| Discovery | Pre-Clinical | Phase 1 | Phase 2 | Phase 3 |
|---|---|---|---|---|
CRN04894, 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.
Inhibition of Basal and ACTH-Stimulated Cortisol Secretion in Humans Using an Oral, Nonpeptide ACTH Antagonist (CRN04894)
CRN04894: Phase 1 Multiple Ascending Dose (MAD) Preliminary Results
May 2022
View presentation:
CRN04894: First In Human Single Ascending Dose Preliminary Results
August 2021
View presentation:
Effects of CRN04894, a Nonpeptide Orally Bioavailable ACTH Antagonist, on Corticosterone in Rodent Models of ACTH Excess
CRN04894 Reduced Effects of Excess ACTH in Animal Model of Cushing’s Disease
Authors
Melissa A. Fowler, PhD, Ana Karin Kusnetzow, PhD, Sangdon Han, PhD, Greg Reinhart, BS, Sun Hee Kim, PhD, Michael Johns, BS, Taylor A. Kredel, BS, Agnes Antwan, BS, Jon Athanacio, BS, Oleg Tsivkovski, BS, Rosa Luo, MS, Ajay Madan, PhD, Yun Fei Zhu, PhD, Stephen F. Betz, PhD, Scott Struthers, PhD, Stacy Markison, PhD. Crinetics Pharmaceuticals, San Diego, CA, USA.
Disclosures
M.A. Fowler: Employee; Self; Crinetics Pharmaceuticals. A.K. Kusnetzow: Employee; Self; Crinetics Pharmaceuticals. S. Han: None. G. Reinhart: Employee; Self; Crinetics Pharmaceuticals. S. Kim: Employee; Self; Crinetics Pharmaceuticals. M. Johns: Employee; Self; Crinetics Pharmaceuticals. T.A. Kredel: Employee; Self; Crinetics Pharmaceuticals. A. Antwan: Employee; Self; Crinetics Pharmaceuticals. J. Athanacio: Employee; Self; Crinetics Pharmaceuticals. O. Tsivkovski: Employee; Self; Crinetics Pharmaceuticals. R. Luo: Employee; Self; Crinetics Pharmaceuticals. A. Madan: Employee; Self; Crinetics Pharmaceuticals. Y. Zhu: Employee; Self; Crinetics Pharmaceuticals. S.F. Betz: Employee; Self; Crinetics Pharmaceuticals. S. Struthers: Employee; Self; Crinetics Pharmaceuticals. S. Markison: Employee; Self; Crinetics Pharmaceuticals.
Abstract
CRN04894 is an orally administered nonpeptide that is a potent and selective antagonist for adrenocorticotropic hormone (ACTH) acting at the melanocortin 2 receptor (MC2R) and is currently under development for the treatment of diseases of ACTH excess such as Cushing’s disease, congenital adrenal hyperplasia, and ectopic ACTH-secreting tumors. Cushing’s disease results from an adenoma derived from pituitary corticotropic cells that secrete excess ACTH, whereas ectopic ACTH syndrome arises from nonpituitary ACTH secreting tumors. Congenital adrenal hyperplasia is a genetic disease that results in cortisol deficiency leading to high levels of ACTH and adrenal androgens. Each of these indications is characterized by high ACTH levels that act on MC2R expressed in the adrenal cortex to drive pathological elevations of adrenally derived steroid hormones. CRN04894 blocks the action of ACTH at MC2R, providing a potential novel treatment for these diseases. Preclinical models of chronic hypercortisolemia include implantation of ACTH-secreting pituitary tumor cells in mice and continuous administration of ACTH via subcutaneously implanted osmotic pumps in rats. These models induce
features consistent with human diseases of ACTH excess including hypercortisolemia and hypertrophy of the adrenal glands. We employed both rodent models to examine the pharmacodynamic effects of CRN04894 on corticosterone levels and adrenal gland morphology. In the mouse pituitary tumor model, subcutaneous inoculation of the ACTH-secreting mouse pituitary tumor cell line, AtT-20, into immunodeficient mice resulted in formation of tumors and increased plasma ACTH and corticosterone levels. Repeated daily oral administration of CRN04894 for 14 days dose-dependently and robustly suppressed plasma corticosterone levels in mice with AtT-20 tumors. In the rat model, subcutaneous implantation of osmotic pumps delivering ACTH resulted in increased corticosterone levels, reduction in body weight, and hypertrophy of the adrenal glands after 7 days. Daily oral administration of CRN04894 over 7 days dose-dependently suppressed corticosterone levels, mitigated the effect of ACTH excess on body weight, and rescued the adrenal gland hypertrophy. These findings provide evidence that CRN04894 functions as an effective ACTH antagonist at MC2R to suppress adrenal corticosterone secretion in both mouse and rat models of ACTH excess and hypercortisolemia, thus providing a strong rationale for its potential therapeutic utility in diseases of ACTH excess. This work was supported in part by an SBIR grant from the NIH awarded to Dr. Struthers (R43- DK115245)
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.