Neurocrine Biosciences has announced that the U.S. Food and Drug Administration (FDA) has accepted two New Drug Applications (NDAs) for crinecerfont, and granted them Priority Review designations. These applications target the treatment of children, adolescents, and adults with classic congenital adrenal hyperplasia (CAH). If approved, crinecerfont would represent the first new treatment for CAH in 70 years and the first-in-class therapy offering a novel mechanism of action to address this rare and serious endocrine disorder.
Congenital Adrenal Hyperplasia (CAH) Overview
CAH refers to a rare group of inherited autosomal recessive disorders that impair hormone production in the adrenal glands. These glands, located atop the kidneys, normally produce corticosteroids, mineralocorticoids, and androgens. CAH is primarily caused by mutations in the 21-hydroxylase gene, accounting for over 90% of cases. Less frequently, mutations in the 11-hydroxylase gene can also lead to CAH.
In the 7MM (the United States, EU5, and Japan), the U.S. accounted for the highest number of prevalent cases of congenital adrenal hyperplasia in 2023, representing approximately 50% of the total. These numbers are expected to increase during the forecast period from 2024 to 2034.
DelveInsight's analysis indicates that a higher prevalence of diagnosed congenital adrenal hyperplasia is observed in the 18-year-old and above age group across the 7MM. Among mutation-based congenital adrenal hyperplasia cases, 21 OHD (CYP21A2 gene mutation) represents a higher prevalence compared to 11-Beta hydroxylase (CYP11B1 gene mutation) and others.
Current Treatment Landscape and Crinecerfont's Potential
The management of classic CAH focuses on correcting adrenal insufficiency, lowering adrenal androgens to appropriate levels, and preventing iatrogenic hypercortisolism. Hydrocortisone is the primary glucocorticoid used, administered two to three times daily to align with the body's natural circadian rhythm. Currently, EFMODY (Hydrocortisone Modified-release Hard Capsules) by Neurocrine Biosciences is approved in Europe for CAH treatment.
Crinecerfont is an investigational oral medication that acts as a selective antagonist for the corticotropin-releasing factor Type 1 receptor (CRF1). It is being developed to manage and regulate high levels of Adrenocorticotropic Hormone (ACTH) and adrenal androgens without relying on glucocorticoids, specifically for treating congenital adrenal hyperplasia caused by 21-hydroxylase deficiency. By blocking the CRF1 receptor, crinecerfont reduces the overproduction of ACTH, which in turn decreases the excess production of androgens seen in CAH patients. This mechanism aims to normalize hormone levels and address the root cause of the condition.
The NDAs for crinecerfont include (1) a capsule formulation (NDA# 218808) and (2) an oral solution formulation (NDA# 218820), both addressing the efficacy and safety of crinecerfont for classic CAH. The FDA has set Prescription Drug User Fee Act (PDUFA) target action dates for these applications as December 29 and December 30, 2024, respectively. The FDA has indicated it does not plan to hold an advisory committee meeting regarding these NDAs.
Regulatory Designations and Clinical Trial Data
Crinecerfont received an Orphan Drug designation (ODD) in March 2019 and a Breakthrough Therapy designation (BTD) in December 2023. The results from the CAHtalyst Phase III trial, involving both pediatric and adult patients with CAH caused by 21-OHD, were published online in The New England Journal of Medicine on June 2 and June 1, respectively, and were also presented at ENDO 2024.
Market Growth and Future Therapies
The anticipated launch of these emerging therapies for congenital adrenal hyperplasia are poised to transform the market landscape in the coming years. DelveInsight estimates that the market size for congenital adrenal hyperplasia is expected to grow from USD 20 billion in 2023 with a tremendous CAGR of ~40% by 2034. This growth can be attributed to the introduction of upcoming therapies and the rising prevalence of the disease.
