ISSN 1662-4009 (online)

ESPE Yearbook of Paediatric Endocrinology (2022) 19 8.8 | DOI: 10.1530/ey.19.8.8

ESPEYB19 8. Adrenals Clinical Trials – New Treatments (2 abstracts)

8.8. Crinecerfont lowers elevated hormone markers in adults with 21-hydroxylase deficiency congenital adrenal hyperplasia

Auchus AR , Sarafoglou K , Fechner PY , Vogiatzi MG , Imel EA , Davis SM , Giri N , Sturgeon J , Roberts E , Chan JL & Farber RH



J Clin Endocrinol Metab. 2022; 107(3): 801-812. PMID: 34653252 https://pubmed.ncbi.nlm.nih.gov/34653252/

Brief Summary: This clinical trial evaluated the safety and efficacy of crinecerfont, a CRF1R antagonist, in suppressing adrenal androgen secretion in adult patients with classic congenital adrenal hyperplasia (CAH) during a treatment period of 14 days.

Classical CAH due to 21-hydroxylase deficiency (21OHD) is characterized by impaired cortisol synthesis and excess adrenal androgen secretion. Sufficient suppression of adrenal andogen production may be difficult (1). Novel therapeutic approaches with corticotropin-releasing factor type 1 receptor (CRF1R) antagonists such as crinecerfont could overcome this difficult. CRF1R antagonists decrease ACTH concentrations, thereby suppressing adrenal androgen excess and avoiding the need for supraphysiologic doses of glucocorticoids (2, 3).

In this phase-2 open label study, the CRF1R antagonist crinecerfont was administered orally to 18 adults with classical CAH (age range 18-50 yrs; mean age 31 yrs) for 14 days. Inclusion criteria were: BMI 18-45 kg/m2; Serum 17OHP in the morning prior to GC medication >= 30.3 nmol/L; Serum cortisol<138 nmol/L; Plasma ACTH >= 4.4 pmol/L. All patients also continued their normal daily GC regimen. Outcome measures included ACTH, 17OHP, A4 and testosterone at baseline and after 14 days of treatment with either 50 or 100 mg of crinecerfont at bedtime; 100 mg in the evening; and 100 mg twice daily.

The highest crinecerfont dose reduced ACTH, A4 and 17OHP concentrations by ~60%. In females, testosterone concentrations decreased by 50% in most participants (8/11), while males there showed a substantial decrease in A4/testosterone ratios. Dose-response effects were seen, with the largest effect seen on A4 concentrations. No severe adverse effects were reported.

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 adults with 21OHD. Longer-term studies are required to evaluate the effects of crinecerfont on clinical end points of disordered steroidogenesis and glucocorticoid exposure in patients with 21OHD. Studies in children and adolescents with classic CAH are on-going.

Reference: 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.

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