CRF1 Antagonist

 

What is CRF?

Corticotropin-Releasing Factor (CRF) is a peptide released directly from the hypothalamus in the central nervous system into a discrete network of blood vessels where it functions via specific G-Protein Coupled Receptors on cells in the anterior pituitary gland to regulate the release of pituitary hormones including adrenocorticotropic hormone (ACTH). The primary role of ACTH is the stimulation of synthesis and release of adrenal steroids including cortisol. The glucocorticoid cortisol is tightly coupled in a negative manner to the release of both hypothalamic CRF and pituitary ACTH thus providing a very tightly regulated feedback loop.  This is commonly known as the Hypothalamic-Pituitary-Adrenal Axis (HPA).  In diseases or disorders of dysregulated cortisol, levels of ACTH and CRF increase and if left uncontrolled, lead to an overproduction of a number of adrenal steroids including androgens.  Blockade of the specific CRF receptors on the pituitary gland has been shown to decrease the release of ACTH and subsequently attenuate the production and release of adrenal steroids.  A CRF1 antagonist is being investigated to determine whether this effect may potentially alleviate the symptoms associated with an overproduction or excess of adrenal steroids in a number of endocrine disorders.

Clinical Development: Classical Congenital Adrenal Hyperplasia

The Company is currently assessing multiple CRF compounds in preclinical assays. The goal is to file an Investigational New Drug Application for at least one of these compounds in classic congenital adrenal hyperplasia later in 2016.

Results from the Initial Pilot Clinical Study

The pilot clinical trial was a blinded, single-site, pharmacokinetic/pharmacodynamic study assessing two single, ascending doses of NBI-77860 against placebo in adult females with refractory CAH. The eight study participants visited the investigative site for three separate overnight visits consisting of bedtime dosing with placebo or one of two active doses of NBI-77860. Each of the visits was separated by a three-week washout period. Key biomarker measures included adrenocorticotropic hormone (ACTH), 17-hydroxyprogesterone (17-OHP), androgen, and cortisol levels collected in the morning after dosing. Data from this initial single dose exploratory study demonstrated a robust decrease in ACTH and 17-OHP.