SUN-417 Crinecerfont Maintains Adrenocorticotropic Hormone and 17-Hydroxyprogesterone Levels with Reduced Glucocorticoid Doses in Adults with Classic Congenital Adrenal Hyperplasia: 1-Year Results from the CAHtalyst™ Adult Study

Abstract Disclosure: R.J. Auchus: Has been involved in contracted research with companies such as Neurocrine Biosciences/Neurocrine UK, LTD, Spruce Biosciences, Corcept Therapeutics, Crinetics Pharmaceuticals, Recordati Rare Diseases, Adrenas Therapeutics, and Mineralys Pharmaceuticals, Served as a consultant for organizations like Quest Diagnostics, Corcept Therapeutics, Xeris Pharmaceuticals, Crinetics Pharmaceuticals, Novo Nordisk, Neurocrine Biosciences/Neurocrine UK, LTD, Recordati Rare Diseases, H Lundbeck A/S, Sparrow Pharmaceuticals, Astellas Pharmaceuticals, and Acerand Therapeutics. O. Hamidi: Advisory board member for Neurocrine Biosciences, Corcept Therapeutics, Recordati Rare Diseases, Crinetics Pharmaceuticals, Inc, Camurus, Xeris Pharmaceuticals, Inc, Educational speaking engagement with Recordati Rare Diseases. C. Liu: None. F.W. Kiefer: None. A. Rees: None. A. Gambineri: None. C. Simeoli: Consultant for Neurocrine UK Ltd, and Recordati Rare diseases. R. Pivonello: Research funding from Corcept Therapeutics, Neurocrine Biosciences, Recordati AG, Spruce Bioscience and Xeris Pharmaceuticals (Strongbridge Biopharma), Consultant for Corcept Therapeutics, Crinetics Pharmaceuticals, H Lundbeck A/S and Recordati Rare Diseases. E. Jen: Full-time employee of Neurocrine Biosciences, Inc. V.H. Lin: Full-time employee of Neurocrine Biosciences, Inc. J. Sturgeon: 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 as an adjunct to glucocorticoid (GC) replacement to control androgens in patients with classic congenital adrenal hyperplasia (CAH). In two phase 3 trials, crinecerfont significantly reduced excess androstenedione (A4), 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 adults with CAH who received up to 1 year of crinecerfont. Methods: Participants from the 24-week double-blind placebo-controlled (DBPC) period of CAHtalyst™ Adult (NCT04490915) continued taking crinecerfont (100 mg BID) (CFT/CFT) or switched from placebo to crinecerfont (PBO/CFT) in the 6-month open-label (OL) period. In both periods, GC doses were kept stable for 4 weeks to measure the impact on androgens and then reduced to a target of 8-10 mg/m2/d in hydrocortisone equivalents. After GC reduction, GC doses could be adjusted as needed to maintain or improve 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 at the end of DBPC and OL treatment (Week 24, Month 12). 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 ACTH was 261 pg/mL (crinecerfont) and 269 pg/mL (placebo); mean 17-OHP was 9314 ng/dL (crinecerfont) and 9787 ng/dL (placebo). In the DBPC period, the LS mean decrease from BL at Week 4 in ACTH was greater with crinecerfont than placebo (-158 vs -5.6 pg/mL; LSMD -152 pg/mL; P<0.0001). At Week 24, despite a substantial LS mean percent reduction in GC dose (-27.3% vs -10.3% for placebo; LSMD -17.0%, P<0.0001), ACTH was maintained near BL with crinecerfont (+12.5 vs +172 pg/mL; LSMD -159 pg/mL, P=0.0005). For 17-OHP, the LS mean decrease from BL at Week 4 was greater with crinecerfont than placebo (-5994 vs -156 ng/dL; LSMD -5838 ng/dL, P<0.0001), and it remained below BL at Week 24 with crinecerfont but not placebo (-521 vs +5488 ng/dL). In the OL period, despite large percent decreases in GC dose at Month 12 in participants who continued crinecerfont (-24.6%) and those who switched from placebo (-29.7%), ACTH and 17-OHP were maintained near or below BL levels in both groups (CFT/CFT and PBO/CFT): ACTH (+21.3 and -18.0 pg/mL); 17-OHP (+100 and -741 ng/dL). Conclusion: Mean ACTH and 17-OHP were maintained near or below BL in adults with CAH who received up to 1 year of crinecerfont, allowing for substantial reductions in GC dose. Crinecerfont is a non-GC approach for managing excess ACTH and adrenal androgens, enabling GC doses to be lowered and thereby reducing androgens and the adverse effects of chronic supraphysiologic GC exposure. Presentation: Sunday, July 13, 2025