#1703016 Baseline Characteristics of Adults with Classic Congenital Adrenal Hyperplasia Enrolled in CAHtalyst, a Phase 3 Study of Crinecerfont, a Corticotropin-Releasing Factor Type 1 Receptor Antagonist

To describe the baseline characteristics of individuals enrolled in CAHtalyst (NCT04490915), a randomized, double-blind, placebo-controlled, Phase 3 study evaluating the safety and efficacy of crinecerfont (a corticotropin-releasing factor type 1 receptor [CRF1] antagonist) in adults with classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency (21OHD). The study included adults (age ≥18 yrs) with classic 21OHD. Key eligibility criteria included glucocorticoid dose >13 mg/m2/day in hydrocortisone equivalents (HCe; conversion factors: 4x for predni[so]lone, 60x for dexamethasone) adjusted for body surface area (BSA) with stable dose for ≥1 month prior to screening, and normal or elevated androstenedione (A4). Baseline demographics and characteristics were summarized descriptively in all randomized participants. Of 182 enrolled participants, 51% were men and 90% were White. Mean (±SD) age was 30.8±9.9 yrs (range: 18-58 yrs), mean BSA was 1.8±0.2 m2, and mean body mass index (BMI) was 29.8±7.0 kg/m2 (with BMI ≥30 kg/m2 in 47% of participants). The mean total daily glucocorticoid dose was 17.6±4.9 mg/m2/d (32.3±9.3 mg/d) HCe, with 57% on hydrocortisone alone, 30% on a predniso(lo)ne-containing regimen, and 13% on a dexamethasone-containing regimen. In addition, 86% of participants were on fludrocortisone (mean dose: 136±72 mcg/d). Mean (±SD) hormone concentrations prior to the morning glucocorticoid dose were as follows: adrenocorticotropic hormone, 264±317 pg/mL; 17-hydroxyprogesterone, 9467±8829 ng/dL; A4, 620±729 ng/dL; testosterone (T) in females, 86±85 ng/dL; A4/T in males, 2.2±2.4; follicle-stimulating hormone in males, 6.3±9.4 IU/L; and luteinizing hormone in males, 4.6±5.0 IU/L. Among the 90 females, 42 (47%) reported a history of hirsutism; of the 66 females of childbearing potential not on hormonal or intrauterine contraception, 35 (53%) reported a history of amenorrhea or menstrual irregularities. Among the 92 males, 44 (48%) reported ta history of testicular adrenal rest tumors (TARTs) while 53 (58%)s had evidence of TARTs by ultrasound at baseline. Comorbidities included osteopenia (15%), hypertension (10%), osteoporosis (5%), and diabetes mellitus (2%). In a Phase 3 trial evaluating crinecerfont (a CRF1 antagonist) in adults with classic 21OHD, clinical evidence of glucocorticoid and androgen excess (e.g., high prevalence of obesity, hirsutism [females], and TARTs [males]) were observed at baseline. Androgens and other steroid biomarkers were elevated despite treatment with supraphysiological doses of glucocorticoids. These findings emphasize the urgent need for novel glucocorticoid-sparing treatments for this chronic condition.