MON-458 Crinecerfont Allows for More Physiologic Glucocorticoid Dosing Regimens in Patients With Classic Congenital Adrenal Hyperplasia: Results from the Phase 3 CAHtalyst™ Adult and CAHtalystTM Pediatric Studies

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Abstract Disclosure: N. Nokoff: Consultant for Neurocrine Biosciences, Inc.; expert panel member for World Athletics. K.B. Krishna: None. L. Antonio: Sandoz, Merck, Advisory board member for Simple Pharma. R.H. Farber: Full-time employee of Neurocrine Biosciences, Inc. J.L. Chan: Full-time employee of Neurocrine Biosciences, Inc. J. Sturgeon: Full-time employee of Neurocrine Biosciences, Inc. G.B. Rosales: Full-time employee of Neurocrine Biosciences, Inc. G.S. Jeha: Full-time employee of Neurocrine Biosciences, Inc. V.H. Lin: Full-time employee of Neurocrine Biosciences, Inc. A.N. Dauber: Consultant and grant recipient for BioMarin and Pfizer; consultant for Novo Nordisk and QED Therapeutics. Background: Crinecerfont, a corticotropin releasing factor type 1 receptor (CRF1) antagonist, is a first-in-class medication that is FDA-approved for 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 adrenal androgens, enabling reductions in GC doses in pediatric and adult patients with CAH. Objective: To evaluate changes in GC regimens in patients with CAH treated with crinecerfont. Methods: Individuals with CAH were randomized to crinecerfont (25, 50, or 100 mg BID in CAHtalyst™ Pediatric [NCT04806451]; 100 mg BID in CAHtalyst Adult [NCT04490915]) or placebo. In both studies, GC was kept stable for the first 4 weeks to measure the impact on androgens and then reduced to a target of 8-10 mg/m2/d in hydrocortisone (HC) equivalents at the end of double-blind treatment (Week 28 [pediatric]; Week 24 [adult]) while maintaining or improving androstenedione (A4) relative to baseline (BL). Long-acting, synthetic GCs (dexamethasone [DEX], (methyl)prednis(ol)one [PRED]) and timing (bedtime dose) were to be decreased first. Changes in dosing frequency and GC regimens (switching from with PRED or DEX to without PRED or DEX) were evaluated with nominal P-values. Fludrocortisone was continued as needed. Results: In CAHtalyst Pediatric (N=103), mean GC dose at BL was 16.4 mg/m2/d; 92.2% were taking only HC (no DEX or PRED). Percent changes in GC dose at Week 28 while maintaining/improving A4 showed a decrease with crinecerfont but not placebo (least squares mean difference [LSMD]: -23.5%; P<0.0001 [key secondary endpoint]). In participants taking only HC at BL, reduction in dosing frequency by ≥1 dose/d at Week 28 was more common with crinecerfont (16.1% vs 3.6%; P=0.1087). In CAHtalyst Adult (N=182), mean GC dose at BL was 17.6 mg/m2/d (32.3 mg/d) and 58.2% were taking only HC; 29.1% were taking PRED±HC and 12.6% were taking DEX (±another GC). At Week 24, the percent reduction in GC dose while maintaining/improving A4 was greater with crinecerfont than placebo (LSMD: -17.0%; P<0.0001 [primary endpoint]). In participants taking only HC at BL, reduction in dosing frequency was more common with crinecerfont than placebo (36.5% vs 12.5%; P=0.0253). Switching from a DEX-containing regimen at BL to a DEX-free regimen at Week 24 was more common with crinecerfont (87.5% vs 40.0%; P=0.0740), as was switching from PRED±HC to HC only (32.4% vs 10.5%; P=0.0418). Conclusion: Patients with CAH who received crinecerfont for ∼6 months had greater mean decreases in GC doses while maintaining or improving A4 compared to placebo. HC dosing frequency was more likely to decrease with crinecerfont, as was switching to DEX- and PRED-free regimens. These changes reduce the CAH treatment burden and may decrease the risk of adverse effects of chronic treatment with synthetic GCs. Presentation: Monday, July 14, 2025

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