Neurocrine Biosciences has announced promising new results from exploratory analyses of their Phase 3 CAHtalyst Pediatric study, demonstrating that CRENESSITY (crinecerfont) consistently reduces glucocorticoid dosing while maintaining or improving androstenedione levels across all patient subgroups with classic congenital adrenal hyperplasia (CAH).
The findings, which will be presented at the 2025 Joint Congress of the European Society for Paediatric Endocrinology and the European Society of Endocrinology in Copenhagen, Denmark, show consistent benefits across diverse demographic subgroups, baseline androstenedione levels, and baseline glucocorticoid doses.
Addressing a Critical Unmet Need in CAH Management
Congenital adrenal hyperplasia is a rare genetic condition affecting approximately 1 in 15,000 births worldwide. The disorder results from an enzyme deficiency—primarily 21-hydroxylase deficiency in 95% of cases—that disrupts the production of essential adrenal steroid hormones including cortisol and aldosterone.
The overproduction of androstenedione, a key adrenal androgen, in pediatric patients with CAH can lead to serious developmental issues including abnormal growth, premature puberty, and various developmental challenges. For decades, the standard treatment has involved high-dose glucocorticoids (GCs) to suppress excess androgens, but this approach comes with significant drawbacks.
"High-dose steroids are often accompanied by side effects and complications," said Eiry W. Roberts, M.D., Chief Medical Officer at 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."
Comprehensive Study Design and Significant Results
The CAHtalyst Pediatric study included 103 patients aged 4 to 17 years who were randomly assigned to receive either CRENESSITY (N=69) or placebo (N=34) for 28 weeks. The study was designed to answer two key questions: whether CRENESSITY could improve androgen control after four weeks of treatment, and whether an additional 24 weeks of treatment could enable customized glucocorticoid down-titration while maintaining or improving androstenedione levels.
The primary endpoint was the least-squares (LS) mean change from baseline in androstenedione (A4) levels at Week 4, with a key secondary endpoint of glucocorticoid dose reduction at Week 28.
The results were compelling across all subgroups analyzed:
-
Substantial Reduction in Adrenal Androgens at Week 4: CRENESSITY significantly reduced A4 levels from baseline compared with placebo (overall, -6.9 versus +2.5 nmol/L; LS mean difference: -9.3 nmol/L; p=0.0002).
-
Significant Reduction in GC Doses at Week 28: While maintaining or improving A4 levels, glucocorticoid doses were significantly reduced from baseline with CRENESSITY compared with placebo (overall, -18.0% versus +5.6%; LS mean difference: -23.5%; p<0.0001).
Importantly, these benefits were consistent across all prespecified and post-hoc subgroup analyses, which included region, sex, race, age, body mass index, pubertal stage, baseline A4 levels, weight, and baseline GC dose.
Safety Profile and Tolerability
CRENESSITY was generally well tolerated in the CAHtalyst Pediatric study. The most common adverse reactions (≥4% for CRENESSITY and greater than placebo) were headache, abdominal pain, fatigue, nasal congestion, and nosebleed.
Mechanism of Action and Dosing
CRENESSITY is a potent and selective oral corticotropin-releasing factor type 1 receptor (CRF1) antagonist that works through a non-glucocorticoid mechanism. By antagonizing CRF1 receptors in the pituitary, CRENESSITY decreases adrenocorticotropic hormone (ACTH) levels, which in turn reduces the production of adrenal androgens while allowing for lower, more physiologic dosing of glucocorticoids.
The medication is available in both capsule formulation (50 mg and 100 mg) and as an oral solution (50 mg/mL). For pediatric patients aged 4 to 17 years weighing less than 55 kg, the recommended dosage is based on body weight and administered twice daily with meals. For those weighing more than 55 kg, the recommended dosage is 100 mg twice daily.
Implications for CAH Treatment
The ability to reduce glucocorticoid doses while simultaneously maintaining or improving androgen levels represents a significant advancement in CAH management. Historically, patients with CAH have faced a difficult trade-off: either accept the consequences of elevated androgens or endure the side effects of high-dose glucocorticoids, which can include metabolic issues, cardiovascular disease, osteoporosis, and psychological and cognitive impacts.
CRENESSITY, which received FDA approval in December 2024, offers a new approach that addresses both aspects of this challenge. By targeting the underlying hormonal pathway through CRF1 receptor antagonism, it provides a mechanism to control androgen levels without relying solely on high-dose glucocorticoids.
These latest findings suggest that CRENESSITY may improve long-term outcomes in pediatric CAH patients across various subgroups, potentially transforming the treatment landscape for this challenging condition.
Additional presentations at the upcoming Joint Congress will include one-year results from the Phase 3 CAHtalyst Adult Study showing improvements in reproductive hormones, as well as findings from a double-blind study of modified-release hydrocortisones in adrenal insufficiency.
The open-label extension treatment portions of both CAHtalyst studies are ongoing, which will provide further insights into the long-term benefits and safety profile of CRENESSITY in both pediatric and adult populations with classic CAH.
