SUN-415 Crinecerfont Maintains Serum Androstenedione 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: Research with Neurocrine Biosciences/Neurocrine UK, LTD, Spruce Biosciences, Corcept Therapeutics, Crinetics Pharmaceuticals, Recordati Rare Diseases, Adrenas Therapeutics, and Mineralys Pharmaceutics, Consultant for Quest Diagnostics, Corcept Therapeutics, Xeris Pharmaceuticals, Crinetics Pharmaceuticals, Novo Nordisk, Neurocrine Biosciences/Neurocrine UK, LTD, and Recordati Rare Diseases, Consultant for 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). 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 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 A4 levels and GC doses 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 serum A4 (after morning GC dose) were analyzed after stable GC dosing (Week 4, Month 7) and at end of DBPC and OL (Week 24, Month 12). Changes in GC dose were analyzed at Week 24 and Month 12. Decreases in GC dose were set to zero if A4 was not maintained/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 338 ng/dL (crinecerfont) and 370 ng/dL (placebo); mean GC dose was 17.5 mg/m2/d (32.4 mg/d) (crinecerfont) and 17.9 mg/m2/d (32.1 mg/d) (placebo). In the DBPC period, an LS mean decrease from BL at Week 4 in A4 was found with crinecerfont but not placebo (-299 vs +45.5 ng/dL; LSMD 345 ng/dL, 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), A4 was maintained below BL with crinecerfont but not placebo (-16.8 vs +190 ng/dL). In the OL period, mean A4 in the CFT/CFT group was maintained near BL at Month 7 (+17.2 ng/dL) and after GC dose reduction at Month 12 (+53.6 ng/dL). In the PBO/CFT group, mean A4 decreased from BL at Month 7 (-54.9 ng/dL) and Month 12 (-3.6 ng/dL). For GC dose, mean changes and mean percent changes at Month 12 were as follows: CFT/CFT (-4.3 mg/m2/d, -24.6%); PBO/CFT (-5.8 mg/m2/d, -29.7%). Moreover, 48.2% (CFT/CFT) and 58.9% (PBO/CFT) achieved a GC dose ≤11 mg/m2/d while maintaining/improving A4. Conclusion: In adults with CAH, substantial reductions in A4 and in GC doses were observed with crinecerfont in the DBPC period. By the end of OL treatment, A4 was maintained or improved even in the context of lower, more physiologic GC doses. Thus, crinecerfont not only reduces androgen excess; by enabling GC doses to be lowered, crinecerfont can also reduce the adverse effects of chronic supraphysiologic GC exposure. Presentation: Sunday, July 13, 2025