Crinecerfont, a CRF1 Receptor Antagonist, Lowers Adrenal Androgens in Adolescents With Congenital Adrenal Hyperplasia

Abstract

Context: Crinecerfont, a corticotropin-releasing factor type 1 receptor antagonist, has been shown to reduce elevated adrenal androgens and precursors in adults with congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21OHD), a rare autosomal recessive disorder characterized by cortisol deficiency and androgen excess due to elevated adrenocorticotropin.

Objective: To evaluate the safety, tolerability, and efficacy of crinecerfont in adolescents with 21OHD CAH.

Methods: This was an open-label, phase 2 study (NCT04045145) at 4 centers in the United States. Participants were males and females, 14 to 17 years of age, with classic 21OHD CAH. Crinecerfont was administered orally (50 mg twice daily) for 14 consecutive days with morning and evening meals. The main outcomes were change from baseline to day 14 in circulating concentrations of ACTH, 17-hydroxyprogesterone (17OHP), androstenedione, and testosterone.

Results: 8 participants (3 males, 5 females) were enrolled; median age was 15 years and 88% were Caucasian/White. After 14 days of crinecerfont, median percent reductions from baseline to day 14 were as follows: ACTH, -57%; 17OHP, -69%; and androstenedione, -58%. In female participants, 60% (3/5) had ≥50% reduction from baseline in testosterone.

Conclusion: Adolescents with classic 21OHD CAH had substantial reductions in adrenal androgens and androgen precursors after 14 days of oral crinecerfont administration. These results are consistent with a study of crinecerfont in adults with classic 21OHD CAH.

Keywords: 21-hydroxylase deficiency; CRF type 1 receptor antagonist; adolescents; congenital adrenal hyperplasia; crinecerfont; pediatric.

Figure 1.

Study design. ^aShaded boxes indicate overnight stay at study center for 24-hour serial blood sampling. ^bNo crinecerfont dose was administered on days −7/−6 (baseline visit). However, sample collection timepoints during this overnight stay were the same as days 1/2 and 14/15 (postbaseline visits). Triangles indicate timepoints when blood samples were collected. GC, glucocorticoid.

Figure 2.

24-hour concentration profiles. 17OHP, 17-hydroxyprogesterone; ACTH, adrenocorticotropic hormone; GC, glucocorticoid.

Figure 3.

Percent reductions from baseline to day 14. Boxes represent the IQR: lower edge (25th percentile), upper edge (75th percentile), horizontal bar (median). Whiskers extend beyond the box to the minimum and maximum values. Data below represent median [IQR] values, except for the testosterone and androstenedione/testosterone ratio in males, where data represent median [minimum and maximum] values (n = 3). 17OHP, 17-hydroxyprogesterone; ACTH, adrenocorticotropic hormone; IQR, interquartile range.

Figure 4.

Percent changes from baseline to day 14 in individual participants. Based on morning window (ie, average of values taken from 07:00 and 10:00). For glucocorticoid therapy, 6 participants received hydrocortisone (H) and 2 received prednisone (P). 17OHP, 17-hydroxyprogesterone; ACTH, adrenocorticotropic hormone.