Congenital Adrenal Hyperplasia



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 ACTH from the pituitary gland results in excessive androgen levels leading to virilization of females including precocious puberty, menstrual irregularity, 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, we hope 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 (CRF Receptor antagonist) is a potent, selective, orally-active, non-peptide CRF receptor antagonist as demonstrated in a range of in vitro and in vivo assays.  Blockade of CRF receptors at 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 classic CAH.  Lower ACTH levels would also reduce the amount of exogenous corticosteroid necessary for classic CAH patients to thrive avoiding the side-effects currently associated with excessive steroid therapy.  We plan to conduct a Phase I single ascending dose study of NBI-74788 in healthy volunteers in 2017.  If the pharmacokinetic, safey and tolerability data are favorable, we then plan a pilot clinical trial of NBI-74788 in adult patients with refractory classic CAH.  This pilot study is designed to be a blinded, single-site, pharmacokinetic/pharmacodynamic study assessing two single, ascending doses of NBI-74788 in up to twelve study participants.  Key pharmacodynamic biomarker measurements include ACTH, 17-hydroxyprogesterone (17-OHP), androgen, and cortisol levels collected in the morning following bedtime dosing.  We intend to apply for orphan drug designation for NBI-74788 in the treatment of congenital adrenal hyperplasia.