CRN04894 Lowers Blood Cortisol Levels, Top-line Trial Data Show

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by Steve Bryson, PhD |

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CRN04894, a first-in-class, experimental oral medication for Cushing’s disease, led to a dose-dependent drop in blood and urine cortisol levels in healthy volunteers, top-line data from a Phase 1 trial showed.

According to Crinetics Pharmaceuticals, the therapy’s developer, patient studies are expected to launch later this year.

In Cushing’s disease, the adrenocorticotropic hormone (ACTH) is released at high levels due to non-cancerous tumors in the brain’s pituitary gland. Excess ACTH signals the adrenal glands, which sit atop the kidneys, to overproduce the stress hormone cortisol, triggering the onset of Cushing’s.

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CRN04894 is designed to stop the interaction between the melanocortin type 2 receptor (MC2R), an ACTH receptor mainly found in the adrenal glands, and ACTH. In this way, CRN04894 aims to reduce cortisol levels and alleviate disease symptoms.

The investigational medication is also being developed to treat congenital adrenal hyperplasia (CAH), a disorder caused by a deficiency in enzymes needed to make specific hormones that are normally produced by the adrenal glands.

“ACTH is the obvious target for inhibiting excessive stimulation of the adrenal in diseases of ACTH excess,” Scott Struthers, PhD, founder and CEO of Crinetics, said in a press release. “Even though the field of endocrinology has known about its clinical significance for more than 100 years, we are not aware of any other ACTH antagonist that has entered clinical development.”

In the first part of the Phase 1 trial, 39 healthy volunteers received single escalating oral doses of CRN04894 (10 to 80 mg), or a placebo. Researchers examined responses before and after participants were challenged with a lab-made version of ACTH, at an excessively high dose (250 micrograms), as well as at a lower dose (1 microgram) that mimics the levels found in patients.

As previously reported, before the ACTH challenge, CRN04894 led to a rapid and dose-dependent decrease in cortisol levels by up to 56%. After the high-dose ACTH challenge, cortisol dropped by up to 41%, while at the lower dose challenge, the therapy reduced cortisol by a clinically meaningful 48%.

Top-line data, reported by the company, covered the trial’s second and multiple ascending dose part. Here, 49 healthy adults received 40, 60, or 80 mg of the medicine, or a placebo, daily for 10 days. CRN04894 again led to a dose-dependent suppression of cortisol in the bloodstream.

Within 24 hours of exposure, blood cortisol levels were reduced by 17% in participants given the 40 mg dose, by 29% in those given the 60 mg dose, and by 37% in those who received the highest 80 mg dose. In comparison, average cortisol levels increased by 2% among those on placebo.

After 10 days of dosing, evaluable participants were given an ACTH challenge to stimulate adrenal activation to disease-relevant levels. Dose-dependent suppression of bloodstream cortisol, as well as urine-free cortisol, was seen in people given the 60 and 80 mg doses.

Even when additional ACTH was administered, cortisol levels remained below the normal range in those exposed to CRN04894, which was clinically significant, according to Crinetics.

Supporting once-daily dosing, data also showed the therapy had a half-life of 24 hours, meaning it took 24 hours for its initial levels to drop by 50%.

Safety data were consistent with the study’s first part, and there were no discontinuations reported due to treatment-related side effects and no serious adverse events. Given CRN04894’s mechanism of action, glucocorticoid deficiency was the most common treatment-related adverse event in the study’s second part.

“The design of our Phase 1 healthy volunteer study allowed us to demonstrate CRN04894’s potent pharmacologic activity in the presence of ACTH levels that were in similar range to those seen in CAH and Cushing’s disease patients,” said Alan Krasner, MD, Crinetics’ chief medical officer.

“The observation of dose-dependent reductions in serum cortisol levels to below the normal range even in the presence of high ACTH indicates that CRN04894 was effective in blocking the key receptor responsible for regulating cortisol secretion [release]. We believe this is an important finding that may be predictive of CRN04894’s efficacy in patients,” Krasner added.

The company plans to present further safety, efficacy, and biomarker results from the Phase 1 study at an endocrinology-focused meeting this year.