ESPE Yearbook of Paediatric Endocrinology

Brief summary: This study evaluated the safety, tolerability and efficacy of Crinecerfont, a CRF1R antagonist in adolescents with classic congenital adrenal hyperplasia (CAH).

Classic congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21OHD) is characterized by impaired cortisol synthesis and excess adrenal androgen secretion. Sufficient suppression of adrenal andogen production in classic CAH may be difficult with current formulations of glucocorticoid treatment (1). Novel therapeutic approaches with corticotropin-releasing factor type 1 receptor (CRF1R) antagonists could be a potential way forward to overcome this difficulty and improve medical care. CRF1R antagonists decrease ACTH concentrations, thereby suppressing adrenal androgen excess and obviating the need for administration of supraphysiologic doses of glucocorticoids (2, 3).

This open-label, phase 2 study (NCT04045145) evaluated the safety, tolerability, and efficacy of crinecerfont, a CRF1R antagonist, in adolescents with classic CAH at 4 centers in the United States. Participants were 8 adolescents (3 males, 5 females) aged 14–17 years with classic 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. 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.These results are consistent with a study of crinecerfont in adults with classic CAH.

In summary, crinecerfont treatment for 14 days decreased ACTH concentrations and afforded clinically meaningful reductions of elevated 17OHP, androstenedione, testosterone (women), or androstenedione/testosterone ratio (men) in adolescents with classic CAH. Longer-term studies are required to evaluate the effects of crinecerfont on clinical end points of disordered steroidogenesis and glucocorticoid exposure in these patients. Studies in children with classic CAH are on-going.

References: 1. Speiser PW, Arlt W, Auchus RJ, et al. Congenital adrenal hyperplasia due to steroid 21-hydroxylase deficiency: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2018; 103(11): 4043–4088. 2. Chen C. Recent advances in small molecule antagonists of the corticotropin-releasing factor type-1 receptor-focus on pharmacology and pharmacokinetics. Curr Med Chem. 2006; 13(11): 1261–1282. 3. Kehne J, De Lombaert S. Non-peptidic CRF1 receptor antagonists for the treatment of anxiety, depression and stress disorders. Curr Drug Targets CNS Neurol Disord. 2002; 1(5):467–493.