Crinetics Pharmaceuticals Lead ACTH Antagonist for Congenital Adrenal Hyperplasia & Cushing’s Disease Advances Into Phase 1 Study

Crinetics Pharmaceuticals, Inc. recently announced that CRN04894, the company’s lead adrenocorticotropic hormone (ACTH) antagonist for the treatment of diseases associated with excess ACTH such as Cushing’s disease and congenital adrenal hyperplasia (CAH), has advanced into the clinic. Based on encouraging preclinical results, Crinetics has initiated a double-blind, randomized, placebo-controlled Phase 1 study of this orally administered, nonpeptide small molecule drug candidate in healthy volunteers. This study will assess the safety and tolerability of single and multiple doses of CRN04894 and will measure the effect of CRN04894 on suppression of cortisol, cortisol precursors, and adrenal androgens following exogenous ACTH stimulation.

Scott Struthers, PhD, Founder and Chief Executive Officer of Crinetics, said “ACTH is the central hormone mediating the endocrine stress response in humans. While disease due to ACTH excess was first described more than a century ago, until now no agents that can block the action of ACTH have been developed and made available for human clinical studies. This is a major step forward toward a new class of therapeutic for patients suffering from devastating diseases of the stress endocrine axis, such as Cushing’s disease or congenital adrenal hyperplasia. I am extremely proud of our discovery scientists for crafting a molecule that has the potential to solve this long-standing problem in endocrinology.”

“CRN04894 is a nonpeptide, small molecule that is designed to be taken orally to block the interaction of ACTH with its target receptor. It has the potential to offer a life-saving treatment option to patients with Cushing’s disease, CAH, and related diseases,” said Alan Krasner, MD, Chief Medical Officer of Crinetics. “Like the first-in-human study for our lead endocrine drug candidate, paltusotine, this first-in-human study for CRN04894 is designed to evaluate not just safety and pharmacokinetic data, but also to assess the pharmacologic activity to lower cortisol levels. Serum cortisol is the biomarker used to evaluate treatments of Cushing’s disease. It has served as the basis for FDA approval of recent therapies and is a meaningful pharmacodynamic readout to assess the ability of CRN04894 to block ACTH signaling in other conditions of ACTH excess, such as CAH. Like our other programs, we believe that if successful, this healthy volunteer study can provide important clinical proof-of-concept data for the program.”

Crinetics anticipates enrolling approximately 100 healthy volunteers divided into multiple cohorts in the single ascending dose (SAD) and multiple ascending dose (MAD) phases of the study. In the SAD phase, study participants will receive synthetic ACTH during the study to replicate conditions of excess ACTH and create a baseline of elevated serum cortisol. On day 1, volunteers will undergo ACTH stimulation after which they will be administered placebo or ascending doses of study drug. In the MAD phase, participants will undergo ACTH stimulation test at baseline after which they will be administered placebo or ascending doses of study drug daily for 10 days and an ACTH stimulation test will be performed after repeat dosing.

The primary objective is to evaluate the percentage of subjects with treatment-emergent adverse events. In addition to safety, a key endpoint is inhibition of ACTH stimulated serum cortisol levels compared to baseline before treatment with CRN04894. A reduction in serum cortisol could indicate successful blockade of MCR2, the receptor target of ACTH. Pharmacokinetics of CRN04894 will also be assessed.

Adrenocorticotropic hormone (ACTH) is synthesized and secreted by the pituitary gland and binds to melanocortin type 2 receptor (MC2R), which is selectively expressed in the adrenal gland. This interaction of ACTH with MCR2 stimulates the adrenal production of cortisol, a stress hormone that is involved in the regulation of many systems. Cortisol is involved for example, in the regulation of blood sugar levels, metabolism, inflammation, blood pressure, and memory formulation. Diseases associated with excess of ACTH, therefore, can have significant impact on physical and mental health. Crinetics’ ACTH antagonist, CRN04894, has exhibited strong binding affinity for MC2R in preclinical models and demonstrated suppression of adrenally derived glucocorticoids and androgens that are under the control of ACTH, while maintaining mineralocorticoid production.

Cushing’s disease is a rare disease with a prevalence of approximately 10,000 patients in the US. It is more common in women, between 30 and 50 years of age. Cushing’s disease often takes many years to diagnose and may well be under-diagnosed in the general population as many of its symptoms such as lethargy, depression, obesity, hypertension, hirsutism, and menstrual irregularity can be incorrectly attributed to other more common disorders.

Congenital adrenal hyperplasia (CAH) encompasses a set of disorders that are caused by genetic mutations that result in impaired cortisol synthesis with a prevalence of approximately 27,000 patients in the US. This lack of cortisol leads to a loss 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.

Crinetics Pharmaceuticals is a clinical-stage pharmaceutical company focused on the discovery, development, and commercialization of novel therapeutics for rare endocrine diseases and endocrine-related tumors. The company’s lead product candidate, paltusotine (formerly CRN00808), is an investigational, oral, selective nonpeptide somatostatin receptor type 2 biased agonist for the treatment of acromegaly, an orphan disease affecting more than 25,000 people in the US. Crinetics plans to advance paltusotine into a Phase 3 program in acromegaly and a Phase 2 trial for the treatment of carcinoid syndrome associated with NETs in 2021. The company is also developing CRN04777, an investigational, oral, nonpeptide somatostatin receptor type 5 (SST5) agonist for congenital hyperinsulinism, as well as CRN04894, an investigational, oral, nonpeptide ACTH antagonist for the treatment of Cushing’s disease, congenital adrenal hyperplasia, and other diseases of excess ACTH. All of the company’s drug candidates are new chemical entities resulting from in-house drug discovery efforts and are wholly owned by the company. For more information, visit crinetics.com.