More Benefits Reported With Crinecerfont in Adults, Kids With CAH

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Researchers detailed reductions in androstenedione, improvement in reproductive hormones

by
Kristen Monaco, Senior Staff Writer, MedPage Today
May 15, 2025 • 3 min read

ORLANDO — New results from the randomized CAHtalyst trials shed light on the benefits of crinecerfont (Crenessity) for adult and pediatric patients with congenital adrenal hyperplasia (CAH), a rare genetic condition where patients do not produce enough cortisol and produce too many androgens.

In adults, open-label data showed a sustained steroid-reducing benefit with the oral corticotropin-releasing factor type 1 receptor (CRF1) antagonist, according to findings presented by Sonal Vaid, MD, of the NIH Clinical Center in Bethesda, Maryland.

Patients initially assigned to crinecerfont during the 24-week randomized portion of the adult trial had a 25% reduction in glucocorticoid dose with continued treatment through 1 year, while those initially given placebo had a 30% reduction from baseline after switching to crinecerfont.

For pediatric patients, crinecerfont significantly reduced androstenedione (A4) by the end of the 4-week glucocorticoid stable period (-197 vs 71.0 ng/dL with placebo; least-squares mean difference -268 ng/dL, 95% CI -403 to -132, P=0.0002), said Patricia Fechner, MD, of the University of Washington School of Medicine in Seattle.

In the crinecerfont group, 74% achieved normal A4 levels versus 12% of placebo recipients. Previously reported results in kids showed a benefit for lowering glucocorticoid dose as well.

“This demonstrates that clinicians can focus on reducing androgens, lowering glucocorticoid dose, or both based on the individual patient’s treatment goals,” said Fechner.

Both studies were presented at the annual meeting of the American Association of Clinical Endocrinology.

Crinecerfont gained FDA approval in December 2024 as a first-in-class treatment for CAH patients ages 4 and older based on the CAHtalyst trials, making it the first new drug for the condition in 70 years.

Previously reported 24-week results of the trial in adults demonstrated a 27.3% reduction in glucocorticoid dose with crinecerfont compared with a 10.3% reduction with placebo. And the pediatric trial showed that kids treated with crinecerfont had an 18% reduction in mean glucocorticoid dose versus a 5.6% increase with placebo by week 28.

Acting as a potent and selective oral CRF1 antagonist, the drug works by reducing excessive adrenal androgen production, lowering the amount of glucocorticoids needed.

In the adult trial of 182 patients, 122 were randomized to 100-mg crinecerfont twice-daily and 60 to placebo. The 117 crinecerfont and 57 placebo participants who completed the 6-month trial period then had a 1-month period where glucocorticoid treatment was stabilized to assess androgens.

For months 7 to 10, glucocorticoids were reduced monthly to a target hydrocortisone equivalents (HCe) dose of 8-10 mg/m² per day while maintaining or improving A4. Glucocorticoids were then maintained from months 10 to 12.

At baseline, average daily glucocorticoid dose was 32.3 mg and 17.6 mg/m² adjusted for body surface area. Most (58%) were on hydrocortisone alone, 29% on prednisone with or without hydrocortisone, and 13% on dexamethasone with or without another glucocorticoid.

In male participants, 58% of all participants (those who continued crinecerfont or crossed over from placebo) achieved normalization of luteinizing hormone and 29% achieved normalization of follicle-stimulating hormone. Around a quarter of all crinecerfont-treated males with an elevated androstenedione-to-testosterone ratio achieved normalization.

In females, 5% and 12% achieved normal testosterone and progesterone levels with crinecerfont, respectively.

“Although the study was focused on optimizing glucocorticoid doses rather than reducing androgens at the end of the open-label period, our analyses do demonstrate that normalization of reproductive hormones can be achieved with Crenessity, even in the context of substantial glucocorticoid dose reductions,” said Vaid.

In the 103-person pediatric trial, glucocorticoids were kept stable for 4 weeks after randomization to assess the effect on androgens, and were then adjusted through week 28 to reach a target HCe dose of 8-10 mg/m² per day while maintaining or improving A4 relative to baseline.

Average age was 12.1, and mean daily glucocorticoid dose at baseline was 24.6 mg and 16.4 mg/m² adjusted for body surface area. Nearly all (92%) were on hydrocortisone alone.

By week 28, 30% of crinecerfont-treated kids reached a physiologic glucocorticoid dose (≤11 mg/m² per day) while maintaining or improving A4. A total of 57% achieved a physiologic glucocorticoid dose or a HCe dose reduction of ≥2.5 mg/m² per day by that point.

Crinecerfont was generally safe and well tolerated in adults and children.

In adults, the most common adverse reactions during the 6-month trial period were headache (16% with crinecerfont vs 15% with placebo), fatigue (25% vs 15%), back pain (6% vs 3%), dizziness (8% vs 3%), and arthralgia (7% vs 0%).

As for kids, the most common reaction was also headache (25% vs 6%, respectively), followed by abdominal pain (13% vs 0%), fatigue (7% vs 0%), nasal congestion (7% vs 3%), and epistaxis (4% vs 0%).