SUN-414 Crinecerfont Improves Reproductive Hormones in Classic Congenital Adrenal Hyperplasia: 1-Year Results from the Phase 3 CAHtalyst™ Adult Study

Abstract Disclosure: D.P. Merke: Received research funds from Diurnal Limited, Neurocrine Biosciences and Adrenas Therapeutics, all through the National Institutes of Health Cooperative Research and Development Agreements, Received royalties from UpToDate for writing and editing. S. Vaid: None. M. Salam: Received research grants from Neurocrine Biosciences Inc / Mylan / MBX Biosciences, Inc / Crinetics Pharmaceuticals, Inc / Bayer AG. Consulted for Eli Lilly & Co / Neurocrine Biosciences Inc. D. Pignatelli: Consultant for Neurocrine Biosciences, Inc. A.M. Isidori: Research funding from Corcept, Recordati Rare Diseases Pharma, Pzifer; principal investigator for Neurocrine, Crinetics Pharma. N. Reisch: Consulted for Neurocrine Biosciences, Inc., Spruce Biosciences, H Lundbeck A/S, Crinetics Pharmaceuticals and Diurnal Limited. L. Keener: None. V.H. Lin: Full-time employee of Neurocrine Biosciences, Inc. R.H. Farber: Full-time employee of Neurocrine Biosciences, Inc. E. Jen: 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: Gonadal dysfunction with classic congenital adrenal hyperplasia (CAH) is due to testicular adrenal rest tumors and/or poor hormonal control (males) and to high adrenal androgens and progesterone (P4) (females). 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 CAH. In CAHtalyst™ Adult (NCT04490915), least-squares mean (LSM) percent changes in GC dose at Week 24 (end of double-blind placebo-controlled period) indicated a significant reduction with crinecerfont (-27.3% vs -10.3% for placebo; LSM difference -17.0%; P<0.0001) while androstenedione (A4) was maintained or improved relative to Day 1 baseline (BL). At Month 12 (end of open-label period), mean percent decreases from BL were -24.6% in participants who continued on crinecerfont (CFT/CFT) and -29.7% in those who switched from placebo (PBO/CFT). Objective: To evaluate reproductive hormone changes in adults with CAH who received up to 1 year of crinecerfont, in the context of substantial GC dose reductions. Methods: Analyses conducted at Week 24 and Month 12 were as follows: luteinizing hormone (LH), follicle stimulating hormone (FSH), A4-to-testosterone ratio (A4/T) in males; testosterone (T) and P4 in females. Males included for analysis had abnormal (low or high) LH, abnormal FSH, or A4/T ≥0.5 at BL. Females had elevated T or P4 at BL, with analysis conducted without regard to menstrual cycle phase. In participants with abnormal values at Day 1 BL, results are presented as % (n/N) (n=number achieving normalization; N=number with available assessments at Week 24 or Month 12). Results: The percentages of male participants achieving normal/target levels at Week 24 with crinecerfont vs placebo were as follows: LH (47.4% [9/19] vs 22.2% [2/9]); FSH (13.3% [2/15] vs 14.3% [1/7]); A4/T (18.9% [7/37] vs 4.5% [1/22]). Results at Month 12 for CFT/CFT and PBO/CFT were: LH (64.7% [11/17], 44.4% [4/9]); FSH (35.7% [5/14], 14.3% [1/7]); A4/T (23.5% [8/34], 23.8% [5/21]). The percentage of female participants achieving normal levels at Week 24 with crinecerfont versus placebo were as follows: T (10.7% [3/28] vs 0% [0/11]; P4 (13.5% [5/37] vs 5.9% [1/17]). Results at Month 12 for CFT/CFT and PBO/CFT were: T (3.7% [1/27], 9.1% [1/11]); P4 (8.6% [3/35], 18.8% [3/16]). Conclusion: Crinecerfont has previously been shown to substantially reduce ACTH, adrenal androgens, and androgen precursors in phase 2 and/or phase 3 studies with pediatric and adult patients with CAH. These analyses from the CAHtalyst Adult study indicate that normalization of reproductive hormones could also be achieved with crinecerfont, even in the context of substantial GC dose reductions. CRF1 antagonism may be a promising therapeutic approach for improving reproductive hormones in adults with CAH. Presentation: Sunday, July 13, 2025