| Discovery | Pre-Clinical | Phase 1 | Phase 2 | Phase 3 |
|---|---|---|---|---|
Oral ACTH Antagonist
ACTH acts through the melanocortin type 2 receptor (MC2R) that is primarily expressed in the adrenal gland. This is the first reported oral, selective ACTH antagonist discovered by our team in development for the treatment of Cushing’s disease and other diseases of excess ACTH, such as congenital adrenal hyperplasia.
For the Treatment of Cushing’s Disease
Cushing’s disease results from a pituitary tumor that secretes excess ACTH, which in turn causes the downstream synthesis and over-secretion of cortisol by the adrenal glands. Cortisol is the body’s main stress hormone and excess amounts can cause significant increases in mortality and morbidity.
For the Treatment of Congenital Adrenal Hyperplasia (CAH)
CAH encompasses a set of disorders caused by genetic mutations that result in impaired cortisol synthesis. This lack of cortisol leads to a breakdown of feedback mechanisms and results in persistently high levels of ACTH, which in turn causes overstimulation of the adrenal cortex. The resulting adrenal hyperplasia and over-secretion of other steroids (particularly androgens) and steroid precursors can lead to a variety of effects, from improper gonadal development to life-threatening dysregulation of mineralocorticoids.
We have ongoing efforts to advance the first nonpeptide product candidate to antagonize the peptide adrenocorticotrophic hormone (ACTH) designed for the treatment of Cushing’s disease, CAH, and other diseases of ACTH excess.
Effects of Nonpeptide Orally Bioavailable ACTH Antagonists on Adrenal Gland Size and Function in Rats
Stacy Markison, Melissa A. Fowler, Jon Athanacio, Taylor A. Kredel, Agnes Anwan, Michael Johns, Oleg Tsivkovski, Shirley Cruz, Rosa Luo, Greg Reinhart, Ana Kusnetzow, Ajay Madan, Stephen F. Betz, R. Scott Struthers
Discovery and Identification of Late Stage, Selective Nonpeptide ACTH Antagonists for the Treatment of Cushing’s Disease, Ectopic ACTH Secreting Tumors, and Congenital Adrenal Hyperplasia
Ana K. Kusnetzow, Sangdon Han, Melissa A. Fowler, Jon Athanacio, Greg Reinhart, Elizabeth Rico-Bautista, Sun Hee Kim, Michael Johns, Taylor A. Kredel, Agnes Antwan, Oleg Tsivkovski, Julie Nguyen, Christine Staley, Hannah Tan, Rosalia de Necochea-Campion, Jacob Hawver Pachter, Rosa Luo, Stacy Markison, Ajay Madan, Yun Fei Zhu, R. Scott Struthers, Stephen F. Betz. ENDO Online 2020. June 8-22, 2020.
Nonpeptide, Orally Bioavailable ACTH Antagonists: Suppression of ACTH-induced Corticosterone Secretion and Adrenal Hypertrophy in Rats
Ana Karin Kusnetzow, Melissa A. Fowler, Jon Athanacio, Greg Reinhart, Elizabeth Rico-Bautista, Sangdon Han, Sun Hee Kim, Michael Johns, Taylor A. Kredel, Julie Nguyen, Christine Staley, Hannah Tan, Rosa Luo, Stacy Markison, Ajay Madan, Yun Fei Zhu, R. Scott Struthers, and Stephen F. Betz. ENDO 2019. March 23-26, 2019; New Orleans.