CAH Update: High-Level Examination of Condition Published in Expert Review of Endocrinology & Metabolism, Neurocrine Announces
"Glucocorticoid therapy in classic congenital adrenal hyperplasia: traditional and new treatment paradigms," offers an in-depth look at the disorder and promising therapies.
Neurocrine Biosciences is underscoring the promising shift in management of classic congenital adrenal hyperplasia (CAH) with the publication of a narrative review in Expert Review of Endocrinology & Metabolism. The review1 highlights the limitations of traditional high-dose glucocorticoid (GC) therapy and introduces novel therapeutic approaches, including the recently FDA-approved crinecerfont (Crenessity), a novel non-GC mechanism for treating this complex condition.
Irina Bancos, MD, MS
Courtesy of Mayo Clinic
CAH, a rare genetic disorder characterized by impaired cortisol production and excess androgen levels, has historically been managed with supraphysiologic doses of GCs. While effective at suppressing adrenocorticotropic hormone (ACTH) and androgens, the treatment typically results in significant long-term complications, such as metabolic, cardiovascular, and skeletal disorders, as well as adverse effects on mental health. The review emphasizes the urgent need for innovative treatments to reduce these risks and improve patient outcomes.1
"The treatment paradigm for CAH involves continually monitoring and balancing ACTH and androgen levels and glucocorticoid-dosing to optimize treatment." Irina Bancos, MD, MS, lead author of the review and professor of medicine at the Mayo Clinic, explained in a company statement. New treatments that target ACTH and adrenal androgens through non-glucocorticoid mechanisms allow for reduced GC dosing, which translates to a meaningful reduction in complications, she added.2
Crinecerfont, approved by the FDA in December 2024, is a corticotropin-releasing factor type 1 receptor (CRF1) antagonist, represents a groundbreaking addition to therapeutic options for CAH, the company said. By targeting CRF1 receptors in the pituitary, crinecerfont directly reduces ACTH levels, subsequently decreasing excess androgen production. The mechanism of action allows control of the primary defect in CAH with more physiologic GC doses, minimizing the cumulative adverse effects associated with high-dose therapy.1
The Risks of GC Therapy
In the review, Bancos and colleagues underscore the burden of traditional GC therapy for CAH, particularly its impact on pediatric growth, female reproductive health, and male fertility. For adults, chronic high-dose GCs increase the risk of obesity, diabetes, osteoporosis, cardiovascular disease, and cognitive decline.1 "Over a lifetime, even modest reductions in daily glucocorticoid doses can reduce the risk of these complications and lessen the overall burden of glucocorticoid exposure," Eiry W Roberts, MD, Neurocrine chief medical officer, said in the statement.2
CAH is caused by a deficiency in the 21-hydroxylase enzyme and affects approximately 95% of individuals diagnosed with the condition. The enzymatic defect disrupts cortisol and aldosterone synthesis, leading to excess androgen production and, in severe cases, life-threatening salt wasting. Traditional high-dose GC therapy compensates for cortisol deficiency but creates a separate cascade of complications due to steroid excess.1
Crinecerfont is the first FDA-approved treatment to directly address ACTH-driven pathology in CAH. The therapy is indicated for individuals aged 4 and older as an adjunct to GC replacement and is available in capsules and solution. Dosing is based on weight and age.2
