We Are Crinetics


Crinetics is a pharmaceutical company founded in endocrinology research. Our intense focus is on developing much-needed therapies for people with rare endocrine diseases. For us, it’s all about these underserved patients, who are eager to find therapies that provide effective disease control and bring more simplicity to their lives. To better achieve these goals, we also partner with endocrinologists and other healthcare practitioners to ensure we’re solving real problems for them.

Authors

Elizabeth Rico, PhD, Jian Zhao, PhD, Mi Chen, BS, Ana Karin Kusnetzow, PhD, Yun Fei Zhu, PhD, Stephen F. Betz, PhD.
Crinetics Pharmaceuticals, San Diego, CA, USA.

Disclosures

E. Rico: Employee; Self; Crinetics Pharmaceuticals. J. Zhao: Employee; Self; Crinetics Pharmaceuticals. M. Chen: Employee; Self; Crinetics Pharmaceuticals. A.K. Kusnetzow: Employee; Self; Crinetics Pharmaceuticals. Y. Zhu: Employee; Self; Crinetics Pharmaceuticals. S.F. Betz: Employee; Self; Crinetics Pharmaceuticals.

Abstract

Congenital hyperinsulinism (HI) is the most common cause of persistent hypoglycemia in newborns and infants and arises from dysregulated insulin secretion. Rapid recognition and treatment are vital to prevent seizures, permanent developmental delays, coma, or even death. Very few medical options exist to treat congenital HI patients: the KATP channel activator diazoxide, the injectable somatostatin receptor peptide agonists octreotide and lanreotide, or chronic glucose infusions. However, side effects and/or limited efficacy render these therapies inadequate for many patients.

Somatostatin is a 14-amino acid peptide hormone with a broad spectrum of biological actions, which are regulated through five somatostatin receptor subtypes (SST1-SST5). Somatostatin’s common physiological role is to down- regulate secretion of other hormones in various tissues. Its role in the maintenance of euglycemia is to regulate insulin and glucagon secretion from pancreatic β- and α-cells, respectively. Somatostatin regulates insulin secretion by decreasing the intracellular levels of cAMP, inhibition of voltage-gated calcium channels (VGCC), activation of the G protein-activated inward rectifier K+ channel (GIRK), and direct inhibition of insulin exocytosis.

Several studies have evaluated the effect of somatostatin, somatostatin peptide analogs, and a limited number of nonpeptide somatostatin receptor agonists on insulin secretion in static assays using isolated human islets.

However, the lack of highly selective agonists has made the interpretation of the contribution of SST receptor sub-types difficult to discern. Our programs for the treatment of hyperinsulinism, acromegaly, and other indications have led to the development of selective nonpeptide SST2, SST3, SST4, and SST5 agonists, possessing EC50s < 1 nM in cell-based assays of receptor activation and selectivity > 130 times over the other members of the family. The ability of these selective nonpeptide agonists to regulate glucose- and tolbutamide- stimulated dynamic insulin secretion from human islets was evaluated using a perifusion system (Biorep, FL).

We found that selective SST2 and SST5 agonists potently suppressed dynamic insulin secretion in contrast to SST3 or SST4 selective agonists. Importantly, SST5 agonists were shown to have a greater effect than selective SST2 agonists or diazoxide, demonstrating their potential utility in human conditions such as congenital HI. In addition, SST5 activation is also known to have a smaller effect on glucagon secretion and is also less prone to agonist-driven desensitization than SST2 activation. Taken together, these studies support our program to identify, characterize, and develop potent, nonpeptide, orally-bioavailable, selective SST5 agonists with appropriate pharmaceutical and safety characteristics for the treatment of congenital HI.

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)

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