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Background: Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21-OHD) is an autosomal recessive disorder characterized by insufficient cortisol production resulting in excess adrenocorticotropic hormone (ACTH) and adrenal androgen production. Standard-of-care therapy with glucocorticoids (GC) is suboptimal due to the difficulty of balancing control of the ACTH-driven androgen excess against the serious long-term side effects associated with chronic supraphysiologic GC exposure. Tildacerfont, a second-generation corticotropin-releasing factor type-1 (CRF1) receptor antagonist, lowers excess ACTH, and thus has the potential to reduce adrenal androgen production and to allow for GC dosing closer to physiologic doses. A prior study demonstrated that tildacerfont was effective in reducing ACTH, 17-hydroxyprogesterone (17-OHP) and androstenedione (A4) after 2 weeks of therapy. Here we report results from an open-label 12-week extension study. Methods: Subjects met either of the following criteria: 1) completion of prior study or 2) treatment naïve to tildacerfont with 17-OHP &amp;gt;800 ng/dL while on a stable GC regimen (excluding dexamethasone). Subjects were treated with oral tildacerfont at 400 mg once daily for 12 weeks. Efficacy and safety parameters were assessed at baseline through Week 12. Results: Subject characteristics (n=8) are as follows: median (range) age was 44.5 years (26-67 years; 5 females), median (range) body mass index 30.8 kg/m2 (22-41 kg/m2). In month 3, in the participants with poor control of disease at baseline (elevations in all key biomarkers: ACTH, 17-OHP, and A4) (n=5), maximum mean percentage reductions for ACTH, 17-OHP and A4 were 84%, 82%, and 79%, respectively. In this subgroup, 60% of subjects achieved ACTH normalization and 40% achieved A4 normalization during treatment. Tildacerfont treatment maintained, and did not suppress, biomarkers in participants with good control of disease at baseline (A4 below upper limit of normal) (n=3). Overall, tildacerfont was well tolerated with no serious adverse events. Conclusions: This is the first study of 12 weeks’ duration for a novel, non-steroidal mechanism-of-action agent for the treatment of 21-OHD. Results of this study show that tildacerfont was generally well-tolerated and effective in achieving meaningful reductions in ACTH and A4 in poorly controlled patients over 12 weeks. In addition, this is the first, non-steroidal therapeutic to show evidence of ACTH and A4 normalization over 12 weeks of therapy. Longer term future studies will evaluate whether treatment with tildacerfont can achieve further clinical benefits and allow reduction of GC doses while controlling relevant disease biomarkers.

journal of the endocrine society

Tildacerfont for the Treatment of Patients With Classic Congenital Adrenal Hyperplasia: Results From a 12-Week Phase 2 Clinical Trial in Adults With Classic CAH