Neurocrine Biosciences has received Breakthrough Therapy designation from the U.S. Food and Drug Administration (FDA) for crinecerfont in the treatment of congenital adrenal hyperplasia (CAH). This designation underscores the FDA's recognition of the seriousness of CAH and the significant unmet need for more effective therapies. The company also provided updates on its broader R&D portfolio and strategy at its Analyst Day in New York.
Eiry W. Roberts, Chief Medical Officer of Neurocrine Biosciences, stated, "We are very pleased that the FDA granted Breakthrough Therapy designation for crinecerfont, thus recognizing both the seriousness of congenital adrenal hyperplasia and the significant unmet need currently faced by patients and families living with this condition."
Promising Phase 3 Results for Crinecerfont
The Breakthrough Therapy designation was supported by data from the Phase 3 CAHtalyst studies, which evaluated crinecerfont in both pediatric and adult patients with classic CAH. These studies demonstrated statistically significant improvements in key endpoints. The CAHtalyst Pediatric study showed a statistically significant decrease in serum androstenedione from baseline at Week 4. Both the Pediatric and Adult studies showed statistically significant reductions in daily glucocorticoid dose from baseline while maintaining androgen control at Week 28 and Week 24, respectively.
Crinecerfont was generally well-tolerated in the CAHtalyst Phase 3 studies. In the Pediatric study, common adverse events included headache, fever, vomiting, upper respiratory tract infection, and nasopharyngitis. The Adult study reported fatigue, headache, and coronavirus infection as common adverse events. Completion rates were high in both studies, exceeding 95%.
The Need for New CAH Treatments
Congenital adrenal hyperplasia (CAH) encompasses a group of genetic conditions that disrupt the production of adrenal hormones, which are essential for life. Approximately 95% of CAH cases stem from a mutation causing a deficiency in the enzyme 21-hydroxylase (21-OHD). In classic CAH, this deficiency impairs the adrenal glands' ability to produce cortisol and, in about 75% of cases, aldosterone. Untreated classic CAH can lead to salt wasting, dehydration, and even death.
Currently, there are no non-glucocorticoid treatments approved by the FDA for classic CAH. Glucocorticoids, the current standard of care, are often used at supraphysiologic doses to suppress corticotropin-releasing factor (CRF) and adrenocorticotropic hormone (ACTH) levels, which drive androgen excess. However, long-term use of high-dose glucocorticoids is associated with serious complications, including metabolic issues, cardiovascular disease, and psychological and cognitive impacts. Androgen excess can also lead to abnormal bone growth in children, female health problems, testicular rest tumors in males, and fertility issues in both sexes.
Crinecerfont: A Novel CRF1 Antagonist
Crinecerfont is an investigational, oral, selective corticotropin-releasing factor type 1 receptor (CRF1) antagonist. It is designed to reduce and control excess adrenal androgens through a steroid-independent mechanism. By blocking CRF1 receptors in the pituitary gland, crinecerfont decreases ACTH levels, which in turn reduces the production of adrenal androgens. This mechanism has the potential to lower androgen levels, enabling lower, more physiologic dosing of glucocorticoids and potentially reducing the complications associated with high-dose glucocorticoid exposure.
Neurocrine Biosciences anticipates submitting a New Drug Application (NDA) for crinecerfont in 2024.
Advancing a Broad R&D Portfolio
Neurocrine Biosciences is also advancing a diverse portfolio of other compounds. Key updates from the Analyst Day include:
- Valbenazine: An ongoing Phase 3 study of valbenazine as an adjunctive treatment for schizophrenia will inform the potential advancement of NBI-'890, a next-generation, long-acting VMAT2 inhibitor, anticipated to enter the clinic in 2024.
- NBI-'770: This oral NMDA NR2B negative allosteric modulator is entering Phase 2 for the treatment of major depressive disorder.
- Muscarinic Compounds: Neurocrine has five muscarinic programs in human studies, including NBI-'568, an M4 agonist, currently in Phase 2 for the treatment of schizophrenia. Four Phase 1 programs are also planned for 2024: NBI-'570 (dual M1/M4 agonist), NBI-'567 (M1-preferring agonist), NBI-'569 (M4-preferring agonist), and NBI-'986 (M4 antagonist).
Top-line Phase 2 clinical data is expected in 2024 for NBI-'568 (M4 agonist) for schizophrenia, luvadaxistat (DAAO inhibitor) for cognitive impairment associated with schizophrenia, NBI-'845 (AMPA potentiator) for inadequate response to treatment in major depressive disorder, and efmody (long-acting glucocorticoid) for both adrenal insufficiency and congenital adrenal hyperplasia.
