Diala El-Maouche1,2, Deborah P Merke2,3, Maria G Vogiatzi4, Alice Y Chang5, Adina F Turcu6, Elizabeth G Joyal2, Vivian H Lin7, Lauren Weintraub7, Marianne R Plaunt7, Pharis Mohideen7, Richard J Auchus6. 1. Division of Endocrinology & Metabolism, George Washington University, Washington, DC. 2. The National Institutes of Health Clinical Center, Bethesda, Maryland. 3. The Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland. 4. Division of Endocrinology and Diabetes, Children's Hospital of Pennsylvania, Philadelphia, Pennsylvania. 5. Division of Endocrinology, Diabetes, Metabolism, and Nutrition, Mayo Clinic, Rochester, Minnesota. 6. Division of Metabolism, Endocrinology, and Diabetes, University of Michigan, Ann Arbor, Michigan. 7. Millendo Therapeutics US, Inc, Ann Arbor, Michigan.
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. Published by Oxford University Press on behalf of the Endocrine Society 2020.
RCT Entities:
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. Published by Oxford University Press on behalf of the Endocrine Society 2020.
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