SAT-418 Crinecerfont Allows for More Physiologic Glucocorticoid Treatment With Reduction of Androstenedione to a Normal Range in Pediatric Patients With Classic Congenital Adrenal Hyperplasia: Post Hoc Analysis of the CAHtalyst™ Pediatric Study

Abstract Disclosure: M. Lodish: Consultant for Neurocrine Biosciences, Inc. P.Y. Fechner: Research supportfrom Neurocrine Bioscience, Spruce Bioscience, and Diurnal UK Ltd and have served on an advisory board as a consultant for Neurocrine Bioscience. L.N. Trinh: None. M.S. Kim: Receives research funding from Neurocrine Biosciences, Spruce Biosciences, Adrenas Therapeutics, Diurnal, Serves on advisory boards for Eton Pharmaceuticals, Neurocrine Biosciences, Serves on steering committee for Spruce Biosciences, Receives royalties from UpToDate. M. Bettendorf: None. M. Salerno: None. M.T. Dattani: Received lecturing fees from Meck Serono, Pfizer, Novo Nordisk, Sandoz; served on advisory Boards for Pfizer, Novo Nordisk; consulted for: Sandoz, Pfizer, Besins. G.B. Rosales: Full-time employee of Neurocrine Biosciences, Inc. E. Roberts: Full-time employee of Neurocrine Biosciences, Inc. G.S. Jeha: Full-time employee of Neurocrine Biosciences, Inc. R.H. Farber: 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 androstenedione (A4), enabling subsequent GC dose reductions in pediatric and adult patients with CAH. Objective: To analyze changes in GC doses in conjunction with A4 levels in CAHtalystTM Pediatric (NCT04806451). Methods: Patients with CAH, ages 4-17 years, were randomized 2:1 to 28 weeks of double-blind treatment with crinecerfont (25, 50, or 100 mg BID based on weight) or placebo. GC doses were kept stable for the first 4 weeks to measure the impact on androgens and then reduced (if possible based on A4) to a target dose of 8-10 mg/m2/d in hydrocortisone equivalents (HCe) by Week 28 while maintaining or improving A4 relative to baseline (BL). Achievement of a daily GC dose ≤11 mg/m2/d (protocol-defined “physiologic” range) while A4 was maintained or improved was assessed at Week 28 (secondary endpoint, with nominal P-value). Since A4 could be higher than the upper limit of normal (>ULN) at BL (and thus possibly elevated at Week 28 despite being maintained), a post hoc quadrant analysis was conducted based on A4 normal range, with participants categorized at BL and Week 28 by GC dose (≤11 mg/m2/d or >11 mg/m2/d [“supraphysiologic” range]) and A4 (≤ULN or >ULN). Results: All participants were taking supraphysiologic GC doses at BL per study inclusion criteria (GC >12 mg/m2/d HCe). At Week 28, 30% (20/67) achieved GC ≤11 mg/m2/d with crinecerfont while maintaining or improving A4, compared to no participants (0/31) with placebo (P=0.0009). In the post hoc quadrant analysis, most participants had A4 >ULN at BL: crinecerfont 83% (55/66); placebo 81% (25/31). At Week 28, 36% (24/66) of crinecerfont-treated participants achieved GC ≤11 mg/m2/d; of these, 50% (12/24) also had A4 ≤ULN. In contrast, no participants in the placebo group were taking GC ≤11 mg/m2/d at Week 28, and 68% (21/31) had A4 >ULN despite supraphysiologic GC dosing. Conclusion: In the 28-week CAHtalyst Pediatric study, 30% of participants receiving crinecerfont achieved a physiologic GC dose (≤11 mg/m2/d HCe) while maintaining or improving A4. Post hoc analyses showed 36% achieved a physiologic GC dose with crinecerfont regardless of A4 level; of these, 50% had normal A4. In contrast, no participants achieved a physiologic GC dose with placebo, and 68% had elevated A4 despite supraphysiologic GC dosing. Given the known adverse effects of elevated androgens and chronic supraphysiologic GC treatment, crinecerfont represents a therapeutic approach in which the dual goals of reducing androgen excess and decreasing GC to a more physiologic range can be achieved. Presentation: Saturday, July 12, 2025