Crinecerfont Found to Lower Androstenedione Levels in Pediatric Patients with Congenital Adrenal Hyperplasia

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Findings from the Phase III CAHtalyst Pediatric Study (NCT04806451) show that crinecerfont (Neurocrine Biosciences) is superior to placebo in lowering increased androstenedione levels in pediatric patients with congenital adrenal hyperplasia (CAH) resulting from 21-hydroxylase deficiency.^1,2 The study, published by The New England Journal of Medicine, found crinecerfont also produced a reduction in the glucocorticoid dose from supraphysiologic to physiologic levels while maintaining androstenedione control.

“In two phase 2 studies, adolescents and adults with CAH had clinically meaningful reductions in corticotropin, 17-hydroxyprogesterone (a diagnostic adrenal androgen precursor), and androstenedione (a key adrenal androgen) after 14 days of open-label treatment with crinecerfont, a new corticotropin-releasing factor type 1 receptor antagonist; substantial reductions in testosterone in female participants and in the androstenedione-to-testosterone ratio in male participants were also observed,” the study authors wrote. “These results provided proof-of-concept for the potential therapeutic value of corticotropin-releasing factor type 1 receptor antagonism in CAH.”¹

Crinecerfont, an investigational, oral, selective corticotropin-releasing factor type 1 receptor antagonist, was granted Priority Review designation by the FDA in June 2024 to treat children, adolescents, and adults with classic CAH. If approved, the first-in-class therapy would be the first new treatment option indicated for CAH in 70 years.³

"Receipt of a Priority Review reflects the FDA's agreement that CAH is a serious condition and there is an urgent need for patients to have access to new treatments," said Eiry W. Roberts, MD, chief medical officer at Neurocrine Biosciences, in a press release. "Crinecerfont's compelling efficacy results and excellent safety profile support our filing, and we look forward to working with the FDA as we head toward the PDUFA dates at the end of 2024."³

The multinational CAHtalyst Pediatric Study randomly assigned 103 pediatric patients with CAH in a 2:1 ratio to receive crinecerfont (n = 69) or placebo (n = 34) for 28 weeks. All patients remained in the trial for 28 weeks.

Patients maintained a stable glucocorticoid dose for four weeks, which was subsequently adjusted to a target of 8.0 to 10.0 mg per square meter of body-surface area per day (hydrocortisone dose equivalents) if the androstenedione level was controlled (≤120% of the baseline level or within the reference range). The trial’s primary endpoint was change in androstenedione level from baseline to week four, with a key secondary endpoint of percent change in glucocorticoid dose from baseline to week 28 while maintaining androstenedione control.

Mean glucocorticoid dose at baseline was 16.4 mg per square meter per day and mean androstenedione level was 431 ng per deciliter (15.0 nmol/liter). After four weeks, investigators observed a substantial decrease in androstenedione among patients in the crinecerfont cohort (−197 ng per deciliter [−6.9 nmol/liter]) compared to an increase in androstenedione in the placebo cohort (71 ng per deciliter [2.5 nmol/liter]) (least-squares mean difference [LSMD], −268 ng per deciliter [−9.3 nmol/liter]; P<0.001).

Observed mean androstenedione value collected prior to the morning glucocorticoid dose was 208 ng per deciliter (7.3 nmol/liter) in the crinecerfont cohort vs. 545 ng per deciliter (19.0 nmol/liter) in the placebo cohort. At week 28, mean glucocorticoid dose dropped by 18.0% while maintaining androstenedione control in the crinecerfont cohort compared to an increase of 5.6% in the placebo cohort (LSMD, −23.5 percentage points; P<0.001).

In terms of safety, the most frequently reported adverse events in the trial were headache, pyrexia, and vomiting.

“Crinecerfont appears to be a potential new therapeutic option for patients with CAH, who face substantial disease burden and adverse health outcomes throughout their lives,” the study authors wrote. “Secondary and exploratory end points related to consequences of long-term supraphysiologic glucocorticoid therapy showed favorable trends, but longer treatment periods are needed to determine the extent of these effects.”¹

References

1. Sarafoglou K., et al. Phase 3 Trial of Crinecerfont in Pediatric Congenital Adrenal Hyperplasia. N Engl J Med 2024;391:493-503. DOI: 10.1056/NEJMoa2404655. Vol. 391 No. 6.

2. Global Safety and Efficacy Registration Study of Crinecerfont in Pediatric Patients With Classic Congenital Adrenal Hyperplasia (CAHtalyst Pediatric Study). ClinicalTrials.gov ID. May 7, 2024. Accessed August 29, 2024. https://clinicaltrials.gov/study/NCT04806451

3. Neurocrine Biosciences Announces U.S. FDA Accepts New Drug Applications and Grants Priority Review for Crinecerfont for Pediatric and Adult Patients with CAH. News release. Neurocrine Biosciences. July 1, 2024. Accessed August 29, 2024. https://neurocrine.gcs-web.com/news-releases/news-release-details/neurocrine-biosciences-announces-us-fda-accepts-new-drug-0