Potential Oral ACTH Inhibitor for Cushing’s Disease Entering Phase 1 Trial

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by Patricia Inacio PhD |

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ACTH inhibitor entering trial

Crinetics Pharmaceuticals is launching a Phase 1 clinical trial to evaluate the safety and tolerability of oral CRN04894, an inhibitor of adrenocorticotropic hormone (ACTH) activity, in healthy volunteers.

The candidate therapy is being developed for Cushing’s disease and congenital adrenal hyperplasia (CAH), both characterized by abnormally high levels of ACTH. In the case of Cushing’s disease, this is usually due to a tumor in the pituitary gland in the middle of the base of the brain.

“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,” Scott Struthers, PhD, founder and CEO of Crinetics, said in a press release.

“This is a major step forward towards 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,” Struthers added.

Too much ACTH leads to an overproduction of cortisol by the adrenal glands, located above both kidneys. After being released into the bloodstream, ACTH binds to the melanocortin type 2 receptor (MC2R), which is found specifically in the adrenal glands. The binding triggers the adrenal gland to produce cortisol.

CRN04894 is a small molecule designed to block the interaction of ACTH with the MC2R, to halt the ACTH-stimulated overproduction of cortisol.

According to Crinetics, CRN04894 showed a strong affinity for MC2R in preclinical models, suppressing cortisol production.

“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, the company’s chief medical officer.

The Phase 1 study, which aims to enroll about 100 healthy volunteers, will randomly assign participants to single ascending and multiple ascending doses of CRN04894 or to a placebo.

Participants in the single-dose groups will on the first day take a lab-made ACTH to create a condition of excessive ACTH. They will then be randomly assigned to single escalating doses of CRN04894 or a placebo.

Those in the multiple-ascending dose groups will undergo an ACTH stimulation test at the study’s start, which measures how well the adrenal glands respond to ACTH. This will be followed by treatment with ascending doses of CRN04894 or a placebo for 10 days. An ACTH stimulation test will be performed again after the repeat dosing.

The study’s primary goals are to assess the therapy’s safety and its ability to block ACTH-induced cortisol production by measuring blood levels of cortisol before and after treatment with CRN04894.

CRN04894’s pharmacokinetics —  its absorption, distribution, and metabolism in the body — will also be evaluated.

“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 [blood] cortisol is the biomarker used to evaluate treatments of Cushing’s disease. It … is a meaningful pharmacodynamic readout to assess the ability of CRN04894 to block ACTH signaling in other conditions of ACTH excess,” Krasner said.

“Like our other programs, we believe that if successful, this healthy volunteer study can provide important clinical proof-of-concept data for the program,” he added.