Single-Dose Study of a Corticotropin-Releasing Factor Receptor-1 Antagonist in Women With 21-Hydroxylase Deficiency

• Published in: The journal of clinical endocrinology and metabolism Vol. 101; no. 3; pp. 1174 - 1180
• Main Authors: Turcu, Adina F, Spencer-Segal, Joanna L, Farber, Robert H, Luo, Rosa, Grigoriadis, Dimitri E, Ramm, Carole A, Madrigal, David, Muth, Tim, O'Brien, Christopher F, Auchus, Richard J
• Format: Journal Article
• Language: English
• Published: United States Endocrine Society 01.03.2016; Copyright by The Endocrine Society
• Subjects: 17-alpha-Hydroxyprogesterone - blood; Adrenal Hyperplasia, Congenital - drug therapy; Adrenal Hyperplasia, Congenital - metabolism; Adrenocorticotropic Hormone - blood; Adult; Azabicyclo Compounds - administration & dosage; Azabicyclo Compounds - adverse effects; Azabicyclo Compounds - pharmacokinetics; Dose-Response Relationship, Drug; Female; Humans; Middle Aged; Original; Oxadiazoles - administration & dosage; Oxadiazoles - adverse effects; Oxadiazoles - pharmacokinetics; Receptors, Corticotropin-Releasing Hormone - antagonists & inhibitors; Time Factors; Young Adult
• ISSN: 0021-972X; 1945-7197
• DOI: 10.1210/jc.2015-3574

Context: Treatment of 21-hydroxylase deficiency (21OHD) is difficult to optimize. Normalization of excessive ACTH and adrenal steroid production commonly requires supraphysiologic doses of glucocorticoids. Objectives: We evaluated the safety and tolerability of the selective corticotropin releasing factor type 1 (CRF1) receptor antagonist NBI-77860 in women with classic 21OHD and tested the hypothesis that CRF1 receptor blockade decreases early-morning ACTH and 17α-hydroxyprogesterone (17OHP) in these patients. Participants: The study enrolled eight classic 21OHD females, ages 18–58 years, seen at a single tertiary referral university setting. Design: This was a phase Ib, single-blind, placebo-controlled, fixed-sequence, single-dose trial. During three treatment periods separated by 3-week washout intervals, patients sequentially received placebo, NBI-77860 300 mg, and NBI-77860 600 mg at 10 pm; glucocorticoid therapy was withheld for 20 hours. We evaluated ACTH, 17OHP, androstenedione, and testosterone as well as NBI-77860 pharmacokinetics over 24 hours. Results: Dose-dependent reductions of ACTH and/or 17OHP were observed in six of eight subjects. Relative to placebo, NBI-77860 led to an ACTH and 17OHP reduction by a mean of 43% and 0.7% for the 300 mg dose, respectively, and by 41% and 27% for the 600 mg dose, respectively. Both NBI-77860 doses were well tolerated. Conclusion: The meaningful reductions in ACTH and 17OHP following NBI-77860 dosing in 21OHD patients demonstrate target engagement and proof of principle in this disorder. These promising data provide a rationale for additional investigations of CRF1 receptor antagonists added to physiologic doses of hydrocortisone and fludrocortisone acetate for the treatment of classic 21OHD.