Sarafoglou, KyriakieBarnes, Chris N.Huang, MichaelImel, Erik A.Madu, Ivy-JoanMerke, Deborah P.Moriarty, DavidNakhle, SamerNewfield, Ron S.Vogiatzi, Maria G.Auchus, Richard J.2023-03-212023-03-212021Sarafoglou K, Barnes CN, Huang M, et al. Tildacerfont in Adults With Classic Congenital Adrenal Hyperplasia: Results from Two Phase 2 Studies [published correction appears in J Clin Endocrinol Metab. 2022 Jul 14;107(8):e3546]. J Clin Endocrinol Metab. 2021;106(11):e4666-e4679. doi:10.1210/clinem/dgab438https://hdl.handle.net/1805/31982Context: 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 to 1000 mg once daily (QD) (n = 10) or 100 to 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 ≤ 2× upper limit of normal (ULN) or A4 > 2× ULN. Safety was evaluated using adverse events (AEs) and laboratory assessments. Results: In Study 1, evaluable participants with baseline A4 > 2× 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 > 2× 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 ≤ 2× 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.en-USAttribution-NonCommercial-NoDerivatives 4.0 InternationalTildacerfontCRF-receptor antagonistCongenital adrenal hyperplasiaAndrostenedioneAdrenocorticotropic hormone17-hydroxyprogesteroneArticle