Congenital Adrenal Hyperplasia

NBI-74788:  AN INVESTIGATIONAL NEW TREATMENT FOR CLASSIC CONGENITAL ADRENAL HYPERPLASIA (CAH)

Targeting CRF1 for the treatment of Classic CAH

Classic congenital adrenal hyperplasia (CAH) is a rare genetic disorder affecting 20,000-30,000 people in the United States. The condition results in an enzyme deficiency altering the production of adrenal steroids. Because of this deficiency, the adrenal glands have little to no cortisol biosynthesis resulting in a potentially life-threatening condition. If left untreated, classic CAH can result in salt wasting, dehydration and eventually death. Even with cortisol replacement, persistent elevation of adrenocorticotropic hormone (ACTH) from the pituitary gland results in excessive androgen levels leading to virilization and menstrual irregularities in females; both males and females may also experience precocious puberty, short stature, hirsutism, acne and fertility problems.

Corticosteroids are the current standard of care for classic CAH. They are used to both correct the endogenous cortisol deficiency and reduce the excessive ACTH levels and androgen excess. However, the dose and duration of steroid use required to suppress ACTH is well above the normal physiological level of cortisol; resulting in bone loss, growth impairment, metabolic syndrome, and Cushing’s syndrome as common and serious side effects. Through modulation of CRF, Neurocrine Biosciences hopes to lower ACTH levels in individuals with CAH. In doing so, the goal would be to reduce the amount of exogenous corticosteroid necessary for classic CAH patients.

NBI-74788 is a proprietary, potent, selective, orally-active, non-peptide corticotropin-releasing factor type 1 (CRF1) receptor antagonist under evaluation for the treatment of classic CAH. Blockade of CRF receptors in the pituitary has been shown to decrease the release of ACTH, which in turn decreases the production of adrenal steroids, including androgens, and potentially the symptoms associated with CAH. Research suggests that lowering ACTH levels could reduce the amount of corticosteroid treatment necessary for classic CAH patients.