MON-466 Crinecerfont Enables Reduction of Glucocorticoid Doses While Maintaining or Improving Androstenedione in Adults with Classic Congenital Adrenal Hyperplasia: Subgroup Analyses From the Phase 3 CAHtalyst™ Adult Study

Abstract Disclosure: D.P. Merke: Research funding from Diurnal Limited, Neurocrine Biosciences, Inc., and Adrenas Therapeutics, and the National Institutes of Health Cooperative Research and Development Agreements, Received royalties from UpToDate for writing and editing. E.A. Imel: Consulting and clinical trial research funds from Neurocrine Biosciences, Inc., Clinical trial research funds from Spruce Biosciences. A. German: None. H. Falhammar: None. N. Reisch: Consulted for Neurocrine Biosciences, Inc., Spruce Biosciences, H Lundbeck A/S, Crinetics Pharmaceuticals and Diurnal Limited. L. Keener: None. J. Sturgeon: Full-time employee of Neurocrine Biosciences, Inc. J.L. Chan: Full-time employee of Neurocrine Biosciences, Inc. R.H. Farber: 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 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 GC dose reduction in pediatric and adult patients with CAH. Objective: To analyze changes in androstenedione (A4) and reductions in GC doses while maintaining or improving A4 in subgroups of participants from the CAHtalyst™ Adult study (NCT04490915). Methods: Participants were randomized 2:1 to crinecerfont 100 mg BID or placebo for 24 weeks. GC doses were kept stable for 4 weeks to evaluate the impact on androgens, followed by a planned GC down-titration over 8 weeks to a target of 8-10 mg/m2/d in hydrocortisone (HC) equivalents. GC doses were then adjusted as needed during the last 12 weeks to achieve the lowest GC dose while maintaining or improving A4 relative to baseline (BL). Changes from BL in A4 at Week 4 and in GC dose at Week 24 were analyzed in the overall population and in subgroups categorized by: region (US, outside US), sex (male, female), body mass index (<30, ≥30 kg/m2); race (white, non-white); BL dexamethasone (yes, no); BL GC regimen (HC alone, synthetic GCs); BL GC dose (<20, ≥20 mg/m2/d HC equivalents); and BL A4 (≤ULN [upper limit of normal], >ULN; evaluated for A4 change only). Results: In 182 randomized participants (crinecerfont, n=122; placebo, n=60), mean A4 at BL was 620±729 ng/dL; mean GC dose was 17.6±4.9 mg/m2/d (32.3±9.3 mg/d). Least-squares (LS) mean changes at Week 4 indicated significant A4 reduction with crinecerfont but not placebo (-299 vs +45.5 ng/dL; LS mean difference [LSMD]: -345 ng/dL; p<0.0001 [key secondary endpoint]). LSMDs of the point estimates for A4 change at Week 4 favored crinecerfont over placebo in all subgroups; treatment difference for A4 change was lower in the BL A4 ≤ULN subgroup, as these participants were already in the normal range. At Week 24, LS mean percent changes in GC dose indicated significantly greater reduction with crinecerfont (while maintaining/improving A4) than with placebo (-27.3% vs -10.3%; LSMD: -17.0%; p<0.0001 [primary endpoint]). LSMDs of the point estimates for GC dose percent change at Week 24 favored crinecerfont over placebo in all subgroups. For both A4 and GC, subgroup analyses were consistent with the primary and key secondary endpoint results in the overall population. Conclusions: Crinecerfont was effective in enabling GC dose reductions while maintaining or improving A4 in adults with CAH across all subgroups analyzed. These results demonstrate that adults with CAH can derive the androgen-lowering and GC-lowering benefits of crinecerfont treatment regardless of sex, race, BMI, or pre-treatment A4 levels, GC dose, or GC regimen. Presentation: Monday, July 14, 2025