Crinecerfont outperforms placebo in lowering increased androstenedione levels in young Congenital adrenal hyperplasia patients: NEJM

United States: A recent study published in The New England Journal of Medicine concluded that crinecerfont performed a placebo in reducing increasing androstenedione levels in Congenital adrenal hyperplasia pediatric participants. Crinecerfont was also associated with decrease in glucocorticoid dose from supraphysiologic to physiologic levels.

Congenital Adrenal Hyperplasia is a genetic condition that affects the adrenal gland located at the top of each kidney. It is a group of rare inherited autosomal recessive disorders characterized by the deficiency of one of the enzymes that are needed to make specific hormones. The formation of too little cortisol, too little aldosterone and too many androgens are the symptoms of CAH. It occurs due to 21-hydroxylase deficiency and requires treatment with glucocorticoids, usually at supraphysiologic doses, to address cortisol insufficiency and reduce excess adrenal androgens. Considering this Kyriakie Sarafoglou, M.D from the University of Minnesota Medical School and College of Pharmacy, Minneapolis (K.S.) et.al, conducted a study to evaluate the effect of crinecerfont in Pediatric patients with Congenital Adrenal Hyperplasia.

In order to do this, the study team carried out an international, randomized experiment in which pediatric CAH patients were randomly allocated to receive a placebo for 28 weeks at a ratio of 2:1. They maintained a stable glucocorticoid dose for 4 weeks, then they adjust the dose for the target of 8.0 to 10.0 mg per square meter of body- surface area per day.

A total of 103 participants were randomly assigned to the study. They move the baseline aldosterone level's primary efficacy end point to week 4. The percentage change in glucocorticoid dosage from baseline to week 28 with androstenedione control maintained was the secondary endpoint.

The study revealed that:

• At 28 weeks, 100 (97%) of the 69 participants who were assigned to crinecerfont and 34 who received a placebo were still in the trial.
• The mean androstenedione level was 431 ng per deciliter (15.0 nmol/liter) and the mean glucocorticoid dose was 16.4 mg per square meter per day at baseline.
• By week four, androstenedione levels in the crinecerfont group were significantly lower (−197 ng per deciliter) while they were higher (71 ng per deciliter) in the placebo group.
• Before the morning glucocorticoid dose, the observed mean androstenedione value was 208 ng per deciliter (7.3 nmol/liter) in the crinecerfont group and 545 ng per deciliter (19.0 nmol/liter) in the placebo group.
• By week 28, the mean glucocorticoid dosage had increased by 5.6% with placebo but had dropped by 18.0% with crinecerfont (while maintaining androstenedione control).
• The most frequent side effects were vomiting, pyrexia, and headaches.

“Crinecerfont was more effective than a placebo in children with CAH at lowering elevated levels of androstenedione. It was also linked to a reduction in glucocorticoid dosage from supraphysiologic to physiologic levels while maintaining androstenedione management”, the researchers concluded.

Reference

Sarafoglou, K., Kim, M. S., Lodish, M., Felner, E. I., Martinerie, L., Nokoff, N. J., Clemente, M., & the CAHtalyst Pediatric Trial Investigators. (2024). Phase 3 trial of crinecerfont in pediatric congenital adrenal hyperplasia. New England Journal of Medicine, 391(6), 493-503. https://doi.org/10.1056/NEJMoa2404655