Neurocrine Biosciences presented positive results from a phase 2 study of crinecerfont (NBI-74788) in adult patients with classic congenital adrenal hyperplasia (CAH). Data showed meaningful reductions in all three key disease hormone markers after 14 days of treatment. Results were presented at the Endocrine Society’s ENDO Online 2020 meeting.
The phase 2 open-label, multiple-dose, dose-finding study assessed the safety, tolerability, pharmacokinetics and pharmacodynamics of crinecerfont in 18 adults with classic 21-hydroxylase deficiency CAH. The study’s sequential-cohort design evaluated four crinecerfont oral dosing regimens: 50 mg at bedtime (Cohort 1; n=8); 100 mg at bedtime (Cohort 2; n=7); 100 mg once-daily with an evening meal (Cohort 3; n=8); and 100 mg twice-daily with meals (Cohort 4; n=8). Participants in Cohorts 1 and 2 could enroll in Cohorts 3 and/or 4. Each regimen was administered for 14 consecutive days.
Crinecerfont treatment produced meaningful reductions in elevated adrenocorticotropic hormone (ACTH) and 17-hydroxyprogesterone (17-OHP) levels (by 54% to 75%) at all doses studied, together with a dose-related decrease in androstenedione (A4) levels, ranging from 21% to 64%. At the highest dose of crinecerfont (100 mg twice daily), 75% of patients showed a response of at least 50% reduction from baseline for each of the three hormone markers at day 14. Treatment with crinecerfont was well tolerated with a favorable safety profile with no related serious adverse events reported. Adverse events reported in two or more participants included headache, upper respiratory tract infection, fatigue, contusion, insomnia and nausea.
Based on these results, Neurocrine Biosciences plans to initiate a single, global registrational study of crinecerfont in adult patients with classic CAH in the second half of 2020.
Crinecerfont is a novel, potent, selective, oral, non-steroidal corticotropin-releasing factor type 1 (CRF1) receptor antagonist. The blockade of CRF receptors in the pituitary has been shown to decrease the release of adrenocorticotropic hormone (ACTH), which in turn decreases the production of adrenal androgens, and potentially the symptoms associated with CAH. Lowering ACTH and adrenal androgen levels could reduce the amount of glucocorticoid treatment necessary for disease control and thus could avoid the complications associated with long-term supraphysiologic glucocorticoid therapy.
About Classic Congenital Adrenal Hyperplasia (CAH)
Classic CAH is a genetic disorder, in which an enzyme deficiency alters the production of adrenal steroids. Because of this deficiency, the adrenal glands fail to produce enough cortisol and, sometimes, aldosterone, resulting in a potentially life-threatening condition. The lack of cortisol stimulates the release of high levels of adrenocorticotropic hormone (ACTH) from the pituitary gland, leading to excessive adrenal androgen levels. These levels can lead to virilization, menstrual irregularities, hirsutism, acne in females and accelerated growth and precocious puberty in childhood (resulting in short stature and fertility problems in both males and females). CAH affects approximately 20,000 to 30,000 people in the United States and approximately 50,000 people in Europe.