Abstract
Disclosure: 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. S.A. Imran: None. A.M. Isidori: Research funding from Corcept, Recordati Rare Diseases Pharma, Pzifer, Principal Investigator for Neurocrine Biosciences, Inc, Crinetics Pharma. H. Falhammar: None. N. Reisch: Consulted for Neurocrine Biosciences, Inc., Spruce Biosciences, H Lundbeck A/S, Crinetics Pharmaceuticals and Diurnal Limited. P. Rodien: None. R.H. Farber: Full-time employee of Neurocrine Biosciences, Inc. J. Sturgeon: Full-time employee of Neurocrine Biosciences, Inc. V.H. Lin: 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 (CRF(1)) 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 classic CAH. Objective: To analyze changes in GC doses in conjunction with A4 levels in CAHtalyst™ Adult (NCT04490915). Methods: Adults with CAH were randomized 2:1 to 24 weeks of double-blind treatment with crinecerfont (100 mg BID) or placebo. GC doses were kept stable for the first 4 weeks to measure the impact on androgens, followed by a planned GC down-titration over 8 weeks to achieve a target dose of 8-10 mg/m(2)/d in hydrocortisone equivalents (HCe). GC doses were then adjusted as needed over 12 weeks to maintain or improve A4 relative to baseline (BL). Achievement of a daily GC dose ≤11 mg/m(2)/d (protocol-defined “physiologic” range) while A4 was maintained/improved was assessed at Wk24 (key secondary endpoint). Since A4 could be higher than the upper limit of normal (>ULN) at BL (thus possibly elevated at Wk24 despite being maintained), a post hoc quadrant analysis was conducted based on GC dose and A4 normal range, with participants categorized at BL and Wk24 by GC dose (≤11 mg/m(2)/d or >11 mg/m(2)/d [“supraphysiologic” range]) and A4 (≤ULN or >ULN). Results: All participants were taking supraphysiologic GC doses at BL per study inclusion criteria (GC >13 mg/m(2)/d HCe). At Wk24, a higher percentage of participants achieved GC ≤11 mg/m(2)/d while maintaining/improving A4 with crinecerfont (63% [74/118] vs 18% [10/57] for placebo, P<0.0001). In the post hoc quadrant analysis, 50% had A4 >ULN at BL: crinecerfont 51% (60/118); placebo 49% (28/57). At Wk24, 82% (97/118) of crinecerfont-treated participants achieved GC ≤11 mg/m(2)/d regardless of A4 level; of these, 53% (51/97) had A4 ≤ULN. With placebo, 37% (21/57) were taking GC ≤11 mg/m(2)/d at Wk24; of these, 43% (9/21) had A4 ≤ULN. Moreover, 49% (28/57) of placebo-treated participants had A4 >ULN despite supraphysiologic GC dosing vs 11% (13/118) with crinecerfont. Conclusion: In CAHtalyst Adult, 63% of participants taking crinecerfont achieved a physiologic GC dose (≤11 mg/m(2)/d HCe) at Wk24 while maintaining/improving A4. Post hoc analyses showed 82% achieved a physiologic GC dose with crinecerfont regardless of A4 level; of these, 53% had normal A4. In contrast, 37% achieved a physiologic GC dose with placebo, and 49% had elevated A4 despite supraphysiologic GC dosing. Given the known adverse effects of elevated androgens and chronic supraphysiologic GC exposure, crinecerfont represents a therapeutic approach where the dual goals of reducing androgen excess and decreasing GC to a more physiologic range can be achieved. Presentation: Saturday, July 12, 2025