Crinecerfont Reduces GC Dosing, Improves Androstenedione Levels Across Multiple Pediatric Subgroups
Data for GC reduction and improved A4 levels were consistent across subgroups stratified by sex, race, age, BMI, and baseline A4 levels, according to Neurocrine Biosciences.
Crinecerfont (Crenessity; Neurocrine Biosciences), a corticotropin-releasing factor type 1 receptor (CRF1) antagonist, consistently reduced glucocorticoid (GC) dosing while maintaining or improving androstenedione (A4) levels across all patient subgroups in the phase 3 CAHtalyst Pediatric study for classic congenital adrenal hyperplasia (CAH).1
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The subgroup analyses, presented at the 2025 Joint Congress of the European Society for Paediatric Endocrinology and the European Society of Endocrinology, demonstrated that these benefits occurred regardless of demographic characteristics, baseline A4 levels, or baseline GC dose, according to a Neurocrine statement.2
The CAHtalyst Pediatric study enrolled 103 patients aged 4-17 years with classic CAH, and randomly assigned them to receive either crinecerfont (n = 69) or placebo (n = 34) for 28 weeks. The trial measured 2 key outcomes: change in A4 levels at week 4 as the primary endpoint and GC dose reduction at week 28 as a secondary endpoint.1
Results showed that crinecerfont significantly reduced A4 levels from baseline compared with placebo (overall, -6.9 versus +2.5 nmol/L; least-squares mean difference: -9.3 nmol/L; P =.002). Investigators also reported significant reductions from baseline in GC doses with crinecerfont compared with placebo (overall, -18.0% versus +5.6%; LSMD: -23.5%; P <.001).1
The researchers conducted comprehensive subgroup analyses across multiple patient characteristics, including geographic region, sex, race, age, body mass index, pubertal stage, baseline A4 levels, weight, and baseline GC dose. The treatment effects remained consistent across all these subgroups, suggesting broad applicability of the therapy, according to Neurocrine.2
"High-dose steroids are often accompanied by side effects and complications," Eiry W Roberts, MD, Neurocrine chief medical officer said in the statement. "By enabling patients to maintain or improve their androgen levels while reducing their reliance on high-dose glucocorticoids, [crinecerfont] has the potential to meaningfully enhance long-term outcomes."2
CAH results from genetic variants that cause enzyme deficiencies, primarily of 21-hydroxylase deficiency, leading to cortisol deficiency and excess androgen production. The overproduction of androgens like A4 can cause abnormal growth and development, premature puberty, and various developmental challenges in children.3
Traditional treatment has relied solely on GCs, often at supraphysiologic doses, to suppress adrenocorticotropin hormone (ACTH) and reduce androgen production. However, long-term high-dose GC therapy carries risks of significant complications, including metabolic disorders, cardiovascular disease, osteoporosis, and psychological and cognitive impacts.4
By suppressing CRF1 crinecerfont reduces ACTH levels, subsequently reducing adrenal androgen production without directly using GCs. Lower, more physiologic dosing of GCs can then be administered for cortisol replacement.4
The medication was generally well tolerated in the study. The most common adverse reactions (≥4% for crinecerfont and greater than placebo) were headache, abdominal pain, fatigue, nasal congestion, and nosebleed.1
Crinecerfont received FDA approval in December 2024 and is available in capsule formulation (50 mg and 100 mg doses) and as an oral solution (50 mg/mL). For pediatric patients aged 4-17 years weighing less than 55 kg, dosing is weight-based and administered twice daily with meals. For those weighing more than 55 kg, the recommended dosage matches the adult dose of 100 mg twice daily.5
Importantly, patients receiving crinecerfont must continue glucocorticoid therapy for cortisol replacement, as the drug does not address the underlying cortisol deficiency characteristic of CAH.5
The CAHtalyst Phase 3 program represents the largest interventional clinical trial program ever conducted in classic CAH, including 285 pediatric and adult patients. Open-label extension portions of the studies are ongoing.2
