ESPE2023 Free Communications Adrenals and HPA Axis (6 abstracts)
Response to Crinecerfont Treatment in Adolescents with Classic Congenital Adrenal Hyperplasia Is Correlated with Elevated Baseline Hormone Concentrations but Not Glucocorticoid Dose
Ron S. Newfield 1,2 , Kyriakie Sarafoglou 3 , Patricia Y. Fechner 4,5 , Natalie J. Nokoff 6,7 , Richard J. Auchus 8 , Maria G. Vogiatzi 9 , George S. Jeha 10 , Nagdeep Giri 10 , Eiry Roberts 10 , Julia Sturgeon 10 , Jean L. Chan 10 & Robert H. Farber 10
1University of California San Diego, San Diego, USA. 2Rady Children's Hospital, San Diego, USA. 3University of Minnesota Medical School, Minneapolis, USA. 4University of Washington School of Medicine, Seattle, USA. 5Seattle Children's, Seattle, USA. 6University of Colorado Anschutz Medical Campus, Aurora, USA. 7Children's Hospital Colorado, Aurora, USA. 8University of Michigan Medical School, Ann Arbor, USA. 9The Children’s Hospital of Philadelphia, Philadelphia, USA. 10Neurocrine Biosciences, Inc., San Diego, USA
Introduction: Classic congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21OHD) is a rare, autosomal disorder characterized by deficiency of cortisol and oftentimes aldosterone, elevated adrenocorticotropic hormone (ACTH), and excess androgen production. In a phase 2 study of adolescents with classic 21OHD, 14 days of treatment with the corticotropin-releasing factor type 1 receptor (CRF1) antagonist, crinecerfont, led to median percent reductions of 69% for 17-hydroxyprogesterone (17OHP), 57% for ACTH, and 58% for androstenedione (A4). Post hoc analyses were conducted to assess whether baseline hormone concentrations and glucocorticoid (GC) dose correlated with treatment response.
Methods: Adolescent males and females with 21OHD and elevated 17OHP concentrations (≥800 ng/dL) received open-label crinecerfont 50 mg twice daily for 14 days. Participants’ glucocorticoid and fludrocortisone regimens were maintained stable prior to and during crinecerfont treatment. Pearson correlations between baseline ACTH, 17OHP, A4, and GC dose against the magnitude of change from baseline (CFB) to Day 14 hormone concentrations were assessed using the average value of samples collected during the morning window (0700h and 1000h, before the morning GC dose) as well as the average over the full 24-hour sampling period.
Results: Eight participants (3 males, 5 females; mean age, 15 years [range, 14-16 years]) were enrolled and included for analysis. Baseline GC regimens were hydrocortisone alone (n=6) or prednisone alone (n=2), with median total daily dose (in hydrocortisone equivalents) of 16.2 mg/m2/day (range, 11.9-18.5 mg/m2/day). A significant negative correlation was found between baseline concentration and CFB to Day 14 for 17OHP (morning window, r=-0.876 [P=0.004]; 24-hour average, r= -0.904 [P=0.002]), with the greatest reductions from baseline in 17OHP observed in participants with the highest baseline concentrations. Similar relationships were observed for ACTH (morning window, r= -0.949 [P<0.001]; 24-hour average, r= -0.988 [P<0.001]) and A4 (morning window, r= -0.781 [P=0.022]; 24-hour average, r= -0.789 [P=0.020]). No correlation was found between baseline GC dose and CFB to Day 14 for 17OHP (morning window, r= 0.007 [P=0.987]; 24-hour average, r= -0.038 [P=0.929]), ACTH (morning window, r= -0.057 [P=0.893]; 24-hour average, r= -0.177 [P=0.674]), or A4 (morning window, r= -0.286 [P=0.492]; 24-hour average, r= -0.290 [P=0.486]).
Conclusions: In adolescents with 21OHD CAH treated with crinecerfont, there was a strong correlation between treatment response and baseline hormone concentration, but not with baseline GC dose. These data suggest that higher baseline hormone concentrations (i.e., worse disease control) predict greater response in children with 21OHD, and that androgen reduction might occur across a broad range of GC doses in this population.
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