Merke, Deborah P

Abstract Background Children with congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency typically have height, weight, and body mass index (BMI) growth patterns that differ from the general population due to increased androgen and/or glucocorticoid exposures. With the recent surge in the development of new therapies, CAH-specific growth charts are needed to evaluate the effectiveness of these new treatments. Methods Retrospective data from patients aged 0 to 20 years with classic CAH, confirmed by hormonal testing and/or CYP21A2 genotyping, from 2 large clinical databases were analyzed. Specialized charts were developed using the lamda-mu-sigma semiparametric modeling method to generate CAH-specific percentile curves from 0 to 20 years. Nodal-point analyses were conducted to assess differences in incremental growth at 4, 8, 12, 16, and 20 years of age relative to Centers for Disease Control and Prevention (CDC) 2000 normative charts using 1-sided quantile tests and age of adiposity rebound estimated with curve derivative solutions. Results A total sample of 8692 visits from 515 patients was used. Growth (height-, weight-, BMI-for-age) channels of CAH patients were significantly different over the entire growing period and characterized by diminished pubertal spurt relative to the CDC reference. Onset of adiposity rebound based on BMI-for-age occurred earlier for CAH patients (females 3.3 years, males 3.9 years) compared to their normative counterparts (5-8 years). Conclusion Our study showed that at incremental time points throughout childhood, children with CAH collectively follow specific differences in growth trajectories as compared to unaffected children. These variations highlight the need for CAH-specific charts to assist in clinical management, appraisal of growth trajectories, and assessment of the impact of new therapies.

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.