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The US Food and Drug Administration has approved crinecerfont (Crenessity) for use in combination with glucocorticoids in the treatment of adults and children aged 4 years or older with classic congenital adrenal hyperplasia (CAH).

In CAH, a genetic mutation causes deficiency in an enzyme, most often 21-hydroxylase, leading to impaired cortisol synthesis and excess androgen production. Until now, glucocorticoid replacement has been the only available treatment. The glucocorticoids have been given in supraphysiologic doses to not only correct the deficiency but also lower adrenocorticotropic hormone levels and adrenal androgen production. 

However, those high doses also lead to complications, including weight gain, type 2 diabetes, cardiovascular disease, and osteoporosis. Moreover, research presented in May 2024 at the annual meeting of the American Association of Clinical Endocrinology (AACE) showed that some patients don’t achieve adequate androgen control despite the supraphysiologic glucocorticoid dosing.

Crinecerfont, an oral selective corticotropin-releasing factor type 1 receptor antagonist, reduces adrenal androgen overproduction through a glucocorticoid-independent mechanism, thereby allowing for a reduction in the overall glucocorticoid dose. 

The new approval was based on two randomized, double-blind, placebo-controlled trials, one in 182 adults and the other in 103 children with classic CAH. Results from both studies were presented in June 2024 at the Endocrine Society meeting. They were also published in The New England Journal of Medicine, the adult data on June 1 and the pediatric data on June 2. 

In the adult trial, 122 participants received crinecerfont and 60 received placebo, both twice daily for 24 weeks. After the first 4 weeks of the trial, the glucocorticoid dose was reduced to replacement levels, then adjusted on the basis of androstenedione levels. Crinecerfont enabled a 27% reduction in glucocorticoid dose while maintaining control of androstenedione, vs a reduction by 10% in the placebo group — a significant difference (P < .001). 

In the pediatric trial, 69 participants received crinecerfont and 34 received placebo, both twice daily for 28 weeks. By week 4, the children receiving crinecerfont experienced a significant reduction in serum androstenedione from baseline, compared with an increase in the placebo group (P < .001). 

In addition, by 24 weeks, daily glucocorticoid doses were reduced by 18% in children receiving crinecerfont while maintaining androstenedione control, vs an almost 6% increase in glucocorticoid dose among children receiving placebo. 

The most common adverse events were fatigue and headache in the adult trial and headache, pyrexia, and vomiting in the pediatric trial. 

The product label carries a warning for acute adrenal insufficiency or adrenal crisis when a patient with underlying adrenal insufficiency does not also receive adequate doses of glucocorticoid replacement therapy in situations associated with increased cortisol need (ie, “stress dose” steroids). 

During the AACE meeting, Anupam Kotwal, MD, assistant professor in the Division of Diabetes, Endocrinology and Metabolism at the University of Nebraska Medical Center, Omaha, told Medscape Medical News, “Right now, all the medicines we have just suppress the adrenal production, but once we can get something upstream, to reduce the oversecretion of these androgens without causing as much side effect from too much steroids, I think that would be close to a game-changer.”

Kotwal reported no disclosures in May 2024. 

Miriam E. Tucker is a freelance journalist based in the Washington, DC, area. She is a regular contributor to Medscape, with other work appearing in the Washington Post, NPR’s Shots blog, and Diatribe. She is on X (formerly Twitter) @MiriamETucker.