna bağlı androjen üretimini baskılamak için fizyolojik sınırların üzerinde GC dozlarının kullanımını gerektiren, yönetimi zor bir hastalıktır. Bu durum, çocukluk döneminde kısa boy ve erken ergenlik, ye tişkinlikte ise hiperandrojenizm, infertilite ve iyatrojenik Cushing sendromu gibi komplikasyonlara yol açabilir. Bu makale, KAH için mevcut tedavi seçeneklerini, tedavi alanındaki eksiklikleri ve gelişmekte olan yeni tedavi yaklaşımlarını kapsamlı bir şekil de ele almaktadır. Bunlar arasında kortikotropin salıcı faktör tip 1 (CRF1) reseptör antagonistleri, ACTH inhibitörleri ve 21-OH enzimatik aktivitesini yerine koymayı hedefleyen deneysel gen tedavileri bulunmaktadır. Yeni geliştirilen ajanların ana hedefi, androjen seviyelerini azaltmak ve suprafizyolojik GC dozlarına duyulan ihtiyacı en aza indirmektir. CRF1 reseptör antagonis ti olan crinecerfont, androjen seviyelerinde önemli iyileşmeler göstermesi nedeniyle; 4 yaş ve üzeri çocuk ve yetişkin klasik KAH hastalarında kısa bir süre önce Amerikan Gıda ve İlaç Dai resi (FDA) tarafından onaylanmıştır. Üretici firma, bu ilacın son 70 yıl içerisinde onaylanan ilk yenilikçi KAH tedavisi olduğunu öne sürmektedir. Ancak, bu tedavi yöntemi, GC dozlarını azaltırken düşük androjen seviyelerini sürdürebilme hedefini karşılayamamıştır. Bu nedenle, güncel araştırmalar, her iki hedefe aynı anda ulaşılıp ulaşılamayacağı veya hastalığın tamamen tedavi edilip edilemeyeceği sorularına yanıt aramaktadır. Bu umut verici te davi yaklaşımlarının uzun vadeli güvenliği ve etkinliği daha fazla araştırma ile kapsamlı bir şekilde değerlendirilmelidir.

Keywords

Konjenital Adrenal Hiperplazi 21-Hidroksi laz Eksikliği Melanokortin Tip 2 Reseptörü Kortikotropin Salgı latıcı Faktör genetik tedavi

References

  • Merke DP, Auchus RJ. Congenital adrenal hyperplasia due to 21-Hydroxylase deficiency. N Engl J Med 2020;383(13):1248-61. [CrossRef] google scholar
  • El-Maouche D, Arlt W, Merke DP. Congenital adrenal hyperplasia. Lancet 2017;390(10108):2194-210. [CrossRef] google scholar
  • Prete A, Auchus RJ, Ross RJ. Clinical advances in the pharmacotherapy of congenital adrenal hyperplasia. Eur J Endocrinol 2021;186(1):R1-14. [CrossRef] google scholar
  • Pofi R, Ji X, Krone NP, Tomlinson JW. Long-term health consequences of congenital adrenal hyperplasia. Clin Endocrinol (Oxf) 2024;101(4):318-31. [CrossRef] google scholar
  • Nordenstrom A, Lajic S, Falhammar H. Long-term outcomes of congenital adrenal hyperplasia. Endocrinol Metab (Seoul) 2022;37(4):587-98. [CrossRef] google scholar
  • Lee HH, Kuo JM, Chao HT, Lee YJ, Chang JG, Tsai CH, et al. Carrier analysis and prenatal diagnosis of congenital adrenal hyperplasia caused by 21-hydroxylase deficiency in Chinese. J Clin Endocrinol Metab 2000;85(2):597-600. [CrossRef] google scholar
  • Pang S, Murphey W, Levine LS, Spence DA, Leon A, LaFranchi S, et al. A pilot newborn screening for congenital adrenal hyperplasia in Alaska. J Clin Endocrinol Metab 1982;55(3):413-20. [CrossRef] google scholar
  • Speiser PW, Arlt W, Auchus RJ, Baskin LS, Conway GS, Merke DP, et al. Congenital adrenal hyperplasia due to steroid 21-hydroxylase deficiency: an endocrine society clinical practice guideline. J Clin Endocrinol Metab 2018;103(11):4043-88. [CrossRef] google scholar
  • Merke DP, Mallappa A, Arlt W, Brac de la Perriere A, Linden Hirschberg A, Juul A, et al. Modified-release hydrocortisone in congenital adrenal hyperplasia. J Clin Endocrinol Metab 2021;106(5):e2063-77. [CrossRef] google scholar
  • Mallappa A, Merke DP. Management challenges and therapeutic advances in congenital adrenal hyperplasia. Nat Rev Endocrinol 2022;18(6):337-52. [CrossRef] google scholar
  • Yogi A, Kashimada K. Current and future perspectives on clinical management of classic 21-hydroxylase deficiency. Endocr J 2023;70(10):945-57. [CrossRef] google scholar
  • Sheng JA, Bales NJ, Myers SA, Bautista AI, Roueinfar M, Hale TM, et al. The Hypothalamic-pituitary-adrenal axis: development, programming actions of hormones, and maternal-fetal interactions. Front Behav Neurosci 2020;14:601939. [CrossRef] google scholar
  • Smith SM, Vale WW. The role of the hypothalamic-pituitary-adrenal axis in neuroendocrine responses to stress. Dialogues Clin Neurosci 2006;8(4):383-95. [CrossRef] google scholar
  • Sarafoglou K, Kim MS, Lodish M, Felner EI, Martinerie L, Nokoff NJ, et al. Phase 3 trial of crinecerfont in pediatric congenital adrenal hyperplasia. N Engl J Med 2024;391(6):493-503. [CrossRef] google scholar
  • Kulshreshtha B, Eunice M, Ammini AC. Pubertal development among girls with classical congenital adrenal hyperplasia initiated on treatment at different ages. Indian J Endocrinol Metab 2012;16(4):599-603. [CrossRef] google scholar
  • Torky A, Sinaii N, Jha S, Desai J, El-Maouche D, Mallappa A, et al. Cardiovascular disease risk factors and metabolic morbidity in a longitudinal study of congenital adrenal hyperplasia. J Clin Endocrinol Metab 2021;106(12):e5247-57. [CrossRef] google scholar
  • Barbot M, Mazzeo P, Lazzara M, Ceccato F, Scaroni C. Metabolic syndrome and cardiovascular morbidity in patients with congenital adrenal hyperplasia. Front Endocrinol (Lausanne) 2022;13:934675. [CrossRef] google scholar
  • Li L, Bensing S, Falhammar H. Rate of fracture in patients with glucocorticoid replacement therapy: a systematic review and meta-analysis. Endocrine 2021;74(1):29-37. [CrossRef] google scholar
  • Sun X, Wu Y, Lu L, Xia W, Zhang L, Chen S, et al. Bone microarchitecture and volumetric mineral density assessed by HR-pQCT in patients with 21- and 17alpha-hydroxylase deficiency. Calcif Tissue Int 2023;113(5):515-25. [CrossRef] google scholar
  • Nermoen I, Falhammar H. Prevalence and characteristics of adrenal tumors and myelolipomas in congenital adrenal hyperplasia: a systematic review and meta-analysis. Endocr Pract 2020;26(11):1351-65. [CrossRef] google scholar
  • Claahsen-van der Grinten HL, Stikkelbroeck N, Falhammar H, Reisch N. Management of endocrine disease: Gonadal dysfunction in congenital adrenal hyperplasia. Eur J Endocrinol 2021;184(3):R85-97. [CrossRef] google scholar
  • Auchus RJ, Sarafoglou K, Fechner PY, Vogiatzi MG, Imel EA, Davis SM, et al. Crinecerfont lowers elevated hormone markers in adults with 21-hydroxylase deficiency congenital adrenal hyperplasia. J Clin Endocrinol Metab 2022;107(3):801-12. [CrossRef] google scholar
  • Auchus RJ, Hamidi O, Pivonello R, Bancos I, Russo G, Witchel SF, et al. Phase 3 trial of crinecerfont in adult congenital adrenal hyperplasia. N Engl J Med 2024;391(6):504-14. [CrossRef] google scholar
  • Newfield RS, Sarafoglou K, Fechner PY, Nokoff NJ, Auchus RJ, Vogiatzi MG, et al. Crinecerfont, a CRF1 receptor antagonist, lowers adrenal androgens in adolescents with congenital adrenal hyperplasia. J Clin Endocrinol Metab 2023;108(11):2871-8. [CrossRef] google scholar
  • U.S. Food and Drug Administration. FDA approves new treatment for congenital adrenal hyperplasia 2024. 01.20.2025. https://www.fda.gov/news-events/press-announcements/fda-approves-new-treatment-congenital-adrenal-hyperplasia. google scholar
  • Sarafoglou K, Barnes CN, Huang M, Imel EA, Madu IJ, Merke DP, et al. Tildacerfont in adults with classic congenital adrenal hyperplasia: results from two phase 2 studies. J Clin Endocrinol Metab 2021;106(11):e4666-79. [CrossRef] google scholar
  • Kim SH, Han S, Zhao J, Wang S, Kusnetzow AK, Reinhart G, et al. Discovery of CRN04894: A novel potent selective MC2R antagonist. ACS Med Chem Lett 2024;15(4):478-85. [CrossRef] google scholar
  • Fowler MA, Kusnetzow AK, Han S, Reinhart G, Kim SH, Johns M, et al. Effects of CRN04894, a nonpeptide orally bioavailable ACTH antagonist, on corticosterone in rodent models of ACTH excess. J Endocr Soc 2021;5(Supplement_1):A167. [CrossRef] google scholar
  • Trainer P, Ferrara-Cook C, Ayala A, Luo R, Miller S, Wang Y, et al. CRN04894: an oral, nonpeptide adrenocorticotropic hormone (ACTH) receptor antagonist decreases basal and stimulated cortisol secretion in healthy volunteers. Endocrine Abstracts 2022;86:344. [CrossRef] google scholar
  • ClinicalTrials.gov. Evaluate the safety, efficacy, and pharmacokinetics of CRN04894 in participants with congenital adrenalhyperplasia(TouCAHn).11.03.2024.https://clinicaltrials. gov/study/NCT05907291?term=NCT05907291&rank=1. google scholar
  • Pharmaceuticals C. Topline phase 2 results from atumelnant in congenital adrenal hyperplasia (CAH). 17.01.2025. https:// ir.crinetics.com/static-files/62ecfe1f-0938-4de5-a73e-0436f5ecd127. google scholar
  • Auchus RJ, Trainer PJ, Lucas KJ, Bruera D, Marko J, Ayala A, et al. 12537 Once daily oral atumelnant (CRN04894) induces rapid and profound reductions of androstenedione and 17-hydroxyprogesterone in participants with classical congenital adrenal hyperplasia: initial results from a 12-week, phase 2, open-label study. J Endocr Soc 2024;8(Supplement_1):bvae163.249. [CrossRef] google scholar
  • Srirangalingam U, Velusamy A, Louise Binderup M, Baker B, Folden Flensburg M, Pickering Boserup L, et al. 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. J Endocr Soc 2024;8(Supplement_1):bvae163.285. [CrossRef] google scholar
  • Feldhaus AL, Anderson K, Dutzar B, Ojala E, McNeill PD, Fan P, et al. ALD1613, a novel long-acting monoclonal antibody to control ACTH-Driven pharmacology. Endocrinolog 2016;158(1):1-8. [CrossRef] google scholar
  • ClinicalTrials.gov. Study of Lu AG13909 in participants with congenital adrenal hyperplasia. 11.04.2024. https:// clinicaltrials.gov/study/NCT05669950?term=Lu%20 AG13909&rank=1. google scholar
  • ClinicalTrials.gov. A Trial of Lu AG13909 in Adult Participants With Cushing’s Disease (BalanCeD). 11.04.2024. https:// clinicaltrials.gov/study/NCT06471829?term=Lu%20 AG13909&rank=2. google scholar
  • Merke DP, Auchus RJ, Sarafoglou K, Geffner ME, Kim MS, Escandon RD, et al. Design of a phase 1/2 open-label, dose-escalation study of the safety and efficacy of gene therapy in adults with classic congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency through administration of an adeno-associated virus (AAV) serotype 5-based recombinant vector encoding the human CYP21A2 gene. J Endocr Soc 2021;5(Suppl_1):A82. [CrossRef] google scholar
  • Bharucha K, Weinstein D, Kirby K, Auchus R, Geffner M, Kim M, et al. ODP046 Initial lessons from a prescreening protocol to identify participants with classic CAH potentially eligible for gene therapy treatment with BBP-631, an adeno-associated virus (AAV) serotype 5-based recombinant vector encoding the human CYP21A2 gene. J Endocr Soc 2022;6(Suppl_1):A60-1. [CrossRef] google scholar
  • White PC. Emerging treatment for congenital adrenal hyperplasia. Curr Opin Endocrinol Diabetes Obes 2022;29(3):271-6. [CrossRef] google scholar
  • Philippidis A. Astellas Shutting Gene Therapy facility in South San Francisco, CA. Hum Gene Ther 2024;35(19-20):777-80. [CrossRef] google scholar
  • Halsey G. FDA Approves Crinecerfont for Congenital Adrenal Hyperplasia in Adults and Children in Landmark Decision. Patient Care (Online). 2024. google scholar
  • U.S. Food and Drug Administration. Highlights of prescribing information. 01.29.2025. https://www.accessdata.fda.gov/ drugsatfda_docs/label/2024/218808s000,218820s000lbl. pdf. google scholar
  • Auchus RJ, Sturgeon J, Lin VH. Crinecerfont in adult congenital adrenal hyperplasia. Reply. N Engl J Med 2024;391(16):1557-8. [CrossRef] google scholar
  • Elenius H, McGlotten R, Moore C, Ayala A, Wu Y, Trainer PJ, et al. Atumelnant (CRN04894) induces rapid and sustained reductions in serum and urine cortisol in patients with ACTH-Dependent Cushing Syndrome during a phase 1b/2a, single center, 10-day, inpatient, open-label study. 01.29.2025. https://crinetics.com/wp-content/ uploads/2024/05/Elenius-et-al_ENDO2024_CS-Poster_ FINAL.pdf. [CrossRef] google scholar
  • Malik S, Dolan TM, Maben ZJ, Hinkle PM. Adrenocorticotropic hormone (ACTH) responses require actions of the melanocortin-2 receptor accessory protein on the extracellular surface of the plasma membrane. J Biol Chem 2015;290(46):27972-85. [CrossRef] google scholar
  • Ory J, Nackeeran S, Balaji NC, Hare JM, Ramasamy AR. Secondary Polycythemia in men receiving testosterone therapy increases risk of major adverse cardiovascular events and venous thromboembolism in the first year of therapy. J Urol 2022;207(6):1295-301. [CrossRef] google scholar
  • Yang Y. Structure, function and regulation of the melanocortin receptors. Eur J Pharmacol 2011;660(1):125-30. [CrossRef] google scholar
  • Hunt G, Donatien PD, Lunec J, Todd C, Kyne S, Thody AJ. Cultured human melanocytes respond to MSH peptides and ACTH. Pigment Cell Res 1994;7(4):217-21. [CrossRef] google scholar
  • Hasenmajer V, Bonaventura I, Minnetti M, Sada V, Sbardella E, Isidori AM. Non-canonical effects of ACTH: Insights into adrenal insufficiency. Front Endocrinol (Lausanne) 2021;12:701263. [CrossRef] google scholar
  • van Dijk EB, Ginn SL, Alexander IE, Graves LE. Genome editing in the adrenal gland: a novel strategy for treating congenital adrenal hyperplasia. Exploration of Endocrine and Metabolic Diseases 2024;1(3):101-21. [CrossRef] google scholar

LATEST ADVANCES FOR TREATING CONGENITAL ADRENAL HYPERPLASIA DUE TO 21-HYDROXYLASE DEFICIENCY

Year 2025, Volume: 88 Issue: 2, 155 - 163, 28.04.2025

Ecesu Çetin , Mehmet Furkan Burak

https://doi.org/10.26650/IUITFD.1626109

Abstract

Congenital adrenal hyperplasia (CAH) is a group of inherit ed diseases characterised by disrupted glucocorticoid (GC) and mineralocorticoid (MC) synthesis in the adrenal glands. Most cases are caused by 21-hydroxylase (21-OH) enzyme de ficiency, which leads to diminished cortisol and aldosterone levels, a reactional increase in adrenocorticotropic hormone (ACTH), resulting in excessive adrenal androgen production. CAH is a challenging condition that often requires supraphys iological doses of GCs to suppress ACTH and subsequent androgen production. It can lead to complications such as short stature and premature puberty during childhood, hy perandrogenism, infertility, and iatrogenic Cushing syndrome in adulthood. This manuscript reviews the current therapeutic landscape, unmet needs, and emerging therapies for CAH, including corticotropin-releasing factor type 1 (CRF1) recep tor antagonists, ACTH inhibitors, and investigational gene therapies to replace 21-OH enzymatic activity. The main fo cus of the pipeline agents is to reduce androgen levels and the need for supraphysiological dosing of GCs. Crinecerfont, a CRF1 receptor antagonist, has recently been approved by the Food and Drug Administration (FDA) after showing sig nificant improvements in androgen levels in adults and pae diatric patients aged 4 years and older with classic CAH. The manufacturer claims it is the first novel CAH treatment in 70 years. However, it failed to maintain low androgen levels while reducing GC dosing. Hence, further pipeline is investi gating whether it is possible to achieve both goals or cure the disease. The long-term safety and efficacy of these promising therapeutic approaches require further investigation and elu cidation.

Keywords

Congenital Adrenal Hyperplasia 21-Hydroxy lase Melanocortin Type 2 Receptor CRF Receptor Type 1 Genetic Therapy

References

  • Merke DP, Auchus RJ. Congenital adrenal hyperplasia due to 21-Hydroxylase deficiency. N Engl J Med 2020;383(13):1248-61. [CrossRef] google scholar
  • El-Maouche D, Arlt W, Merke DP. Congenital adrenal hyperplasia. Lancet 2017;390(10108):2194-210. [CrossRef] google scholar
  • Prete A, Auchus RJ, Ross RJ. Clinical advances in the pharmacotherapy of congenital adrenal hyperplasia. Eur J Endocrinol 2021;186(1):R1-14. [CrossRef] google scholar
  • Pofi R, Ji X, Krone NP, Tomlinson JW. Long-term health consequences of congenital adrenal hyperplasia. Clin Endocrinol (Oxf) 2024;101(4):318-31. [CrossRef] google scholar
  • Nordenstrom A, Lajic S, Falhammar H. Long-term outcomes of congenital adrenal hyperplasia. Endocrinol Metab (Seoul) 2022;37(4):587-98. [CrossRef] google scholar
  • Lee HH, Kuo JM, Chao HT, Lee YJ, Chang JG, Tsai CH, et al. Carrier analysis and prenatal diagnosis of congenital adrenal hyperplasia caused by 21-hydroxylase deficiency in Chinese. J Clin Endocrinol Metab 2000;85(2):597-600. [CrossRef] google scholar
  • Pang S, Murphey W, Levine LS, Spence DA, Leon A, LaFranchi S, et al. A pilot newborn screening for congenital adrenal hyperplasia in Alaska. J Clin Endocrinol Metab 1982;55(3):413-20. [CrossRef] google scholar
  • Speiser PW, Arlt W, Auchus RJ, Baskin LS, Conway GS, Merke DP, et al. Congenital adrenal hyperplasia due to steroid 21-hydroxylase deficiency: an endocrine society clinical practice guideline. J Clin Endocrinol Metab 2018;103(11):4043-88. [CrossRef] google scholar
  • Merke DP, Mallappa A, Arlt W, Brac de la Perriere A, Linden Hirschberg A, Juul A, et al. Modified-release hydrocortisone in congenital adrenal hyperplasia. J Clin Endocrinol Metab 2021;106(5):e2063-77. [CrossRef] google scholar
  • Mallappa A, Merke DP. Management challenges and therapeutic advances in congenital adrenal hyperplasia. Nat Rev Endocrinol 2022;18(6):337-52. [CrossRef] google scholar
  • Yogi A, Kashimada K. Current and future perspectives on clinical management of classic 21-hydroxylase deficiency. Endocr J 2023;70(10):945-57. [CrossRef] google scholar
  • Sheng JA, Bales NJ, Myers SA, Bautista AI, Roueinfar M, Hale TM, et al. The Hypothalamic-pituitary-adrenal axis: development, programming actions of hormones, and maternal-fetal interactions. Front Behav Neurosci 2020;14:601939. [CrossRef] google scholar
  • Smith SM, Vale WW. The role of the hypothalamic-pituitary-adrenal axis in neuroendocrine responses to stress. Dialogues Clin Neurosci 2006;8(4):383-95. [CrossRef] google scholar
  • Sarafoglou K, Kim MS, Lodish M, Felner EI, Martinerie L, Nokoff NJ, et al. Phase 3 trial of crinecerfont in pediatric congenital adrenal hyperplasia. N Engl J Med 2024;391(6):493-503. [CrossRef] google scholar
  • Kulshreshtha B, Eunice M, Ammini AC. Pubertal development among girls with classical congenital adrenal hyperplasia initiated on treatment at different ages. Indian J Endocrinol Metab 2012;16(4):599-603. [CrossRef] google scholar
  • Torky A, Sinaii N, Jha S, Desai J, El-Maouche D, Mallappa A, et al. Cardiovascular disease risk factors and metabolic morbidity in a longitudinal study of congenital adrenal hyperplasia. J Clin Endocrinol Metab 2021;106(12):e5247-57. [CrossRef] google scholar
  • Barbot M, Mazzeo P, Lazzara M, Ceccato F, Scaroni C. Metabolic syndrome and cardiovascular morbidity in patients with congenital adrenal hyperplasia. Front Endocrinol (Lausanne) 2022;13:934675. [CrossRef] google scholar
  • Li L, Bensing S, Falhammar H. Rate of fracture in patients with glucocorticoid replacement therapy: a systematic review and meta-analysis. Endocrine 2021;74(1):29-37. [CrossRef] google scholar
  • Sun X, Wu Y, Lu L, Xia W, Zhang L, Chen S, et al. Bone microarchitecture and volumetric mineral density assessed by HR-pQCT in patients with 21- and 17alpha-hydroxylase deficiency. Calcif Tissue Int 2023;113(5):515-25. [CrossRef] google scholar
  • Nermoen I, Falhammar H. Prevalence and characteristics of adrenal tumors and myelolipomas in congenital adrenal hyperplasia: a systematic review and meta-analysis. Endocr Pract 2020;26(11):1351-65. [CrossRef] google scholar
  • Claahsen-van der Grinten HL, Stikkelbroeck N, Falhammar H, Reisch N. Management of endocrine disease: Gonadal dysfunction in congenital adrenal hyperplasia. Eur J Endocrinol 2021;184(3):R85-97. [CrossRef] google scholar
  • Auchus RJ, Sarafoglou K, Fechner PY, Vogiatzi MG, Imel EA, Davis SM, et al. Crinecerfont lowers elevated hormone markers in adults with 21-hydroxylase deficiency congenital adrenal hyperplasia. J Clin Endocrinol Metab 2022;107(3):801-12. [CrossRef] google scholar
  • Auchus RJ, Hamidi O, Pivonello R, Bancos I, Russo G, Witchel SF, et al. Phase 3 trial of crinecerfont in adult congenital adrenal hyperplasia. N Engl J Med 2024;391(6):504-14. [CrossRef] google scholar
  • Newfield RS, Sarafoglou K, Fechner PY, Nokoff NJ, Auchus RJ, Vogiatzi MG, et al. Crinecerfont, a CRF1 receptor antagonist, lowers adrenal androgens in adolescents with congenital adrenal hyperplasia. J Clin Endocrinol Metab 2023;108(11):2871-8. [CrossRef] google scholar
  • U.S. Food and Drug Administration. FDA approves new treatment for congenital adrenal hyperplasia 2024. 01.20.2025. https://www.fda.gov/news-events/press-announcements/fda-approves-new-treatment-congenital-adrenal-hyperplasia. google scholar
  • Sarafoglou K, Barnes CN, Huang M, Imel EA, Madu IJ, Merke DP, et al. Tildacerfont in adults with classic congenital adrenal hyperplasia: results from two phase 2 studies. J Clin Endocrinol Metab 2021;106(11):e4666-79. [CrossRef] google scholar
  • Kim SH, Han S, Zhao J, Wang S, Kusnetzow AK, Reinhart G, et al. Discovery of CRN04894: A novel potent selective MC2R antagonist. ACS Med Chem Lett 2024;15(4):478-85. [CrossRef] google scholar
  • Fowler MA, Kusnetzow AK, Han S, Reinhart G, Kim SH, Johns M, et al. Effects of CRN04894, a nonpeptide orally bioavailable ACTH antagonist, on corticosterone in rodent models of ACTH excess. J Endocr Soc 2021;5(Supplement_1):A167. [CrossRef] google scholar
  • Trainer P, Ferrara-Cook C, Ayala A, Luo R, Miller S, Wang Y, et al. CRN04894: an oral, nonpeptide adrenocorticotropic hormone (ACTH) receptor antagonist decreases basal and stimulated cortisol secretion in healthy volunteers. Endocrine Abstracts 2022;86:344. [CrossRef] google scholar
  • ClinicalTrials.gov. Evaluate the safety, efficacy, and pharmacokinetics of CRN04894 in participants with congenital adrenalhyperplasia(TouCAHn).11.03.2024.https://clinicaltrials. gov/study/NCT05907291?term=NCT05907291&rank=1. google scholar
  • Pharmaceuticals C. Topline phase 2 results from atumelnant in congenital adrenal hyperplasia (CAH). 17.01.2025. https:// ir.crinetics.com/static-files/62ecfe1f-0938-4de5-a73e-0436f5ecd127. google scholar
  • Auchus RJ, Trainer PJ, Lucas KJ, Bruera D, Marko J, Ayala A, et al. 12537 Once daily oral atumelnant (CRN04894) induces rapid and profound reductions of androstenedione and 17-hydroxyprogesterone in participants with classical congenital adrenal hyperplasia: initial results from a 12-week, phase 2, open-label study. J Endocr Soc 2024;8(Supplement_1):bvae163.249. [CrossRef] google scholar
  • Srirangalingam U, Velusamy A, Louise Binderup M, Baker B, Folden Flensburg M, Pickering Boserup L, et al. 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. J Endocr Soc 2024;8(Supplement_1):bvae163.285. [CrossRef] google scholar
  • Feldhaus AL, Anderson K, Dutzar B, Ojala E, McNeill PD, Fan P, et al. ALD1613, a novel long-acting monoclonal antibody to control ACTH-Driven pharmacology. Endocrinolog 2016;158(1):1-8. [CrossRef] google scholar
  • ClinicalTrials.gov. Study of Lu AG13909 in participants with congenital adrenal hyperplasia. 11.04.2024. https:// clinicaltrials.gov/study/NCT05669950?term=Lu%20 AG13909&rank=1. google scholar
  • ClinicalTrials.gov. A Trial of Lu AG13909 in Adult Participants With Cushing’s Disease (BalanCeD). 11.04.2024. https:// clinicaltrials.gov/study/NCT06471829?term=Lu%20 AG13909&rank=2. google scholar
  • Merke DP, Auchus RJ, Sarafoglou K, Geffner ME, Kim MS, Escandon RD, et al. Design of a phase 1/2 open-label, dose-escalation study of the safety and efficacy of gene therapy in adults with classic congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency through administration of an adeno-associated virus (AAV) serotype 5-based recombinant vector encoding the human CYP21A2 gene. J Endocr Soc 2021;5(Suppl_1):A82. [CrossRef] google scholar
  • Bharucha K, Weinstein D, Kirby K, Auchus R, Geffner M, Kim M, et al. ODP046 Initial lessons from a prescreening protocol to identify participants with classic CAH potentially eligible for gene therapy treatment with BBP-631, an adeno-associated virus (AAV) serotype 5-based recombinant vector encoding the human CYP21A2 gene. J Endocr Soc 2022;6(Suppl_1):A60-1. [CrossRef] google scholar
  • White PC. Emerging treatment for congenital adrenal hyperplasia. Curr Opin Endocrinol Diabetes Obes 2022;29(3):271-6. [CrossRef] google scholar
  • Philippidis A. Astellas Shutting Gene Therapy facility in South San Francisco, CA. Hum Gene Ther 2024;35(19-20):777-80. [CrossRef] google scholar
  • Halsey G. FDA Approves Crinecerfont for Congenital Adrenal Hyperplasia in Adults and Children in Landmark Decision. Patient Care (Online). 2024. google scholar
  • U.S. Food and Drug Administration. Highlights of prescribing information. 01.29.2025. https://www.accessdata.fda.gov/ drugsatfda_docs/label/2024/218808s000,218820s000lbl. pdf. google scholar
  • Auchus RJ, Sturgeon J, Lin VH. Crinecerfont in adult congenital adrenal hyperplasia. Reply. N Engl J Med 2024;391(16):1557-8. [CrossRef] google scholar
  • Elenius H, McGlotten R, Moore C, Ayala A, Wu Y, Trainer PJ, et al. Atumelnant (CRN04894) induces rapid and sustained reductions in serum and urine cortisol in patients with ACTH-Dependent Cushing Syndrome during a phase 1b/2a, single center, 10-day, inpatient, open-label study. 01.29.2025. https://crinetics.com/wp-content/ uploads/2024/05/Elenius-et-al_ENDO2024_CS-Poster_ FINAL.pdf. [CrossRef] google scholar
  • Malik S, Dolan TM, Maben ZJ, Hinkle PM. Adrenocorticotropic hormone (ACTH) responses require actions of the melanocortin-2 receptor accessory protein on the extracellular surface of the plasma membrane. J Biol Chem 2015;290(46):27972-85. [CrossRef] google scholar
  • Ory J, Nackeeran S, Balaji NC, Hare JM, Ramasamy AR. Secondary Polycythemia in men receiving testosterone therapy increases risk of major adverse cardiovascular events and venous thromboembolism in the first year of therapy. J Urol 2022;207(6):1295-301. [CrossRef] google scholar
  • Yang Y. Structure, function and regulation of the melanocortin receptors. Eur J Pharmacol 2011;660(1):125-30. [CrossRef] google scholar
  • Hunt G, Donatien PD, Lunec J, Todd C, Kyne S, Thody AJ. Cultured human melanocytes respond to MSH peptides and ACTH. Pigment Cell Res 1994;7(4):217-21. [CrossRef] google scholar
  • Hasenmajer V, Bonaventura I, Minnetti M, Sada V, Sbardella E, Isidori AM. Non-canonical effects of ACTH: Insights into adrenal insufficiency. Front Endocrinol (Lausanne) 2021;12:701263. [CrossRef] google scholar
  • van Dijk EB, Ginn SL, Alexander IE, Graves LE. Genome editing in the adrenal gland: a novel strategy for treating congenital adrenal hyperplasia. Exploration of Endocrine and Metabolic Diseases 2024;1(3):101-21. [CrossRef] google scholar
There are 50 citations in total.

Details

Primary Language English
Subjects Health Services and Systems (Other)
Journal Section Reviews
Authors

Ecesu Çetin 0000-0001-7682-3597

Mehmet Furkan Burak 0000-0001-6222-1552

Publication Date April 28, 2025
Submission Date January 24, 2025
Acceptance Date February 7, 2025
Published in Issue Year 2025 Volume: 88 Issue: 2

Cite

APA Çetin, E., & Burak, M. F. (2025). LATEST ADVANCES FOR TREATING CONGENITAL ADRENAL HYPERPLASIA DUE TO 21-HYDROXYLASE DEFICIENCY. Journal of Istanbul Faculty of Medicine, 88(2), 155-163. https://doi.org/10.26650/IUITFD.1626109
AMA Çetin E, Burak MF. LATEST ADVANCES FOR TREATING CONGENITAL ADRENAL HYPERPLASIA DUE TO 21-HYDROXYLASE DEFICIENCY. İst Tıp Fak Derg. April 2025;88(2):155-163. doi:10.26650/IUITFD.1626109
Chicago Çetin, Ecesu, and Mehmet Furkan Burak. “LATEST ADVANCES FOR TREATING CONGENITAL ADRENAL HYPERPLASIA DUE TO 21-HYDROXYLASE DEFICIENCY”. Journal of Istanbul Faculty of Medicine 88, no. 2 (April 2025): 155-63. https://doi.org/10.26650/IUITFD.1626109.
EndNote Çetin E, Burak MF (April 1, 2025) LATEST ADVANCES FOR TREATING CONGENITAL ADRENAL HYPERPLASIA DUE TO 21-HYDROXYLASE DEFICIENCY. Journal of Istanbul Faculty of Medicine 88 2 155–163.
IEEE E. Çetin and M. F. Burak, “LATEST ADVANCES FOR TREATING CONGENITAL ADRENAL HYPERPLASIA DUE TO 21-HYDROXYLASE DEFICIENCY”, İst Tıp Fak Derg, vol. 88, no. 2, pp. 155–163, 2025, doi: 10.26650/IUITFD.1626109.
ISNAD Çetin, Ecesu - Burak, Mehmet Furkan. “LATEST ADVANCES FOR TREATING CONGENITAL ADRENAL HYPERPLASIA DUE TO 21-HYDROXYLASE DEFICIENCY”. Journal of Istanbul Faculty of Medicine 88/2 (April 2025), 155-163. https://doi.org/10.26650/IUITFD.1626109.
JAMA Çetin E, Burak MF. LATEST ADVANCES FOR TREATING CONGENITAL ADRENAL HYPERPLASIA DUE TO 21-HYDROXYLASE DEFICIENCY. İst Tıp Fak Derg. 2025;88:155–163.
MLA Çetin, Ecesu and Mehmet Furkan Burak. “LATEST ADVANCES FOR TREATING CONGENITAL ADRENAL HYPERPLASIA DUE TO 21-HYDROXYLASE DEFICIENCY”. Journal of Istanbul Faculty of Medicine, vol. 88, no. 2, 2025, pp. 155-63, doi:10.26650/IUITFD.1626109.
Vancouver Çetin E, Burak MF. LATEST ADVANCES FOR TREATING CONGENITAL ADRENAL HYPERPLASIA DUE TO 21-HYDROXYLASE DEFICIENCY. İst Tıp Fak Derg. 2025;88(2):155-63.
 Download Cover Image

Contact information and address

Addressi: İ.Ü. İstanbul Tıp Fakültesi Dekanlığı, Turgut Özal Cad. 34093 Çapa, Fatih, İstanbul, TÜRKİYE

Email: itfdergisi@istanbul.edu.tr

Phone: +90 212 414 21 61