Neurocrine Biosciences has announced promising results from subgroup analyses of its Phase 3 CAHtalyst pediatric study evaluating crinecerfont (CRENESSITY) in children with classic congenital adrenal hyperplasia (CAH). The data, presented at the 2025 Joint Congress of the European Society for Paediatric Endocrinology and the European Society of Endocrinology in Copenhagen, Denmark, showed consistent benefits across all patient subgroups.
The study demonstrated that pediatric patients receiving crinecerfont could maintain or improve their androstenedione (A4) levels while simultaneously reducing their glucocorticoid (GC) doses. These benefits were observed regardless of geographic region, sex, race, age, body mass index, pubertal stage, baseline A4 levels, weight, or baseline GC dose.
Understanding Congenital Adrenal Hyperplasia
CAH is a rare genetic disorder affecting approximately 1 in 15,000 births worldwide. In about 95% of cases, it results from mutations in the CYP21A2 gene, leading to a deficiency of the enzyme 21-hydroxylase. This enzyme deficiency impairs the body's ability to produce key adrenal steroid hormones, including cortisol and aldosterone.
When 21-hydroxylase is lacking, the body cannot produce sufficient cortisol, often resulting in salt wasting, dehydration, and potentially life-threatening complications. Simultaneously, the body continues to produce adrenal androgens, including androstenedione, at elevated levels. This overproduction can lead to early or abnormal growth, premature puberty, and various developmental challenges in affected children.
Historically, treatment has focused on managing high androstenedione levels through high-dose glucocorticoids. While this approach can control hormone levels, it significantly increases the risk of steroid-related side effects, creating a difficult treatment dilemma for patients and clinicians.
CAHtalyst Study Design and Results
The CAHtalyst pediatric study enrolled 103 children aged 4-17 years with classic CAH. Participants were randomized to receive either crinecerfont (n = 69) or placebo (n = 34) for 28 weeks.
The primary outcome measured was the least-squares mean change in androstenedione levels from baseline at week 4, taken before the morning glucocorticoid dose. A key secondary endpoint was the change in glucocorticoid dosing at week 28.
The results were striking:
Androgen Levels: At week 4, the average androstenedione level in the crinecerfont group decreased by 6.9 nmol/L from baseline, compared with an increase of 2.5 nmol/L in the placebo group. The least-squares mean difference between the groups was -9.3 nmol/L (P = 0.0002).
Glucocorticoid Reduction: By week 28, children receiving crinecerfont experienced an average glucocorticoid dose reduction of 18.0%, compared with a 5.6% increase in the placebo group. The least-squares mean difference was -23.5% (P < 0.0001).
Importantly, subgroup analyses showed these benefits were consistent across all patient populations studied.
Mechanism of Action and Clinical Significance
Crinecerfont works as a corticotropin-releasing factor type 1 receptor (CRF1) antagonist. By suppressing CRF1, the drug reduces adrenocorticotropic hormone (ACTH) levels, subsequently reducing adrenal androgen production without directly using glucocorticoids. This mechanism allows for lower, more physiologic dosing of glucocorticoids for cortisol replacement.
"High-dose steroids are often accompanied by side effects and complications," said Eiry W. Roberts, MD, chief medical officer of Neurocrine Biosciences. "By enabling patients to maintain or improve their androgen levels while reducing their reliance on high-dose glucocorticoids, CRENESSITY has the potential to meaningfully enhance long-term outcomes, helping patients with both the hormonal imbalances that characterize CAH, as well as the challenges associated with chronic high-dose glucocorticoid treatment."
Traditional CAH treatment has relied solely on glucocorticoids, often at supraphysiologic doses, to suppress ACTH and reduce androgen production. However, long-term high-dose glucocorticoid therapy carries risks of significant complications, including metabolic disorders, cardiovascular disease, osteoporosis, and psychological and cognitive impacts.
Safety Profile and Availability
Crinecerfont was generally well tolerated in the study. The most frequently reported adverse reactions (occurring in at least 4% of patients and more often than in the placebo group) included headache, abdominal pain, fatigue, nasal congestion, and nosebleed.
The medication 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.
It's important to note that patients receiving crinecerfont must continue glucocorticoid therapy for cortisol replacement, as the drug does not address the underlying cortisol deficiency characteristic of CAH.
Future Directions
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.
Neurocrine Biosciences will also present additional findings at the Joint Congress, including 1-year results from the CAHtalyst Adult study and data from the CHAMPAIN study comparing modified-release hydrocortisones in adrenal insufficiency.
These comprehensive studies may help establish crinecerfont as a significant advancement in the management of CAH, potentially transforming the treatment landscape for this challenging genetic disorder.
