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.

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.