Tildacerfont in Adults with Classic Congenital Adrenal Hyperplasia: Results from Two Phase 2 Studies.

Context Congenital adrenal hyperplasia due to 21-hydroxylase deficiency (21OHD) is typically treated with lifelong supraphysiologic doses of glucocorticoids (GCs). Tildacerfont, a corticotropin-releasing factor type-1 receptor antagonist, may reduce excess androgen production, allowing for GC dose reduction. Objective Assess tildacerfont safety and efficacy. Design and setting Two Phase 2 open-label studies. Patients Adults with 21OHD. Intervention Oral tildacerfont 200-1000 mg once daily (QD) (n=10) or 100-200 mg twice daily (n=9 and 7) for 2 weeks (Study 1) and 400 mg QD (n=11) for 12 weeks (Study 2). Main outcome measure Efficacy was evaluated by changes from baseline at 8 am in adrenocorticotropic hormone (ACTH), 17-hydroxyprogesterone (17-OHP), and androstenedione (A4) according to baseline A4 ≤2x upper limit of normal (ULN) or A4 >2x ULN. Safety was evaluated using adverse events (AEs) and laboratory assessments. Results In Study 1, evaluable participants with baseline A4 >2x ULN (n=11; 19-67 years, 55% female) had reductions from baseline in ACTH (-59.4% to -28.4%), 17-OHP (-38.3% to 0.3%), and A4 (-24.2% to -18.1%), with no clear dose response. In Study 2, participants with baseline A4 >2x ULN (n=5; 26-63 years, 40% female) had ~80% maximum mean reductions in biomarker levels. ACTH and A4 were normalized for 60% and 40%, respectively. In both studies, participants with baseline A4 ≤2x ULN maintained biomarker levels. AEs (in 53.6% of patients overall) included headache (7.1%) and upper respiratory tract infection (7.1%). Conclusions For patients with 21OHD, up to 12 weeks of oral tildacerfont reduced or maintained key hormone biomarkers toward normal.