A Phase 2, Multicenter Study of Nevanimibe for the Treatment of Congenital Adrenal Hyperplasia

• Published in: The journal of clinical endocrinology and metabolism Vol. 105; no. 8; pp. 2771 - 2778
• Main Authors: El-Maouche, Diala, Merke, Deborah P, Vogiatzi, Maria G, Chang, Alice Y, Turcu, Adina F, Joyal, Elizabeth G, Lin, Vivian H, Weintraub, Lauren, Plaunt, Marianne R, Mohideen, Pharis, Auchus, Richard J
• Format: Journal Article
• Language: English
• Published: US Oxford University Press 01.08.2020
• Subjects: 17-alpha-Hydroxyprogesterone - blood; 17-alpha-Hydroxyprogesterone - metabolism; ACTH; Administration, Oral; Adolescent; Adrenal Cortex - drug effects; Adrenal Cortex - metabolism; Adrenal Hyperplasia, Congenital - blood; Adrenal Hyperplasia, Congenital - diagnosis; Adrenal Hyperplasia, Congenital - drug therapy; Adrenocorticotropic Hormone - metabolism; Adrenogenital syndrome; Adult; Androgens; Androstenedione - blood; Androstenedione - metabolism; Biomarkers - blood; Biomarkers - metabolism; Care and treatment; Clinical s; Clinical trials; Corticosteroids; Cross-Over Studies; Dose-Response Relationship, Drug; Drug Therapy, Combination - adverse effects; Drug Therapy, Combination - methods; Genetic disorders; Glucocorticoids - administration & dosage; Glucocorticoids - adverse effects; Humans; Hydroxyprogesterone; Middle Aged; Treatment Outcome; Urea - administration & dosage; Urea - adverse effects; Urea - analogs & derivatives; Young Adult; ATR-101; clinical trial; nevanimibe; adrenal hypertrophy; congenital adrenal hyperplasia
• ISSN: 0021-972X; 1945-7197; 1945-7197
• DOI: 10.1210/clinem/dgaa381

Abstract Context Patients with classic congenital adrenal hyperplasia (CAH) often require supraphysiologic glucocorticoid doses to suppress adrenocorticotropic hormone (ACTH) and control androgen excess. Nevanimibe hydrochloride (ATR-101), which selectively inhibits adrenal cortex function, might reduce androgen excess independent of ACTH and thus allow for lower glucocorticoid dosing in CAH. 17-hydroxyprogesterone (17-OHP) and androstenedione are CAH biomarkers used to monitor androgen excess. Objective Evaluate the efficacy and safety of nevanimibe in subjects with uncontrolled classic CAH. Design This was a multicenter, single-blind, dose-titration study. CAH subjects with baseline 17-OHP ≥4× the upper limit of normal (ULN) received the lowest dose of nevanimibe for 2 weeks followed by a single-blind 2-week placebo washout. Nevanimibe was gradually titrated up if the primary outcome measure (17-OHP ≤2× ULN) was not met. A total of 5 nevanimibe dose levels were possible (125, 250, 500, 750, 1000 mg twice daily). Results The study enrolled 10 adults: 9 completed the study, and 1 discontinued early due to a related serious adverse event. At baseline, the mean age was 30.3 ± 13.8 years, and the maintenance glucocorticoid dose, expressed as hydrocortisone equivalents, was 24.7 ± 10.4 mg/day. Two subjects met the primary endpoint, and 5 others experienced 17-OHP decreases ranging from 27% to 72% during nevanimibe treatment. The most common side effects were gastrointestinal (30%). There were no dose-related trends in adverse events. Conclusions Nevanimibe decreased 17-OHP levels within 2 weeks of treatment. Larger studies of longer duration are needed to further evaluate its efficacy as add-on therapy for CAH.