7317 CAHtalyst Pediatric: Results From The Randomized, Double-Blind, Placebo-Controlled Period Of A Phase 3 Trial Of Crinecerfont, A Corticotropin-Releasing Factor Type 1 Receptor Antagonist, In Children And Adolescents With Classic Congenital Adrena

Abstract Disclosure: K. Sarafoglou: Consulting Fee; Self; Neurocrine Biosciences, Inc., Crinetics Pharmaceuticals, Eton Pharmaceuticals, Spruce Biosciences. Research Investigator; Self; Neurocrine Biosciences, Inc., Adrenas Therapeutics, Spruce Biosciences. M.S. Kim: Advisory Board Member; Self; Spruce Biosciences. Research Investigator; Self; Neurocrine Biosciences, Inc., Diurnal, Spruce Biosciences. M. Lodish: None. E.I. Felner: None. L. Martinerie: None. N.J. Nokoff: Advisory Board Member; Self; World Athletics. Consulting Fee; Self; Ionis Pharmaceuticals Inc., Neurocrine Biosciences, Inc. M. Clemente: Consulting Fee; Self; AstraZeneca, Boehringer Ingelheim, Eli Lilly & Company, Novo Nordisk. Research Investigator; Self; Eli Lilly & Company, Novo Nordisk. P.Y. Fechner: Consulting Fee; Self; Neurocrine Biosciences, Inc., Eton Pharmaceuticals. Research Investigator; Self; Neurocrine Biosciences, Inc., Diurnal, Spruce Biosciences. M.G. Vogiatzi: Consulting Fee; Self; Adrenas Therapeutics, Eton Pharmaceuticals. Research Investigator; Self; Neurocrine Biosciences, Inc., Spruce Biosciences. P.W. Speiser: Advisory Board Member; Self; Adrenas Therapeutics, Chan Zuckerberg's Rare as One Initiative. Consulting Fee; Self; Roche Diagnostics. Research Investigator; Self; Neurocrine Biosciences, Inc.. Speaker; Self; Medscape, Wolters Kluter Publishing. J. Sturgeon: Employee; Self; Neurocrine Biosciences, Inc. E. Roberts: Employee; Self; Neurocrine Biosciences, Inc. G.S. Jeha: Employee; Self; Neurocrine Biosciences, Inc. J.L. Chan: Employee; Self; Neurocrine Biosciences, Inc. R. Farber: Employee; Self; Neurocrine Biosciences, Inc.. Introduction: Classic congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21OHD), a genetic disorder characterized by cortisol deficiency and excess adrenal androgens, typically requires management with supraphysiological glucocorticoid (GC) doses. Crinecerfont is a novel oral CRF1 antagonist that reduced elevated ACTH and adrenal androgens in patients with 21OHD in 14-day, open-label Phase 2 studies. This Phase 3 study (CAHtalyst Pediatric: NCT04806451) evaluated whether crinecerfont can reduce androstenedione (A4) levels and supraphysiological GC doses in pediatric patients with 21OHD. Methods: Children and adolescents (2-17 yrs) with classic 21OHD, stable GC regimens at doses >12 mg/m2/d in hydrocortisone equivalents (HCe), A4 >midpoint of reference range, and 17-hydroxyprogesterone (17-OHP) >2x upper limit of normal (ULN) were randomized (2:1) to either crinecerfont (25, 50, or 100 mg BID based on weight) or placebo for 28 weeks. GC dosing was maintained stable for 4 weeks and then reduced, if possible, based on A4 levels to achieve a dose of 8-10 mg/m2/d while maintaining A4 control (≤120% of baseline or ≤ULN) by week 28. Results: In the 103 randomized participants (53 male; mean [range] age: 12 [4-17] yrs), demographics and baseline characteristics were similar between treatment arms (69 crinecerfont, 34 placebo). Mean baseline GC dose was 16.4 mg/m2/d HCe (92% on HC alone, 8% on a predniso[lo]ne-containing regimen). Baseline A4 (mean±SD) was 431±461 ng/dL and 17-OHP was 8682±6847 ng/dL. Over 95% completed the double-blind treatment period. At week 4 (end of GC-stable period), crinecerfont led to greater reductions in A4 vs placebo (least squares mean difference [LSMD]: -268 ng/dL; p=0.0002) (primary endpoint) and 17-OHP (LSMD: -6421 ng/dL; p<0.0001) (key secondary endpoint). At week 28, the crinecerfont arm had a greater percent reduction in GC dose while maintaining A4 control, vs placebo (LSMD: -24%; p<0.0001) (key secondary endpoint). Moreover, 30% of participants on crinecerfont achieved a protocol-defined physiological GC dose (≤11 mg/m2/d) while maintaining A4 control, vs 0% on placebo (nominal p=0.0009). The most common treatment-emergent adverse events (AEs) in the crinecerfont arm were headache (25% vs 6% for placebo), pyrexia (23% vs 24%), and vomiting (15% vs 30%). There were few serious AEs (5% overall) with none assessed as related to study drug. Conclusions: Crinecerfont, an oral CRF1 antagonist, represents a novel treatment option to improve androgen control in pediatric patients with classic 21OHD. In the largest interventional Phase 3 study conducted to date in these patients, crinecerfont led to a significant decrease in A4 while the GC dose was stable, enabling a significant percent reduction of supraphysiological GC doses while maintaining A4 control by 28 weeks. Crinecerfont was well tolerated overall. Presentation: 6/2/2024