Study of a corticotropin releasing factor-1 receptor antagonist for the treatment of congenital adrenal hyperplasia

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Abstract

Excess glucocorticoid therapy is often needed to control the overproduction of adrenal androgens in congenital adrenal hyperplasia, a genetic disease of steroidogenesis. High-affinity and selective small-molecule antagonists of CRF type 1 receptors in the pituitary gland might allow for lower glucocorticoid therapy. The mechanism of action has been validated in a previous proof-of-concept study and has been shown to be safe in Phase 1 clinical studies in healthy volunteers and Phase 2 dose finding studies of patients with CAH. In Phase 2 studies, patients with poor disease control at baseline had reductions in biomarkers; while patients with good disease control at baseline showed only minor changes. A 6-month randomized, double-blind, placebo-controlled study was completed in 2024. At week 4, prior to changes in glucocorticoid dose, serum biomarkers of androgen levels decreased with CRF-1 antagonist therapy, but increased with placebo (P<0.001). The primary efficacy end point was the percent change in the daily glucocorticoid dose from baseline to week 24 with maintenance of disease control based on serum biomarker androstenedione. At week 24, the change in the glucocorticoid dose (with disease control) was −27.3% in the CRF-1 antagonist group and −10.3% in the placebo group (P<0.001). A physiologic glucocorticoid dose (with disease control) was reported in 63% of the patients in the CRF-1 antagonist group and in 18% in the placebo group (P<0.001). An extension study is underway. This study represents a novel therapy in the treatment of congenital adrenal hyperplasia. Long-term findings will be key.