Abstract Disclosure: R.J. Auchus: Consulting Fee; Self; Corcept Therapeutics, H Lundbeck A/S, Quest Diagnostics, Sparrow Pharmaceuticals, Neurocrine Biosciences, Novo Nordisk, Recordati Rare Diseases, Diurnal, Xeris Pharmaceuticals. Research Investigator; Self; Corcept Therapeutics, Adrenas Therapeutics, Neurocrine Biosciences, Diurnal, Spruce Biosciences. P.J. Trainer: Employee; Self; Crinetics Pharmaceuticals, Inc.. Stock Owner; Self; Crinetics Pharmaceuticals, Inc.. K.J. Lucas: None. D. Bruera: None. J. Marko: Consulting Fee; Self; Crinetics Pharmaceuticals, Inc. A. Ayala: Employee; Self; Crinetics Pharmaceuticals, Inc.. Stock Owner; Self; Crinetics Pharmaceuticals, Inc. Y. Wu: Employee; Self; Crinetics Pharmaceuticals, Inc.. Stock Owner; Self; Crinetics Pharmaceuticals, Inc. C.T. Ferrara-Cook: Employee; Self; Crinetics Pharmaceuticals, Inc.. Stock Owner; Self; Crinetics Pharmaceuticals, Inc. E. De La Torre: Employee; Self; Crinetics Pharmaceuticals, Inc.. Stock Owner; Self; Crinetics Pharmaceuticals, Inc. A. Krasner: Employee; Self; Crinetics Pharmaceuticals, Inc.. Stock Owner; Self; Crinetics Pharmaceuticals, Inc. H. Lagast: Employee; Self; Crinetics Pharmaceuticals, Inc.. Stock Owner; Self; Crinetics Pharmaceuticals, Inc. R. Luo: Employee; Self; Crinetics Pharmaceuticals Inc.. Stock Owner; Self; Crinetics Pharmaceuticals Inc. T.A. Bachega: Research Investigator; Self; Spruce Biosciences. R.S. Struthers: Employee; Self; Crinetics Pharmaceuticals Inc.. Stock Owner; Self; Crinetics Pharmaceuticals Inc. S.F. Betz: Employee; Self; Crinetics Pharmaceuticals, Inc.. Stock Owner; Self; Crinetics Pharmaceuticals, Inc. U. Srirangalingam: Consulting Fee; Self; Diurnal, H Lundbeck A/S. Atumelnant (CRN04894) is a potent, once-daily, orally bioavailable, nonpeptide, first-in-class competitive and selective melanocortin type 2 receptor (MC2R, or ACTH receptor) antagonist being developed for the treatment of CAH and ACTH-Dependent Cushing’s Syndrome. Here we report initial results from an open-label, dose-finding phase 2 study of atumelnant in patients with CAH (NCT05907291). Patients (aged ≥18-75, ≥16 years in USA) with classical CAH on a stable dose of GC replacement for at least 6 months were enrolled and received once daily, oral atumelnant for 12 weeks. Key efficacy endpoints include early morning androstenedione (A4) and 17-hydroxyprogesterone (17-OHP) levels. Ten (10) participants have been enrolled and dosed. Data from the first 4 participants (3 females, median age 34 [range 25-42] years, methylprednisone 8 mg/day [hydrocortisone equivalent {HCeq} 32 mg/day, n=2], prednisone 10 mg/day [HCeq 40 mg/day, n=2]) who received 80 mg once daily, oral atumelnant are available. Baseline morning A4 levels in these participants ranged from 116 to 604 ng/dL (reference range [RR]: females 30-200 ng/dL; males 40-150 ng/dL). In these 4 participants, treatment with atumelnant resulted in rapid and profound A4 reductions within 2 weeks which were maintained for the duration of therapy. A4 reductions ranged from 74% to 99% throughout the study. There have been no instances of A4 being above the upper limit of normal on treatment with atumelnant. Baseline 17-OHP levels in these participants ranged from 4740 to 6905 ng/dL (RR: females <80 ng/dL [follicular], <285 ng/dL [luteal]; males <220 ng/dL). In these 4 participants, treatment with atumelnant resulted in rapid and profound 17-OHP reductions within 2 weeks which were maintained for the duration of therapy. 17-OHP reductions ranged from 68% to >99% throughout the study. Two female participants in this cohort menstruated for the first time in over 2 years. Mean baseline morning ACTH ranged from 155 to 1009 pg/mL (RR: 7.2-63 pg/mL), and while modest variations were seen with atumelnant, no consistent directional trend was observed. In conclusion, these data demonstrate rapid, profound, and sustained suppression of A4 and 17-OHP with 80 mg once daily, oral atumelnant. There were no serious or treatment-related adverse events and atumelnant was generally well-tolerated. This ongoing study will explore further the safety and efficacy of various doses of atumelnant. Support: Crinetics Pharmaceuticals, Inc. Presentation: 6/3/2024