ESPE2024 Free Communications Adrenals and HPA Axis 1 (6 abstracts)
Crinecerfont, a Corticotropin-Releasing Factor Type 1 Receptor (CRF1) Antagonist, Reduced Excess Adrenal Androgens and Glucocorticoid Doses in Children and Adolescents with Classic Congenital Adrenal Hyperplasia: Results from CAHtalystTM Pediatric
Kyriakie Sarafoglou 1 , Mimi S. Kim 2 , Maya Lodish 3 , Eric I. Felner 4 , Laetitia Martinerie 5 , Natalie J. Nokoff 6 , Maria Clemente 7 , Patricia Y. Fechner 8 , Maria G. Vogiatzi 9 , Phyllis W. Speiser 10,11 , Gelliza B.G. Rosales 12 , Eiry Roberts 12 , George S. Jeha 12 , Robert Farber 12 & Jean L. Chan 12
1University of Minnesota Medical School and College of Pharmacy, Minneapolis, USA. 2Children’s Hospital Los Angeles, Keck School of Medicine of USC, Los Angeles, USA. 3University of California San Francisco, Benioff Children’s Hospital, San Francisco, USA. 4Emory University School of Medicine and Children’s Healthcare of Atlanta (CHOA), Atlanta, USA. 5Hôpital Universitaire Robert Debré, AP-HP, Université Paris Cité, Paris, France. 6University of Colorado School of Medicine, Children’s Hospital Colorado, Aurora, USA. 7University Hospital Vall d'Hebrón, Barcelona, Spain. 8University of Washington School of Medicine, Seattle Children’s Hospital, Seattle, USA. 9The Children’s Hospital of Philadelphia, Philadelphia, USA. 10Cohen Children's Medical Center of NY, New Hyde Park, USA. 11Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, USA. 12Neurocrine Biosciences, Inc., San Diego, USA
Introduction: Children with classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency (CAH) require glucocorticoid (GC) therapy to replace cortisol insufficiency and reduce excess adrenal androgens. Supraphysiological GC doses are typically required, predisposing patients to GC-related comorbidities. In Phase 2 studies, participants with CAH who received crinecerfont, a novel oral CRF1 antagonist, experienced reduction of the adrenal androgen androstenedione. This multinational Phase 3 study (CAHtalyst Pediatric) evaluated whether crinecerfont can reduce androstenedione levels and supraphysiologic GC doses in pediatric patients with CAH.
Methods: Children and adolescents (4-17yrs) with CAH who had stable GC doses >12 mg/m2/d in hydrocortisone equivalents (HCe), androstenedione higher than the midpoint of reference range, and 17 hydroxyprogesterone (17 OHP) >2x upper limit of normal (ULN) were randomized (2:1) to crinecerfont (25, 50, or 100 mg BID based on weight) or placebo. GC dosing was maintained stable for 4wks and then reduced to a target of 8-10 mg/m2/d over 24wks if androstenedione was controlled (≤120% of baseline or ≤ULN).
Results: In 103 randomized participants (69 crinecerfont, 34 placebo), >95% completed 28-wk treatment. Mean±SD baseline GC dose was 16.4±3.9 mg/m2/d HCe, with elevated mean androstenedione (15.0±16.1nmol/L) and 17-OHP (263.1±207.5nmol/L). At Wk4 (end of GC-stable period), crinecerfont led to substantial least-squares (LS) mean±SEM reductions in both androstenedione (-6.9±1.4nmol/L) and 17-OHP (-177.7±17.3nmol/L), compared to increases with placebo (+2.5±2.0nmol/L; LS mean difference [LSMD: -9.3; P = 0.0002] and +16.9±24.8nmol/L [LSMD: -194.6; P <0.0001], respectively). At Wk28, there was greater GC dose reduction while maintaining androstenedione control with crinecerfont (-18±2% [-3.1±0.4 mg/m2/d]) compared to increases with placebo (+6±3% [+0.9±0.3 mg/m2/d; LSMD: -24%; P <0.0001]), and 30% of crinecerfont-treated participants achieved physiologic GC doses (≤11 mg/m2/d) while maintaining androstenedione control, vs 0% on placebo (nominal P = 0.0009). In post-hoc analyses, crinecerfont-treated participants who did not reach physiologic GC had a mean GC reduction of -2.3±0.5 mg/m2/d. Moreover, 57% of crinecerfont-treated participants had a GC reduction to physiologic dose or decrease of ≥2.5 mg/m2/d at Wk28 (with androstenedione control), vs 3% for placebo (nominal P <0.0001).
Conclusion: Crinecerfont, a novel oral CRF1 antagonist, represents a potential treatment option to improve androgen control and reduce supraphysiologic GC dose in pediatric patients with classic CAH. In the largest interventional Phase 3 study conducted to date in CAH, crinecerfont-treated participants experienced decreases in androstenedione and 17-OHP during an initial GC-stable period, enabling a significant reduction of supraphysiologic GC doses by 28wks while maintaining androstenedione control.
Article tools
My recent searches
My recently viewed abstracts
Authors
ESPE Abstracts
© Bioscientifica 2024 |
Privacy policy |
Cookie settings
BiosciAbstracts
Bioscientifica Abstracts is the gateway to a series of products that provide a permanent, citable record of abstracts for biomedical and life science conferences.
Find out more