OR07-05 Crinecerfont Maintains Reductions in Serum Androstenedione Levels and Glucocorticoid Doses in Children and Adolescents with Classic Congenital Adrenal Hyperplasia: 1-Year Results from the CAHtalystTM Pediatric Study

Abstract Disclosure: R.S. Newfield: Clinical trial investigator for Neurocrine Biosciences, Inc. and Spruce Biosciences; consultant for Spruce Biosciences. M.E. Geffner: Research support from Ascendis, Diurnal, Neurocrine Biosciences, Novo Nordisk, Pfizer, and Spruce Biosciences; serves on advisory boards or as a consultant for Adrenas Therapeutics, As. Y. Hsu: Consultant for Neurocrine. M.T. Dattani: Lecturing fees: Meck Serono, Pfizer, Novo Nordisk, Sandoz. Advisory Boards: Pfizer, Novo Nordisk. Consultancy: Sandoz, Pfizer, Besins.. M. Bettendorf: None. R.H. Farber: Full-time employee of Neurocrine Biosciences, Inc. G.B. Rosales: Full-time employee of Neurocrine Biosciences, Inc. G.S. Jeha: Full-time employee of Neurocrine Biosciences, Inc. J.L. Chan: Full-time employee of Neurocrine Biosciences, Inc.. Background: Crinecerfont, a corticotropin-releasing factor type 1 receptor (CRF1) antagonist, is a first-in-class medication that is FDA-approved for adjunctive treatment to glucocorticoid (GC) replacement to control androgens in patients with classic congenital adrenal hyperplasia (CAH). In two phase 3 trials, crinecerfont significantly reduced excess androgens, enabling subsequent reductions in GC doses in pediatric and adult patients with CAH. Objective: To evaluate changes in androstenedione (A4) levels and GC doses in pediatric patients with CAH who received up to 1 year of crinecerfont. Methods: Participants from the 28-week double-blind placebo-controlled (DBPC) period of CAHtalystTM Pediatric (NCT04806451) continued crinecerfont (25, 50, or 100 mg BID based on weight) (CFT/CFT) or were switched from placebo (PBO/CFT) in the 24-week open-label (OL) period. In both periods, GC doses were kept stable for the first 4 weeks and then decreased to a target dose of 8-10 mg/m2/d while maintaining or improving A4 relative to Day 1 baseline (BL). Changes in serum A4 levels (before morning GC dose) were analyzed after stable GC dosing (Weeks 4 and 32) and end of DBPC and OL treatment (Weeks 28 and 52). Changes in GC dose were analyzed at end of DBPC and OL treatment. Decreases in GC dose were set to zero if A4 was not maintained or improved relative to BL. For predefined endpoints in the DBPC period, results are presented as least squares (LS) mean changes with LS mean difference (LSMD) and p-value. Results: At BL, mean A4 was 431 ng/dL; mean GC dose was 16.4 mg/m2/d. In the DBPC period, A4 decreased from BL at Week 4 with crinecerfont and increased with placebo (-197 vs. +71 ng/dL; LSMD: -268 ng/dL, P=0.0002) and Week 28 (-94 vs. +147 ng/dL). A4 reduction with crinecerfont enabled a subsequent percentage decrease in GC dose from BL at Week 28, compared to an increase with placebo (-18% vs. +5.6%; LSMD: -23.5%, P<0.0001). In the OL period, mean A4 decreased to below BL at Week 32 (CFT/CFT, -121 ng/dL; PBO/CFT, -174 ng/dL) and after GC dose reduction at Week 52 (CFT/CFT, -13.8 ng/dL; PBO/CFT, -60.9 ng/dL). Mean changes and mean percentage changes in GC dose at Week 52 were as follows: CFT/CFT (-3.0 mg/m2/d, -17.3%); PBO/CFT (-1.1 mg/m2/d, -6.1%). Moreover, 33.8% and 17.2% of participants achieved a GC dose ≤11 mg/m2/d while maintaining or improving A4 in the CFT/CFT and PBO/CFT groups, respectively. Conclusion: In children and adolescents with CAH, reductions in excess A4 and GC doses observed with crinecerfont during the DBPC period were maintained during the OL period. By the end of OL treatment, mean A4 was maintained below BL levels despite a significant reduction in GC dosing to lower, more physiologic doses. Thus, not only can crinecerfont reduce androgen excess, but by enabling GC doses to be lowered, crinecerfont may also reduce the adverse effects of chronic exposure to supraphysiologic GCs over a lifetime of treatment. Presentation: Saturday, July 12, 2025