Oral ACTH Blocker Safely Reduces Cortisol, Early Data Show

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by Steve Bryson, PhD |

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CRN04894, a first-in-class, investigational oral medication to treat Cushing’s disease, demonstrated pharmacologic proof-of-concept with a dose-dependent suppression of cortisol, according to data from a Phase 1 study.

CRN04894, developed by Crinetics Pharmaceuticals, is designed to block the interaction (antagonist) between the MC2R receptor, found specifically on the adrenal glands, and adrenocorticotropic hormone (ACTH), which is secreted in excess typically due to a non-cancerous tumor in the brain’s pituitary gland.

High levels of ACTH signal the adrenal glands to overproduce and release the stress hormone cortisol, which leads to the onset of Cushing’s. By blocking the interaction between the MC2R receptor and ACTH, CRN04894 is intended to reduce cortisol levels and reduce disease symptoms.

The candidate therapy also is being developed for congenital adrenal hyperplasia (CAH), a condition also characterized by abnormally high ACTH levels.

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“ACTH is the central hormone of the endocrine stress response. Even though we’ve known about its clinical significance for more than 100 years, there has never been an ACTH antagonist available to intervene in diseases of excess stress hormones,” Scott Struthers, PhD, founder and CEO of Crinetics, said in a press release. “This is an important milestone for the field of endocrinology and for our company.”

The first part of the placebo-controlled Phase 1 trial enrolled 39 healthy volunteers in the single-ascending-dose (SAD) study, which evaluated the therapy’s safety along with its pharmacokinetics — how CRN04894 moves into, through, and out of the body. Responses were assessed before and after challenges with a lab-made version of ACTH to evaluate the pharmacologic impact resulting from CRN04894 exposure.

Healthy volunteers first were given escalating oral doses of CRN04894 — from 10 mg to 80 mg — or a placebo.

Analysis of cortisol levels before the ACTH challenge demonstrated that CRN04894 led to a rapid and dose-dependent reduction of cortisol by 25–56%.

After being challenged with an excessively high dose of ACTH (250 micrograms), CRN04894 suppressed cortisol by up to 41%. After being challenged with ACTH that mimicked the levels found in patients (1 microgram), the therapy reduced cortisol by 48%, which was clinically meaningful.

According to Crinetics, these reductions in cortisol levels suggested CRN04894 bound to the target receptor on the adrenal gland, blocking the action of ACTH.

The second part of the trial will be a multiple ascending dose (MAD) study, in which the medicine will be administered in ascending doses daily for 10 days (or placebo). After repeated doses, the safety, pharmacokinetics, and pharmacodynamics — the biochemical, physiologic, and molecular effects of CRN04894 — will be assessed.

“We are very encouraged by these single ascending dose data which clearly demonstrate proof of ACTH antagonism with CRN04894 exposure in healthy volunteers,” said Alan Krasner, MD, chief medical officer of Crinetics. “We look forward to completing this study and assessing results from the multiple ascending dose cohorts.”

“As a clinical endocrinologist, I recognize the pioneering nature of this work and eagerly look forward to further understanding the potential of CRN04894 for the treatment of diseases of ACTH excess,” Krasner added.

In terms of safety, CRN04894 was well-tolerated by the healthy volunteers who participated in the SAD study, and all adverse side effects were considered mild.

“I am extremely proud of our team that conceived, discovered, and developed CRN04894 this far,” Struthers said. “I am very excited to see what it can do in upcoming clinical studies.”