Endocrine Abstracts

Introduction: Corticotropin-releasing factor type 1 (CRF₁) receptor antagonists, such as crinecerfont, have recently been investigated for the treatment of classic congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21OHD), a rare autosomal disease characterized by cortisol deficiency, elevated adrenocorticotropic hormone (ACTH), and excess androgen production. In a study of adults with 21OHD, treatment with crinecerfont for 14 days led to median percent reductions of >60% for 17 hydroxyprogesterone (17OHP, -64%), ACTH (-66%), and androstenedione (-64%). Post hoc analyses were conducted to assess whether baseline hormone levels and glucocorticoid (GC) dose correlated with treatment response.

Methods: Males and females (18-50 years) with 21OHD and elevated 17OHP concentrations (≥1000 ng/dL) were studied in a sequential cohort design with the following open-label crinecerfont regimens: 50 or 100 mg once daily at bedtime (cohorts 1 and 2, respectively); 100 mg once daily with the evening meal (cohort 3); 100 mg twice daily with meals (cohort 4) for 14 days. Participants could enroll in more than 1 cohort. Correlations between baseline ACTH, 17OHP, androstenedione, GC dose, and magnitude of change from baseline (CFB) to Day 14 hormone levels were assessed using the average concentration of samples collected before the morning GC dose (0600h, 0800h, and 1000h) as well as the average concentration over a full 24-hour sampling period.

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). Baseline GC regimens included hydrocortisone (n=10), prednisone or equivalent (n=7), and hydrocortisone+prednisone or equivalent (n=1), with mean total daily dose (hydrocortisone equivalent) of 14 mg/m²/day (range, 6-25). Significant correlation was found between baseline concentration and CFB to Day 14 for 17OHP (morning window, r=0.735; 24 hour average, r=-0.646), with the greatest reductions from baseline observed in participants with the highest baseline concentrations. Similar correlations were observed for ACTH (morning window, r=0.906; 24-hour average, r=-0.828) and androstenedione (morning window, r=0.887; 24-hour average, r=-0.898). No correlation was found between baseline GC dose and CFB to Day 14 for 17OHP (morning window, r=0.115; 24-hour average, r=0.215).

Conclusions: In adults with 21OHD treated with crinecerfont, there was a high correlation between androgen and precursor treatment response and baseline hormone levels, but not with baseline GC dose, indicating that those with more elevated baseline hormone levels could have greater response, whereas androgen reduction could occur across a broad range of GC doses.