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

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.

Trial registration: ClinicalTrials.gov NCT02804178.

Keywords: ATR-101; adrenal hypertrophy; clinical trial; congenital adrenal hyperplasia; nevanimibe.

Published by Oxford University Press on behalf of the Endocrine Society 2020.

Figures

Figure 1.

Study design: phase 2 study of nevanimibe in the treatment of congenital adrenal hyperplasia. The treatment period consisted of 5 dose levels of nevanimibe starting at 125 mg followed by 250, 500, 750, and 1000 mg twice daily for 14 days at each dose level, followed by 14 days of placebo washout after each dose level. Subjects proceeded to the next dose level if the primary endpoint was not met. †Nevanimibe dosing commenced following a 2-week placebo lead-in period. *Subject proceeded if primary endpoint was not yet met.

Figure 2A.

17-Hydroxyprogesterone changes (%) during treatment and placebo in phase 2 study of nevanimibe in congenital adrenal hyperplasia. The white boxes represent changes during nevanimibe treatment. The grey boxes represent changes during treatment with matching placebo for corresponding dose level. Box and whisker plot representations: horizontal lines within the boxes represent the median; top and bottom edges of each box represent the interquartile range([i.e., the 75th percentile [upper quartile] and 25th percentile [lower quartile], respectively); and the high and low whiskers represent the inner fence (i.e., 1.5× the interquartile range above and below the median). Open circles represent outliers. Note: 1 extreme outlier value for the placebo washout period of Dose Level 2 (7850.98% in subject 10) is not shown in the figure. Abbreviation: BID, twice daily. Figure 2B. Androstenedione changes (%) during treatment and placebo in phase 2 study of nevanimibe in congenital adrenal hyperplasia. The white boxes represent changes during nevanimibe treatment. The grey boxes represent changes during treatment with matching placebo for corresponding dose level. Box and whisker plot representations: Horizontal lines within the boxes represent the median; top and bottom edges of each box represent the interquartile range (i.e., the 75th percentile [upper quartile] and 25th percentile [lower quartile], respectively); and the high and low whiskers represent 1.5× the interquartile range above and below the median. Open circles represent outliers. Abbreviation: BID, twice daily.

Figure 3.

Androstenedione and 17-hydroxyprogesterone values during the treatment period in a selected subject. Androstenedione (upper limit of normal range [ULN] for adult females 

Figure 4.

Pharmacokinetics of nevanimibe: mean AUC0-4 in phase 2 study of nevanimibe in congenital adrenal hyperplasia. Area under the concentration-time curve for nevanimibe from time 0 to 4 hours (AUC0-4) increased appropriately with each dose level increase from dose level 1 (125 mg bid) to dose level 5 (1000 mg bid). Values are mean ± SEM. AUC0-4 = area under the curve from time of dose to 4 hours post-dose.