Abstract
Disclosure: 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, Ascendis, Eton Pharmaceuticals, Neurocrine Biosciences, Novo Nordisk, Pfizer, Spruce Biosciences, and Theratechnologies, Inc., serves as an adjudication committee member for ICON Clinical Research, LLC/Aeterna Zentaris, receives royalties from McGraw-Hill and UpToDate. R.S. Newfield: clinical trial investigator for Neurocrine Biosciences and Spruce Biosciences; consultant for Spruce Biosciences on behalf of UCSD but does not receive personal income for this consultancy. 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. J.L. Chan: Full-time employee of Neurocrine Biosciences, Inc. 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..
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 adrenocorticotropic hormone (ACTH) and 17-hydroxyprogesterone (17-OHP) levels in pediatric patients with classic 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 taking crinecerfont (25, 50, or 100 mg BID based on weight) (CFT/CFT) or 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 to measure the impact on androgens and then reduced to a target of 8-10 mg/m2/d in hydrocortisone equivalents while maintaining or improving androstenedione (A4) relative to Day 1 baseline (BL). Changes in plasma ACTH and serum 17-OHP (before morning GC dose) were analyzed after stable GC dosing (Week 4) and after GC reduction (Week 28) in the DBPC period and at the end of OL treatment (Week 52). 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: During the DBPC period, mean decrease from BL in ACTH was greater with crinecerfont than placebo at Week 4 (-218 vs -54 pg/mL) and at Week 28 (-111 vs -1.5 pg/mL; LSMD -110 pg/mL, P=0.0671), despite a significant mean percent reduction in GC dose with crinecerfont at Week 28 (-18% vs +5.6%; LSMD -23.5%, P<0.0001). 17-OHP decreased with crinecerfont and increased with placebo at Week 4 (-5865 vs +556 ng/dL; LSMD -6421 ng/dL, P<0.0001); at Week 28, after GC dose reduction, the mean decrease was greater with crinecerfont than placebo (-2345 vs -430 ng/dL). In the OL period, mean ACTH and 17-OHP remained below Day 1 BL at Week 52 in participants who continued crinecerfont (ACTH: -124 pg/mL; 17-OHP: -1612 ng/dL) and those who switched from placebo (ACTH: -104 pg/mL; 17-OHP: -1891 ng/dL) despite reductions in GC dose (-17.3% [CFT/CFT], -6.1% [PBO/CFT]). Conclusion: In children/adolescents with CAH who received up to 1 year of crinecerfont, ACTH and 17-OHP were reduced to below BL levels, even after reductions in GC dose. These decreases were consistent with the significant A4 reduction reported in the DBPC period. Crinecerfont, a novel oral CRF1 antagonist, is a non-GC approach to manage excess ACTH and adrenal androgens in CAH, enabling GC doses to be lowered and thus achieving the dual goals of reducing androgen excess and the risks associated with long-term supraphysiologic GC exposure.
Presentation: Sunday, July 13, 2025