Crenessity cuts GC dose in CAH

Neurocrine Biosciences, Inc. announced new data from the Phase III CAHtalyst Adult and Pediatric studies of Crenessity (crinecerfont). The data showed that a substantial proportion of pediatric patients with classic congenital adrenal hyperplasia achieved physiologic-range glucocorticoid doses and normal androstenedione levels. Additionally, adult male patients with classic congenital adrenal hyperplasia observed improvements in select reproductive hormone levels. Both adult and pediatric patients achieved substantial reductions in glucocorticoid doses. These results were presented at the 2025 American Association of Clinical Endocrinology Annual Meeting in Orlando.

Congenital adrenal hyperplasia (CAH) is characterized by imbalances in hormone production, including cortisol, aldosterone and androgens, which cause a wide range of symptoms and can lead to long-term health problems. "Historically, CAH has been treated with high-dose glucocorticoids alone. However, this approach can lead to serious and significant complications due to high-dose steroid use," said Eiry W. Roberts, M.D., Chief Medical Officer, Neurocrine Biosciences. "Crenessity, a novel oral corticotropin-releasing factor type 1 receptor antagonist, has demonstrated the potential to achieve two key therapeutic goals: reducing the effects of excess androgens and enabling reduction in glucocorticoid doses. This dual action may help reduce the adverse effects associated with chronic exposure to supraphysiologic doses of glucocorticoids."

More physiologic glucocorticoid (GC) treatment with greater reductions of androstenedione (A4) in pediatric patients:

In the CAHtalyst Pediatric study, children and adolescents with classic CAH (four to 17 years), including both salt-wasting and simple virilizing forms, were randomized to 28 weeks of double-blind treatment with placebo or Crenessity. Changes in GC doses and A4 levels (measured before the morning GC dose) were analyzed using waterfall charts based on individual patient data at baseline and Week 28, along with an analysis that evaluated categorical shifts from baseline to Week 28. Data showed: i) 90% of participants on Crenessity versus 21% on placebo achieved ≥1 threshold for A4 reduction or GC reduction. ii) In contrast, no patients who were treated with placebo achieved a physiologic GC dose, and nearly 70% still had elevated A4 levels (> upper limit of normal [ULN]) despite supraphysiologic GC dosing (>11mg/m2/day). iii) At Week 28, 30% (20/67) of participants on Crenessity reached a physiologic GC dose while maintaining or improving A4 levels, compared with 0% (0/31) of participants on placebo.

In the pediatric study, Crenessity was generally well tolerated, with no adrenal crises reported in the double-blind treatment period. The most common adverse reactions with Crenessity were headache (25% versus 6% for placebo), abdominal pain (13% versus 0%), fatigue (7% versus 0%), nasal congestion (7% versus 3%) and epistaxis (4% versus 0%).

Improvement of select reproductive hormones in adult males:

Select reproductive hormone changes in adult males with classic CAH who received up to one year of Crenessity were evaluated from the CAHtalyst Adult study. At Week 24 (end of double-blind, placebo-controlled period) and Month 12 (end of open-label period), analyses were conducted on luteinizing hormone (LH) and A4-to-testosterone ratio (A4/T; a ratio of >0.5 is indicative of excessive adrenal androgen production) in male patients (during the open-label period from Week 24 to Month 12, all patients received Crenessity). Results were presented as percentages of patients with observed rates of normalization (n) out of those who had abnormal values at baseline (N). Data showed: i) At Week 24, a higher percentage of male patients who had abnormal levels (LH < lower limit of normal or > ULN; A4/T ≥0.5) at baseline had observed rates of normalization of LH (47% versus 22%) and A4/T (19% versus 5%) with Crenessity compared with placebo, respectively, despite greater decreases in GC dose in the Crenessity group. ii) At Month 12, further increases in the percentages of patients with normalization of LH (65%) and A4/T (24%) were observed, while GC doses remained substantially reduced from baseline. iii) At Month 12, patients randomized to placebo who switched to Crenessity during the open-label portion had observed rates of normalization of LH (44%) and A4/T (24%), despite substantial reductions in GC dose during that time.

In the adult study, two patients (1.6%) taking Crenessity experienced adrenal crisis. No patients on placebo experienced adrenal crisis. However, one patient (1.7%) on placebo experienced adrenal insufficiency. The most common adverse reactions with Crenessity were fatigue (25% versus 15% for placebo), headache (16% versus 15%), dizziness (8% versus 3%), arthralgia (7% versus 0%), back pain (6% versus 3%), decreased appetite (4% versus 2%) and myalgia (4% versus 3%).

About The CAHtalyst Studies
The Phase III CAHtalyst global registrational studies were designed to evaluate the safety, efficacy and tolerability of Crenessity in children and adults with classic congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency. The CAHtalyst studies were the largest-ever interventional clinical trial program in classic CAH, including 285 pediatric and adult patients.

The CAHtalyst Pediatric study included 103 pediatric patients four to 17 years of age. The study tested two questions. The first question evaluated whether four weeks of Crenessity treatment could improve androgen control. The second question evaluated whether an additional 24 weeks of Crenessity treatment enabled customized glucocorticoid (GC) down-titration while androstenedione levels were maintained or improved.

The CAHtalyst Adult study included 182 adult patients 18 to 58 years of age. Similarly, the first question of the study evaluated whether four weeks of Crenessity treatment could improve androgen control, and the second question evaluated whether an additional 20 weeks of Crenessity treatment enabled GC reduction to physiologic range while androstenedione levels were maintained or improved.

Data from the CAHtalyst Phase III studies supported approval of Crenessity by the FDA in December 2024. The open-label extension treatment portions of both studies are ongoing.