Crinecerfont Lowers Elevated Hormone Markers in Adults With 21-Hydroxylase Deficiency Congenital Adrenal Hyperplasia

Abstract

Context: Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency (21OHD) is characterized by impaired cortisol synthesis and excess androgen production. Corticotropin-releasing factor type 1 receptor (CRF1R) antagonism may decrease adrenal androgen production.

Objective: This work aimed to evaluate the safety, tolerability, and efficacy of crinecerfont (NBI-74788), a selective CRF1R antagonist, in 21OHD.

Methods: This open-label, phase 2 study, with sequential cohort design (NCT03525886), took place in 6 centers in the United States. Participants included men and women, aged 18 to 50 years, with 21OHD. Interventions included 4 crinecerfont regimens, each administered orally for 14 consecutive days: 50 or 100 mg once daily at bedtime (cohorts 1 and 2, respectively); 100 mg once daily in the evening (cohort 3); and 100 mg twice daily (cohort 4). Participants could enroll in more than 1 cohort. Main outcomes included changes from baseline to day 14 in adrenocorticotropin (ACTH), 17-hydroxyprogesterone (17OHP), androstenedione, and testosterone.

Results: Eighteen participants (11 women, 7 men) were enrolled: cohort 1 (n = 8), cohort 2 (n = 7), cohort 3 (n = 8), cohort 4 (n = 8). Mean age was 31 years; 94% were White. Median percent reductions were more than 60% for ACTH (-66%), 17OHP (-64%), and androstenedione (-64%) with crinecerfont 100 mg twice a day. In female participants, 73% (8/11) had a 50% or greater reduction in testosterone levels; male participants had median 26% to 65% decreases in androstenedione/testosterone ratios.

Conclusion: Crinecerfont treatment for 14 days lowered ACTH and afforded clinically meaningful reductions of elevated 17OHP, androstenedione, testosterone (women), or androstenedione/testosterone ratio (men) in adults with 21OHD. Longer-term studies are required to evaluate the effects of crinecerfont on clinical end points of disordered steroidogenesis and glucocorticoid exposure in patients with 21OHD.

Keywords: 17-hydroxyprogesterone; 21-hydroxylase deficiency; NBI-74788; congenital adrenal hyperplasia; crinecerfont.

© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society.

Figures

Figure 1.

Study design. Blue triangles denote sample collection. In all cohorts, sampling for the 24-hour baseline period (day –7 to –6) matched the sampling schedule during crinecerfont treatment. For the baseline and day 1 visits, participants received their prescribed glucocorticoid dose after sample collection at 10:00 (end of the morning window); for the day 14 visit, glucocorticoid was administered after sample collection at 14:00. GC, glucocorticoid.

Figure 2.

Twenty-four–hour profiles. For cohorts 1 and 2, crinecerfont dosing was at 22:00 on day 14; predose sampling was at 21:45. For cohorts 3 and 4, crinecerfont dosing was at 19:00 on day 14; predose sampling was at 18:45. 17OHP, 17-hydroxyprogesterone; ACTH, adrenocorticotropin; GC, glucocorticoid.

Figure 2.

Twenty-four–hour profiles. For cohorts 1 and 2, crinecerfont dosing was at 22:00 on day 14; predose sampling was at 21:45. For cohorts 3 and 4, crinecerfont dosing was at 19:00 on day 14; predose sampling was at 18:45. 17OHP, 17-hydroxyprogesterone; ACTH, adrenocorticotropin; GC, glucocorticoid.

Figure 3.

Median percent reductions from baseline to day 14 based on morning window values. Based on each participant’s values from the morning window time points (06:00, 08:00, 10:00). The interquartile ranges (absolute value of Q3-Q1) for median percent reductions are shown in brackets. 17OHP, 17-hydroxyprogesterone; ACTH, adrenocorticotropin.

Figure 4.

Percent change from baseline to day 14 in participants with crinecerfont 100 mg twice a day (cohort 4). Based on each participant’s average values from the morning window time points (06:00, 08:00, 10:00) on day 14 compared to the average of their morning window values at baseline. ACTH, adrenocorticotropin.