Relacorilant shows significant benefits in Cushing’s patients in trial

Oral therapy seen to safely reduce high blood pressure, blood sugar levels

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by Andrea Lobo |

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About five months of treatment with relacorilant significantly reduced both high blood pressure and high blood sugar levels in people with endogenous Cushing’s syndrome, according to data from a Phase 3 trial.

Relacorilant also was found to be generally safe and well tolerated, and to be able to significantly ease other Cushing’s symptoms, particularly excessive body weight, waist circumference, and cognition impairments. It also was shown to improve patients’ quality of life.

The trial, called GRACE (NCT03697109), is evaluating the safety and efficacy of relacolirant in Cushing’s patients with high blood pressure, known as hypertension, and/or type 2 diabetes mellitus or impaired glucose tolerance, which is pre-diabetes. The newly reported data pertains to GRACE’s open-label portion, in which both participants and researchers know the treatment being given to the patients.

Corcept Therapeutics, the company sponsoring the trial and developing relacorilant, now plans to soon submit a new drug application (NDA) to U.S. regulatory authorities. That NDA, requesting the therapy’s approval for all forms of Cushing’s syndrome, is expected to be filed in the second quarter of this year, which would mean by the end of June, per the company.

“Patients showed marked improvement across a broad range of signs and symptoms, without significant safety burden,” Richard Auchus, MD, PhD, a professor at the University of Michigan, and chief of the endocrinology and metabolism section at the Ann Arbor Veterans Affairs (VA) Medical Center, said in a company press release.

“Due to relacorilant’s unique mechanism of action, we are not observing other toxicities seen with current therapies,” Auchus added, noting that, overall, this “positions relacorilant to potentially become a new standard of care for patients with this disease.”

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Nearly 1 in 4 people with type 2 diabetes has Cushing’s syndrome

Relacorilant now being tested in Phase 3 GRACE trial

Cushing’s syndrome includes several conditions driven by excessive levels of the hormone cortisol, which is also referred to as hypercortisolism. It is considered endogenous when a problem within a person’s body, most commonly a tumor, is the underlying cause of hypercortisolism. Cushing’s disease is a specific form of endogenous Cushing’s that’s caused by tumors in the brain’s pituitary gland.

Relacorilant is an oral therapy designed to selectively block glucocorticoid receptors — the proteins to which cortisol binds to exert its effects. In so doing, the therapy is expected to prevent the effects that high cortisol levels have on the body, in particular, high blood pressure and high blood sugar.

In a Phase 1 trial involving healthy volunteers, the therapy was found to be generally safe and well-tolerated. Then, in a Phase 2 trial (NCT02804750) enrolling 35 Cushing’s patients, it was shown to reduce blood pressure and improve glucose tolerance.

The GRACE study now is testing the treatment in 152 patients with endogenous Cushing’s. The trial started with an open-label phase, followed by a randomized withdrawal portion.

During the open-label phase, all patients were treated with oral capsules of relacorilant at a daily dose of 100-400 mg, for a total of 22 weeks, or about five months. After that, those deemed to 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 12 weeks, or about three months, in the study’s randomized withdrawal phase.

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Corcept says it’s ‘on track’ to file for FDA approval by June

The newly announced data from the trial’s open-label portion showed that all patients with hypertension experienced rapid and sustained reductions in blood pressure, with more than half (63%) meeting the criteria to be considered responders during that initial phase.

Specifically, after the 22 weeks of treatment, patients’ systolic blood pressure — the pressure measured in the arteries when the heart beats — decreased by a mean of 7.9 millimeters of mercury (mmHg), while diastolic blood pressure, which is measured in the arteries while the heart rests between beats, decreased by a mean of 5.4 mmHg. Reductions were even higher among those who qualified to enter the trial’s randomized withdrawal phase.

The effects of relacorilant on blood sugar levels were evaluated by several diagnostic tests, including those assessing fasting glucose levels and glycated hemoglobin (HbA1c). HbA1c measures the proportion of hemoglobin — the protein that transports oxygen in red blood cells — that is bound to blood sugar.

Patients with high blood sugar levels showed clinically meaningful and statistically significant improvements in glucose metabolism across all measurements. This included individuals with diabetes and pre-diabetes. Half of these participants were considered treatment responders in the open-label phase.

After the 22 weeks, there was a mean reduction of 0.3% in HbA1c and a mean decrease in fasting glucose of 12.4 mg/dL. These reductions also were higher in the subgroup of patients who qualified to enter the study’s randomized withdrawal phase.

Moreover, relacorilant was found to be well-tolerated. The most common side effects reported were mild to moderate in severity and included nausea, swelling, pain in the extremities and back, and fatigue.

“We expect to build on these results in the trial’s randomized withdrawal phase,” said Bill Guyer, chief development officer at Corcept.

According to Guyer, the company is planning to share data from both the open-label and randomized withdrawal phases at a medical conference in June.

“We … remain on track to submit our NDA this quarter,” Guyer said.