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 To evaluate the safety, tolerability, and efficacy of crinecerfont (NBI-74788), a selective CRF1R antagonist, in 21OHD. Design Open-label, phase 2 study, with sequential cohort design (NCT03525886). Setting United States (6 centers). Participants Men and women, 18-50 years, with 21OHD. Interventions Four crinecerfont regimens, each administered orally for 14 consecutive days: 50 or 100 mg oncedaily at bedtime (Cohorts 1 and 2, respectively); 100 mg once-daily in the evening (Cohort 3); 100 mg twice-daily (BID, Cohort 4). Participants could enroll in >1 cohort. Main Outcomes Changes from baseline to Day 14 in adrenocorticotropic hormone (ACTH), 17hydroxyprogesterone (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 >60% for ACTH (-66%), 17OHP (64%), and androstenedione (64%) with crinecerfont 100 mg BID. In female participants, 73% (8/11) had ≥50% reduction in testosterone levels; male participants had median 26-65% decreases in androstenedione/testosterone ratios. Conclusions 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 endpoints of disordered steroidogenesis and glucocorticoid exposure in patients with 21OHD.