SUN-451 A Randomized-Withdrawal, Placebo-Controlled, Phase 3 Study to Assess the Efficacy and Safety of Selective Glucocorticoid Receptor Antagonist, Relacorilant, in Patients with Cushing Syndrome (GRACE Study)

Abstract

Relacorilant is a highly selective glucocorticoid receptor antagonist (GRA) that modulates the effects of excess cortisol while showing no affinity for progesterone, mineralocorticoid, androgen, or estrogen receptors. In a phase 2 study, treatment with relacorilant showed improvement in glycemic and hypertension endpoints as well as other manifestations of cortisol excess in patients with endogenous Cushing syndrome (CS). Relacorilant was well tolerated, with no instances of drug-related hypokalemia or antiprogesterone effects. A multicenter phase 3 clinical trial of relacorilant is underway (GRACE Study: NCT03697109) that uses a randomized withdrawal (RW) design to evaluate efficacy and safety. Based on the mechanism of action of GRAs, clinical efficacy endpoints are being used. The study includes a 6-week (6wk) screening phase, followed by a 22wk open-label (OL) treatment phase, where eligible patients 18-80 years old with a confirmed biochemical diagnosis of endogenous CS, clinical signs and symptoms of CS, and either diabetes mellitus/impaired glucose tolerance (DM/IGT) or hypertension will receive relacorilant (100 mg/day, titrated to 400 mg/day, as tolerated). Those patients who complete the OL phase and meet clinical response criteria (assessed at OL wk22) are eligible to enter the blinded RW phase, where they will receive either placebo or relacorilant at the same dose they received at the end of the OL phase. During the RW phase, increases in antidiabetic and/or antihypertensive agents are allowed if there is a loss of response compared to OL wk22. Criteria for RW entry in the DM/IGT group include one of the following: ≥0.5% decrease in HbA1c from baseline, normalization or ≥50 mg/dL decrease in 2-hour OGTT glucose from baseline, or decrease in daily insulin or sulfonylurea dose and HbA1c unchanged or decreased. Criteria for RW entry in the hypertension group include one of the following: ≥5 mmHg decrease in mean systolic and/or diastolic blood pressure (SBP/DBP) without worsening of either, or a reduction in the number/dose of antihypertensives and no worsening of SBP/DBP. The primary efficacy endpoint in the DM/IGT group is the mean change from OL wk22 to RW wk12 in 2-hour OGTT glucose as compared between treatment groups. In the hypertension group, the primary endpoint is the proportion of patients with a loss of response with respect to hypertension from OL wk22 to RW wk12 as compared between treatment groups. Loss of response is defined as an increase in SBP or DBP ≥5 mmHg or any increase in dose or number of antihypertensive medications. Secondary efficacy endpoints include the proportion of patients meeting any DM/IGT and/or hypertension RW entry criteria at the end of the OL phase. Cushing Quality-of-Life and Global Clinical Response scores are also assessed. In conclusion, GRACE is enrolling participants in the first RW trial to assess relacorilant in the treatment of CS.