BOSTON — Crinecerfont, an investigational oral selective corticotropin-releasing factor type 1 receptor antagonist, benefits both adults and children with congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency, new phase 3 data suggest. 

In CAH, a genetic mutation causes deficiency in an enzyme, most often 21-hydroxylase, leading to impaired cortisol synthesis. This leads to increased secretion of corticotropin-releasing factor and adrenocorticotropic hormone (ACTH), which in turn increases the excess production of adrenal androgens.

Current glucocorticoid replacement treatment is often given in supraphysiologic doses both to correct the deficiency and to lower the levels of ACTH and adrenal androgen production. However, glucocorticoid treatment at supraphysiologic doses has been linked to numerous complications, including weight gain, diabetes, cardiovascular disease, and osteoporosis. 

Crinecerfont reduces adrenal androgen overproduction through a glucocorticoid-independent mechanism. Results from two separate phase 3 trials (one adult, one pediatric) of the agent were presented at the annual Endocrine Society meeting and were published in two papers in the New England Journal of Medicine. The adult data were presented and published on June 1 and the pediatric data were presented and published today. 

In both adults and children with classic CAH, crinecerfont therapy allowed for a significant reduction in glucocorticoid administration to more physiologic doses and reduced adrenal androgen production. 

“For the last 65 years, this has been a frustrating and difficult process, because supraphysiologic doses of glucocorticoids are often needed to control the adrenal androgen excess,” endocrinologist and co-author Richard J. Auchus, MD, professor of medicine at the University of Michigan, Ann Arbor, said in his presentation of results from the adult trial. “The disease control is a difficult balance between the complications of ACTH and androgen excess, growth in developmental problems, male and female reproductive problems, and other health problems vs the complications from supraphysiologic exposure to glucocorticoids. My colleagues and I have been trying for many years to find a better way to manage this disease that is going to control the androgen excess, but yet still be able to reduce the glucocorticoid dose to something physiologic.” 

Asked to comment, session moderator Mabel Yau, MD, assistant professor of pediatrics in the Division of Pediatric Endocrinology at Icahn School of Medicine at Mount Sinai, New York City, told Medscape Medical News, “We’ve been very excited within the endocrinology world t o have a new treatment for patients with CAH. The standard of care has really been to use glucocorticoids at increasing doses to control hormone levels. To have an adjunct therapy, to be able to limit the glucocorticoid dose and possibly limit long-term side effects is great.” 

The adult phase 3 trial randomly assigned 122 patients with CAH to crinecerfont and 60 to placebo for 24 weeks. Glucocorticoid treatment was kept stable for 4 weeks to evaluate androstenedione values. For the subsequent 20 weeks, glucocorticoid doses were reduced and optimized to target the lowest glucocorticoid dose that maintained androstenedione control (≤120% of the baseline value or within the reference range). 

At baseline, the mean glucocorticoid dose was 17.6 mg per square meter of body-surface area per day of hydrocortisone equivalents, with the mean androstenedione level elevated at 620 ng/dL. 

Among 176 patients who remained in the trial at week 24, there was a 27.3% reduction in glucocorticoid dose (with androstenedione control) in the crinecerfont group vs just 10.3% in the placebo group, a significant difference (P <.001).

Physiologic glucocorticoid doses with androstenedione control were achieved in 63% in the crinecerfont group vs 18% in the placebo group (P <.001). 

At week 4, androstenedione levels decreased with crinecerfont by 299 ng/dL but increased with placebo by 45.5 ng/dL (P < .001). 

Adverse events, most commonly fatigue and headache, were similar in the two trial groups. Adverse events leading to glucocorticoid stress dosing were reported in just over 40% of both groups, most involving only oral stress dosing. 

Yao commented, “I found these results very exciting and also reassuring in that there were very few negative effects.” 

Results from the pediatric trial were presented in a poster by Kyriakie Sarafoglou, MD, professor in the Division of Pediatric Endocrinology & Division of Pediatric Genetics and Metabolism, University of Minnesota, Minneapolis. Here, 69 were randomly assigned to crinecerfont and 34 to placebo. As in the adult trial, glucocorticoid doses were kept stable for the first 4 weeks, then adjusted to a target of 8.0-10.0 mg per square meter of body-surface area per day, as long as the androstenedione level was kept at 120% or less of baseline or within reference range. 

Mean baseline glucocorticoid dose was 16.4 mg per square meter per day, and the mean androstenedione level was 431 ng/dL (15.0 nmol/L). 

At week 4, androstenedione levels were reduced by 197 ng/dL in the crinecerfont group, while increasing by 71 ng/dL with placebo (P < .001). 

The mean androstenedione value obtained before the morning glucocorticoid dose was 208 ng/dL in the crinecerfont group vs 545 ng/dL in the placebo group. At week 28, the mean glucocorticoid dose had decreased (while androstenedione control was maintained) by 18% with crinecerfont, while increasing by 5.6% with placebo (P <.001). 

Headache, pyrexia (fever), and vomiting were the most common adverse events. Two participants in the crinecerfont group had adverse events that led to discontinuation of the trial regimen and withdrawal from the trial. 

Adverse events leading to stress dosing of glucocorticoid occurred in approximately half the participants in each treatment group, most involving only oral stress dosing.

Both studies were funded by Neurocrine Biosciences. Auchus reports receiving consultant fees and/or research grants from Adrenas Therapeutics, Crinetics Pharmaceuticals, Diurnal, H. Lundbeck, Neurocrine Biosciences, Novo Nordisk, OMass Therapeutics, Quest, and Spruce Biosciences. 

Sarafoglou receives research support from the Office of Orphan Products Development of the US Food and Drug Administration, Neurocrine Biosciences, Spruce Biosciences, Crinetics Pharmaceuticals, and Adrenas Therapeutics, and serves as a consultant for Crinetics Pharmaceuticals, Eton Pharmaceuticals, Neurocrine Biosciences, and Spruce Biosciences on behalf of the University of Minnesota Medical School. She does not receive personal income for these activities. Yau is a consultant for Eton Pharmaceuticals. 

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.