FDA Accepts NDAs for Crinecerfont in Congenital Adrenal Hyperplasia

Credit: US Food and Drug Administration

The US Food and Drug Administration (FDA) has accepted the New Drug Applications (NDA) with Priority Review designation for crinecerfont in the treatment of children, adolescents, and adults with classic congenital adrenal hyperplasia (CAH).¹

Announced by Neurocrine Biosciences on July 1, 2024, the dual submitted NDAs included the primary presentation of efficacy and safety of crinecerfont for treating classic CAH as a capsule and an oral solution formulation.

The FDA has set Prescription Drug User Fee (PDUFA) target action dates of December 29 and December 30, 2024, for these drug formulations, respectively. No FDA advisory committee meetings are planned to discuss the NDAs for crinecerfont.

“Receipt of a Priority Review reflects the FDA’s agreement that CAH is a serious condition and there is an urgent need for patients to have access to new treatments,” said Eiry W. Roberts, MD, chief medical officer at Neurocrine Biosciences.¹ "Crinecerfont's compelling efficacy results and excellent safety profile support our filing, and we look forward to working with the FDA as we head toward the PDUFA dates at the end of 2024."

A rare genetic condition, CAH results in an enzyme deficiency altering the production of adrenal hormones.² Nearly all (95%) CAH cases are caused by a mutation leading to the deficiency of the enzyme 21-hydroxylase (21-OHD). A severe deficiency of 21-OHD can lead to the inability of cortisol production and in 75% of cases, aldosterone production.²

Without treatment, CAH can lead to salt wasting, dehydration, and death. Glucocorticoids are used to correct the endogenous cortisol deficiency, but the doses are typically higher than the replacement needed to lower levels of adrenocorticotropic hormone (ACTH) and adrenal androgens.

These supraphysiologic doses have been linked to significant complications of steroid excess, including metabolic issues, cardiovascular disease, and osteoporosis.

Crinecerfont is an oral, selective corticotropin-releasing factor type 1 receptor (CRF1) antagonist in development to reduce and control excess ACTH and adrenal androgens through a glucocorticoid-independent mechanism for CAH due to 21-OHD.¹

Phase 3 CAHtalyst Pediatric and CAHtalyst Adult studies supported the two NDA submissions to the FDA in April 2024.^3,4 These global registrational studies are designed to assess the safety, efficacy, and tolerability of crinecerfont in children and adolescents, and adults, respectively, with CAH due to 21-OHD.

These study data demonstrate the lowering of adrenal androgen levels allowed lower, more physiologic dosing of glucocorticoids to manage androgen excess. This may reduce the complications associated with exposure to supraphysiologic glucocorticoid doses in CAH.

In CAHtalyst Pediatric, crinecerfont demonstrated superiority to placebo in the reduction of elevated androstenedione levels, and a decrease in glucocorticoid dose from supraphysiologic to physiologic levels, with maintenance of androstenedione control.³

Meanwhile, in CAHtalyst Adult, use of crinecerfont showed a greater decrease from baseline in the mean daily glucocorticoid dose, including a reduction to the physiologic range, versus placebo, after evaluation of adrenal androgen levels.⁴

Pending FDA approval, crinecerfont would become the first new treatment option for CAH in approximately 70 years and represent a first-in-class therapy with a novel approach for the rare endocrine disorder.¹

If approved, Neurocrine Biosciences can activate its Rare Pediatric Disease Designation Priority Review Voucher obtained in September 2020. Crinecerfont was previously granted Orphan Drug designation in March 2019 and Breakthrough Therapy designation by the agency in December 2023.

References

1. _{Neurocrine Biosciences announces U.S. FDA accepts New Drug Applications and grants priority review for Crinecerfont for pediatric and adult patients with CAH. Neurocrine Biosciences. July 1, 2024. Accessed July 1, 2024. https://neurocrine.gcs-web.com/news-releases/news-release-details/neurocrine-biosciences-announces-us-fda-accepts-new-drug-0.}
2. _{Burdea L, Mendez MD. 21-Hydroxylase Deficiency. [Updated 2023 Jul 31]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK493164/}
3. _{Sarafoglou K, Kim MS, Lodish M, et al. Phase 3 Trial of Crinecerfont in Pediatric Congenital Adrenal Hyperplasia. N Engl J Med. Published online June 2, 2024. doi:10.1056/NEJMoa2404655}
4. _{Auchus RJ, Hamidi O, Pivonello R, et al. Phase 3 Trial of Crinecerfont in Adult Congenital Adrenal Hyperplasia. N Engl J Med. Published online June 1, 2024. doi:10.1056/NEJMoa2404656}