Endocrine Abstracts

Introduction: Classic congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21OHD) is a rare autosomal recessive disorder characterized by deficiency of cortisol and oftentimes aldosterone, with elevated adrenocorticotropic hormone (ACTH) and steroid precursors that are shunted toward excess androgen production. A phase 2 study of adults with classic 21OHD demonstrated that crinecerfont–an oral, non-steroidal, selective corticotropin-releasing factor type 1 (CRF₁) receptor antagonist–substantially reduced elevated hormone markers after 14 days of treatment. The current study evaluated the effect of crinecerfont in adolescents with classic 21OHD, a population that may be especially challenging to manage due to the hormonal changes associated with puberty.

Methods: Eligible adolescents (14–17 years of age) with classic 21OHD received open-label crinecerfont (50 mg BID) for 14 days. Plasma ACTH and serum 17-hydroxyprogesterone (17OHP), androstenedione, and testosterone were assessed over 24 hours before (baseline) and after 14 days of crinecerfont treatment. For each participant, morning window values were calculated by averaging the samples collected at 0700h and 1000h (before morning glucocorticoid dose). Participants’ glucocorticoid and fludrocortisone regimens were maintained during crinecerfont treatment.

Results: Eight participants (3 males, 5 females, ages 14-16 years) were included for analyses. At baseline, median morning window hormone concentrations were as follows: ACTH (226.2 pg/mL); 17OHP (7703.7 ng/dL); androstenedione (367.9 ng/dL); and in females, testosterone (63.5 ng/dL). At Day 14, median percent reductions in these parameters were as follows: ACTH (-57.1%); 17OHP (-69.5%); androstenedione ( 58.3%); and in females, testosterone (-76.2%). A≥50% reduction from baseline to Day 14 in ACTH, 17OHP, and androstenedione was observed in 62.5%, 75.0%, and 50.0% of participants, respectively. Furthermore, 67% (2/3) of males with elevated androstenedione/testosterone ratios (≥0.5) at baseline achieved normal ratios (<0.5) at Day 14. Twelve treatment-emergent adverse events (TEAEs) were reported, with the most common being headache (n=2). Per investigator judgement, all TEAEs were mild and the majority were unrelated to study treatment. There were no serious AEs, discontinuations due to AEs, or safety concerns related to routine laboratory tests, vital signs, or electrocardiograms.

Conclusions: In adolescents with classic 21OHD, substantial median reductions (57-76%) in adrenal androgens and androgen precursors were observed after 14 days of crinecerfont treatment, consistent with results from a similar study of adults with classic 21OHD. Further studies are warranted to evaluate whether longer-term treatment with crinecerfont can allow for lower, more physiologic glucocorticoid dosing, consequently improving clinical outcomes such as weight, metabolic risk, growth/development, and fertility.