The U.S. Food and Drug Administration (FDA) has granted approval to Neurocrine Biosciences' Crenessity (crinecerfont) for the treatment of classic congenital adrenal hyperplasia (CAH) in both adult and pediatric patients aged four years and older. This approval marks a significant milestone as Crenessity is the first and only classic CAH treatment that directly reduces excess adrenocorticotropic hormone (ACTH) and downstream adrenal androgen production, allowing for glucocorticoid dose reduction. The drug, available in capsules and oral solution, is indicated as an adjunctive therapy to glucocorticoid replacement.
Clinical Trial Data
The FDA's decision was supported by data from the CAHtalyst Pediatric and Adult Phase 3 global registrational studies. These studies, published in The New England Journal of Medicine, represent the largest-ever clinical trial program in classic CAH. The CAHtalyst studies evaluated the safety, efficacy, and tolerability of Crenessity in children and adults with classic CAH due to 21-hydroxylase deficiency.
Richard Auchus, M.D., Ph.D., Professor at the University of Michigan Health and Principal Investigator, stated, "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." He further noted the potential for profound benefits due to the ability of patients with CAH to lower their glucocorticoid dose to a more physiologic level.
CAHtalyst Pediatric Study
The CAHtalyst Pediatric study met its primary endpoint, demonstrating that CRENESSITY significantly decreased androstenedione levels from baseline to Week 4 compared to placebo. Children taking CRENESSITY also experienced a significant reduction in glucocorticoid doses at Week 28 while maintaining or improving androgen levels, a key secondary endpoint. Specifically, children on CRENESSITY saw approximately four times greater reduction in androstenedione and steroid dose compared to those on placebo, and approximately 12 times greater reduction in 17-hydroxyprogesterone (17-OHP).
CAHtalyst Adult Study
The CAHtalyst Adult study also met its primary endpoint, with CRENESSITY enabling significant glucocorticoid dose reductions at Week 24 while maintaining or improving baseline androstenedione levels. A significantly higher number of patients taking CRENESSITY (63%) achieved a glucocorticoid dose in the physiologic range while androstenedione was maintained or improved, compared with patients taking placebo (18%). Participants on CRENESSITY experienced approximately two times greater steroid dose reduction and an eight times greater reduction in androstenedione compared to those on placebo. Additionally, they saw a 37 times greater reduction in 17-OHP.
Safety and Tolerability
CRENESSITY was generally well-tolerated in both CAHtalyst studies, with few treatment-related adverse events. In the pediatric study, the most common adverse reactions were headache, abdominal pain, fatigue, nasal congestion, and nosebleed. In the adult study, the most common adverse reactions were fatigue, headache, dizziness, joint pain, back pain, decreased appetite, and muscle pain. No treatment-related serious adverse events were reported in either study.
Dosing and Availability
CRENESSITY is available in capsules (50 mg and 100 mg) and as an oral solution (50 mg/mL). The recommended dosage for adults is 100 mg twice daily taken orally with a meal. For pediatric patients, the dosage is based on body weight and administered twice daily with a meal. Neurocrine Biosciences expects CRENESSITY to be commercially available in approximately one week, distributed through PANTHERx Rare, a specialty pharmacy.
About Congenital Adrenal Hyperplasia
Congenital adrenal hyperplasia (CAH) is a rare genetic condition that results in an enzyme deficiency, altering the production of adrenal steroid hormones, such as cortisol, aldosterone, and adrenal androgens. Approximately 95% of CAH cases are caused by variants of the CYP21A2 gene, leading to a deficiency of the enzyme 21-hydroxylase. Historically, treatment has involved high doses of glucocorticoids, leading to potential complications such as metabolic issues, cardiovascular disease, and osteoporosis. CRENESSITY offers a new approach by directly reducing excess ACTH and adrenal androgen production, potentially mitigating the need for high-dose steroids.
