RARE Daily

Neurocrine Biosciences Reports Positive Phase 2 Data for CAH Therapy

June 9, 2020

Rare Daily Staff

Neurocrine Biosciences said a phase 2 study of its experimental therapy crinecerfont showed meaningful reductions in all three key disease hormone markers in adult patients with classic congenital adrenal hyperplasia, a genetic disorder affecting the adrenal glands.

Classic congenital adrenal hyperplasia (CAH) causes an enzyme deficiency that 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).

Corticosteroids, the current standard of care, are used both to correct the endogenous cortisol deficiency and to reduce the high ACTH levels and androgen excess. However, the dose and duration of glucocorticoids required to suppress ACTH are often well above the normal physiological level of cortisol, which can result in serious complications typical of iatrogenic Cushing’s syndrome, including metabolic issues, bone loss, growth impairment, and infection risk.

Crinecerfont is a novel, potent, selective, oral, non-steroidal corticotropin-releasing factor type 1 (CRF1) receptor antagonist under evaluation for the treatment of classic CAH. 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.

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. Each regimen was administered for 14 consecutive days. ACTH, 17-OHP and A4, key disease hormone markers in CAH patients, were measured over a 24-hour period at baseline and after 14 consecutive days of dosing.

Crinecerfont treatment produced meaningful reductions in elevated adrenocorticotropic hormone (ACTH) and 17-hydroxyprogesterone (17-OHP) levels (by 54 percent to 75 percent) at all doses studied, together with a dose-related decrease in androstenedione (A4) levels, ranging from 21 percent to 64 percent.

At the highest dose of crinecerfont (100 mg twice daily), 75 percent of patients showed a response of at least 50 percent 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.

“It is encouraging to see that crinecerfont, a non-steroidal therapy, provided meaningful reductions in three key disease biomarkers in patients with classic CAH,” said Richard Auchus, the study’s lead investigator and professor of internal medicine, division of metabolism, endocrinology and diabetes at Michigan Medicine. “These data suggest that crinecerfont has the potential to improve CAH symptoms and to reduce the burden of daily glucocorticoid exposure for these patients. Hopefully, this approach might provide a new treatment option to better manage the androgen excess of classic CAH while mitigating the adverse consequences of current treatment schemes.”

Neurocrine Biosciences plans to initiate a single, global registrational study of crinecerfont in adult patients with classic CAH in the second half of 2020.


Photo: Richard Auchus, the study’s lead investigator and professor of internal medicine, division of metabolism, endocrinology & diabetes at Michigan Medicine.

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