New CAH Treatment for Children and Adults Receives FDA Approval

In December, the U.S. Food and Drug Administration (FDA) approved crinecerfont capsules and oral solution adjunctive treatment to glucocorticoid replacement to control androgens in adult and pediatric patients four years of age and older with classic congenital adrenal hyperplasia (CAH).  

Crinecerfont is a selective oral corticotropin-releasing factor type 1 receptor (CRF₁) antagonist that directly reduces excess adrenocorticotropic hormone (ACTH) and downstream adrenal androgen production, allowing for glucocorticoid dose reduction. Neurocrine Biosciences is marketing the drug as CRENESSITY.

The FDA approval is supported by the largest-ever clinical trial program of classic CAH, the CAHtalyst Pediatric and Adult Phase 3 global registrational studies. CAHtalyst Phase 3 data results in pediatric and adult patients with classic CAH were published in The New England Journal of Medicine.

In both CAHtalyst studies, CRENESSITY enabled lower steroid doses and decreased androgen levels.

Phase 3 CAHtalyst Pediatric Study:

• The CAHtalyst Pediatric study met its primary endpoint, with CRENESSITY significantly decreasing androstenedione levels from baseline to Week 4 versus patients taking placebo who experienced a substantial increase in androstenedione levels.
• Children taking CRENESSITY were also able to significantly reduce their GC doses at Week 28 while maintaining or improving androgen levels, a key secondary endpoint.
• Children taking CRENESSITY saw approximately four times greater reduction in androstenedione compared with those taking placebo.
• Approximately four times greater steroid dose reduction in children taking CRENESSITY was seen compared with those taking placebo.
• Children taking CRENESSITY saw approximately 12 times greater reduction in 17-hydroxyprogesterone (17-OHP) compared with those taking placebo.
• Headache, abdominal pain, fatigue, nasal congestion and nosebleed were the most common adverse drug reactions (ADRs) among the pediatric population treated with CRENESSITY. Most side effects were temporary and mild to moderate in severity.

“In this phase 3 trial,” the authors write in their conclusion, “crinecerfont was superior to placebo in reducing elevated androstenedione levels in pediatric participants with CAH and was also associated with a decrease in the glucocorticoid dose from supraphysiologic to physiologic levels while androstenedione control was maintained. 

“Chronic treatment with supraphysiologic glucocorticoids can cause a number of short- and long-term health consequences, such as obesity, hypertension, and osteoporosis, so the ability for patients with CAH to lower their glucocorticoid dose to a more physiologic level can have profound benefits.” – Richard Auchus, MD, PhD, professor, University of Michigan Health

Phase 3 CAHtalyst Adult Study:

• The CAHtalyst Adult study met its primary endpoint with CRENESSITY enabling significant GC dose reductions at Week 24 (while maintaining or improving baseline androstenedione levels) and key secondary endpoint of decreasing androstenedione levels at Week 4.
• A significantly higher number of patients taking CRENESSITY (63%) achieved a GC dose in the physiologic range while androstenedione was maintained or improved compared with patients taking placebo (18%).
• Approximately two times greater steroid dose reduction was seen in people taking CRENESSITY compared with those taking placebo.
• People taking CRENESSITY saw an eight times greater reduction in androstenedione compared with those taking placebo.
• People taking CRENESSITY saw a 37 times greater reduction in 17-OHP compared with those taking placebo.
• Fatigue, headache, dizziness, joint pain, back pain, decreased appetite and muscle pain were the most common ADRs in the CRENESSITY treatment group. Most side effects were temporary and mild to moderate in severity.

The authors conclude: “Among patients with CAH, the use of crinecerfont resulted in a greater decrease from baseline in the mean daily glucocorticoid dose, including a reduction to the physiologic range, than placebo following evaluation of adrenal androgen levels.” 

“The clinical results across both CAHtalyst studies support the efficacy and safety profile of CRENESSITY and its ability to reduce the overproduction of adrenal androgens, allowing for a meaningful reduction in glucocorticoid dosage, while maintaining or enhancing control of these androgens,” says Richard Auchus, MD, PhD, a professor at the University of Michigan Health, and principal investigator. “Chronic treatment with supraphysiologic glucocorticoids can cause a number of short- and long-term health consequences, such as obesity, hypertension, and osteoporosis, so the ability for patients with CAH to lower their glucocorticoid dose to a more physiologic level can have profound benefits.”