ESPE Abstracts

In the 1950s, Lawson Wilkins and colleagues described cortisone therapy for classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency (21OHD). Wilkins also correctly reasoned that cortisol, derived from cortisone, would exert negative feedback on the hypothalamic-pituitary-adrenal axis and lower adrenal-derived androgens. In the decades following commercial availability of glucocorticoids, children with 21OHD have survived into adulthood; however, long-term complications of the disease and its treatment are now apparent. Management of children and adults with 21OHD is difficult balance between androgen and glucocorticoid excess, and new approaches are needed to improve outcomes. Circadian delivery of hydrocortisone improves control of 21OHD compared to conventional hydrocortisone and over time results in lower glucocorticoid exposure. Glucocorticoid-sparing therapies offer the potential for a block-and-replace strategy, with physiological replacement dosing of cortisol. The P450 17A1 inhibitor abiraterone acetate directly blocks androgen production but at the expense of progesterone accumulation. The corticotropin-releasing factor type 1 receptor (CRF1) antagonists crinecerfont and tildacerfont have shown efficacy in suppressing ACTH and adrenal biomarkers in phase 2 trials. In phase 3 trials of children and adults with 21OHD, crinecerfont was markedly superior to placebo in lowering androstenedione and permitting glucocorticoid dose reduction. The melanocortin type 2 (ACTH) receptor antagonist atumelnant is showing promise early in phase 2 trials, and an anti-ACTH antibody is in phase 1 trials. Gene therapy is also under study with an AAV5 vector (BBP-631). These modern approaches to deliver cortisol replacement and the suppress adrenal androgen production should simplify management, improve disease control, and mitigate the long-term consequences of 21OHD and chronic non-physiologic glucocorticoid exposure.