A phase 3 trial of crinecerfont, a corticotropin-releasing factor type 1 receptor antagonist, demonstrated significant reductions in androgen levels and glucocorticoid doses in pediatric patients with congenital adrenal hyperplasia.
Published in the New England Journal of Medicine, the multinational, randomized study enrolled 103 pediatric participants with congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency. Participants were assigned in a 2:1 ratio to receive crinecerfont or placebo for 28 weeks. Glucocorticoid doses were maintained for the first 4 weeks, followed by dose adjustments targeting 8.0 to 10.0 mg/m²/day in hydrocortisone dose equivalents, provided androstenedione levels remained controlled (defined as ≤120% of baseline or within the reference range).
At week 4, crinecerfont reduced androstenedione levels by a mean of -197 ng/dL (-6.9 nmol/L), while placebo showed an increase of +71 ng/dL (+2.5 nmol/L). The least-squares mean difference (LSMD) between groups was -268 ng/dL (-9.3 nmol/L; P<0.001). Additionally, 17-hydroxyprogesterone levels decreased significantly in the crinecerfont group (LSMD, -6421 ng/dL; P<0.001).
By week 28, the glucocorticoid dose in the crinecerfont group decreased by 18.0%, compared to a 5.6% increase in the placebo group (LSMD, -23.5 percentage points; P<0.001). Among crinecerfont-treated participants, 30% achieved a physiologic glucocorticoid dose (≤11.0 mg/m²/day) with maintained androstenedione control, compared to none in the placebo group. Overall, 57% of participants in the crinecerfont group experienced either a reduction to physiologic dosing or a glucocorticoid dose decrease greater than 2.5 mg/m²/day.
High adherence (97%) was reported, and the incidence of adverse events was similar between groups (84% in the crinecerfont group and 82% in the placebo group). The most common adverse events in the crinecerfont group included headache (25%), pyrexia (23%), and vomiting (14%). Serious adverse events were more frequent in the placebo group (12% vs. 1%). No adrenal crises were reported during the trial.
"The results of this trial showed that crinecerfont therapy reduced production of excess adrenal androgens, which allowed substantial and clinically meaningful reduction of glucocorticoid doses to more physiologic levels in pediatric participants with CAH," stated Kyriakie Sarafoglou, MD, et al.
This study highlights crinecerfont’s potential to address the long-standing challenge of balancing effective androgen suppression with minimizing glucocorticoid-related complications in CAH. While these findings suggest a shift in therapeutic strategies, further research is needed to evaluate long-term safety and efficacy.
The trial was funded by Neurocrine Biosciences and registered with ClinicalTrials.gov (NCT04806451). Full disclsoures can be found in the study.
