Relacorilant for Cushing’s disease

Last updated Sep. 7, 2023, by Lindsey Shapiro, PhD
Fact-checked by Joana Carvalho, PhD

What is relacorilant for Cushing’s disease?

Relacorilant is an experimental oral therapy designed for people with all forms of endogenous Cushing’s syndrome, including Cushing’s disease. It aims to ease the effects of excess cortisol, namely the high blood pressure and elevated blood sugar seen in some patients.

Developed by Corcept Therapeutics, Relacorilant has been granted orphan drug status in the U.S. and Europe for endogenous Cushing’s. Those designations are expected to accelerate the therapy’s development via a number of incentives. The company has said it plans to seek approval of relacorilant in the U.S. in the second quarter of 2024.

The medication also is being developed for people with certain forms of cancer.

Therapy Snapshot

How does relacorilant work in Cushing’s disease?

All forms of endogenous Cushing’s syndrome are marked by the excess production of the hormone cortisol due to problems within the body itself. In Cushing’s disease, this occurs due to a tumor in the pituitary gland, located at the base of the brain.

In patients, the disorder can lead to a wide range of symptoms, including blood pressure and blood sugar changes.

Cortisol, which regulates a wide range of vital processes in the body, exerts its many effects by binding to glucocorticoid receptor proteins. Relacorilant, also known as CORT125134, is designed to selectively block these glucocorticoid receptors. That, in turn, is expected to prevent the effects of high cortisol in all forms of endogenous Cushing’s syndrome, regardless of its underlying cause.

How will relacorilant be administered in Cushing’s disease?

In clinical trials involving Cushing’s patients, relacorilant has been given as oral capsules at doses ranging from 100 to 400 mg per day. In ongoing studies, patients are starting with the 100 mg per day dose, which is increased sequentially to reach the target dose of 400 mg once daily, based on tolerability and clinical responses.

Relacorilant in Cushing’s disease clinical trials

After relacorilant was found safe in a Phase 1 trial involving healthy volunteers, an open-label Phase 2 trial (NCT02804750) was launched to evaluate the safety and efficacy of two doses of the medication in people with endogenous Cushing’s syndrome.

Phase 2 trial

That study enrolled 35 patients with this form of the disorder, all with high blood pressure, known as hypertension, and/or high blood sugar levels, called hyperglycemia. For each of these individuals, surgical interventions were not an option. Among the patients, 23 had Cushing’s disease.

Participants were assigned to receive a low (100-200 mg) or a high dose (250-400 mg) of oral relacorilant once per day for 12 and 16 weeks, or three or four months, respectively. The dose of relacorilant started at 100 mg in the first group and 250 mg in the second, and was increased in 50 mg increments every four weeks until the 200 mg and 400 mg doses were reached.

The therapy generally was found to be well tolerated. In the low dose group, 41.7% of the patients with hypertension were considered to have clinically meaningful reductions in blood pressure, based on predefined criteria. Patients with hyperglycemia also saw clinically meaningful reductions, of 15.4%, in blood sugar.

In the high dose group, similar reductions were observed in 63.6% of patients with hypertension and 50% of those with hyperglycemia.

Other benefits associated with relacorilant included weight loss and improvements in markers of bone and liver health. Additionally, significant improvements were seen in blood clotting parameters, and in cognition, depression, and life quality.

Ongoing trials

Two Phase 3 trials are ongoing to confirm the benefits of relacorilant in a larger population of Cushing’s patients.

GRACE trial

The fully enrolled Phase 3 GRACE trial (NCT03697109), launched in 2018, is evaluating relacorilant’s efficacy in 152 adults with Cushing’s syndrome. The participants have high blood pressure and/or type 2 diabetes and impaired glucose tolerance — with two groups with high blood sugar.

All are being treated with relacorilant, given as daily oral capsules, for about five months. The starting daily dose is 100 mg, which is gradually increased up to a target daily dose of 400 mg. After that, those who respond to the therapy based on predefined criteria related to blood sugar and blood pressure are randomly assigned to receive relacorilant or a placebo for about three more months.

Patients who fail to meet responder criteria in the initial five months will end treatment; however, they may still be eligible to roll over into an extension safety study. Data from GRACE are expected in 2024.

GRADIENT trial

The Phase 3 GRADIENT trial (NCT04308590) is testing relacorilant in patients with Cushing’s syndrome caused by adrenal adenomas, or tumors in the adrenal glands that produce cortisol.

To be eligible, patients must have uncontrolled high blood pressure, as well as type 2 diabetes or impaired glucose tolerance. Each is randomly assigned to receive relacorilant or a placebo for about five months, with the dose increasing progressively from 100 mg to a target dose of 400 mg. Overall, GRADIENT will involve about 130 participants at sites in the U.S., Europe, and Israel.

The trial’s main goal is to determine the treatment’s safety, as well as changes in glucose levels for patients with hyperglycemia, and in blood pressure for those whose levels are high. Data are expected in 2024.

Open-label extension

Participants who complete any Corcept-sponsored study of relacorilant and who showed signs of clinical benefit from treatment will be eligible to enter an open-label long-term extension study (NCT03604198). Those in the extension study will continue treatment until relacorilant becomes commercially available or the study is terminated by investigators.

Common side effects of relacorilant

The most common side effects associated with relacorilant in Cushing’s clinical trials include:

• back pain
• headache
• swelling
• nausea
• pain in the extremities
• diarrhea
• dizziness.

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