Relacorilant, a Selective Glucocorticoid Receptor Modulator, Induces Clinical Improvements in Patients With Cushing Syndrome: Results From A Prospective, Open-Label Phase 2 Study

• Published in: Frontiers in endocrinology (Lausanne) Vol. 12; p. 662865
• Main Authors: Pivonello, Rosario, Bancos, Irina, Feelders, Richard A, Kargi, Atil Y, Kerr, Janice M, Gordon, Murray B, Mariash, Cary N, Terzolo, Massimo, Ellison, Noel, Moraitis, Andreas G
• Format: Journal Article
• Language: English
• Published: Switzerland Frontiers Media S.A 14-07-2021
• Subjects: clinical trial; cortisol; Cushing syndrome; Cushing Syndrome - complications; Cushing Syndrome - drug therapy; Cushing Syndrome - pathology; Diabetes Mellitus, Type 2 - complications; Diabetes Mellitus, Type 2 - drug therapy; Diabetes Mellitus, Type 2 - pathology; Endocrinology; Female; Follow-Up Studies; glucocorticoid; Humans; hypercortisolism; hyperglycemia; Hyperglycemia - complications; Hyperglycemia - drug therapy; Hyperglycemia - pathology; Hypertension - complications; Hypertension - drug therapy; Hypertension - pathology; Isoquinolines - therapeutic use; Male; Middle Aged; Prognosis; Prospective Studies; Pyrazoles - therapeutic use; Pyridines - therapeutic use; Receptors, Glucocorticoid - antagonists & inhibitors; clinical trial; hypercortisolism; cortisol; hyperglycemia; glucocorticoid; Cushing syndrome; relacorilant; hypertension
• DOI: 10.3389/fendo.2021.662865
• EISSN: 1664-2392

Relacorilant is a selective glucocorticoid receptor modulator (SGRM) with no progesterone receptor activity. We evaluated the efficacy and safety of relacorilant in patients with endogenous Cushing syndrome (CS).
A single-arm, open-label, phase 2, dose-finding study with 2 dose groups (NCT02804750, https://clinicaltrials.gov/ct2/show/NCT02804750) was conducted at 19 sites in the U.S. and Europe. Low-dose relacorilant (100-200 mg/d; n = 17) was administered for 12 weeks or high-dose relacorilant (250-400 mg/d; n = 18) for 16 weeks; doses were up-titrated by 50 mg every 4 weeks. Outcome measures included proportion of patients with clinically meaningful changes in hypertension and/or hyperglycemia from baseline to last observed visit. For patients with hypertension, clinical response was defined as a ≥5-mmHg decrease in mean systolic or diastolic blood pressure, measured by a standardized and validated 24-h ABPM. For patients with hyperglycemia, clinical response was defined ad-hoc as ≥0.5% decrease in HbA1c, normalization or ≥50-mg/dL decrease in 2-h plasma glucose value on oral glucose tolerance test, or decrease in daily insulin (≥25%) or sulfonylurea dose (≥50%).
35 adults with CS and hypertension and/or hyperglycemia (impaired glucose tolerance or type 2 diabetes mellitus) were enrolled, of which 34 (24 women/10 men) received treatment and had postbaseline data. In the low-dose group, 5/12 patients (41.7%) with hypertension and 2/13 patients (15.4%) with hyperglycemia achieved response. In the high-dose group, 7/11 patients (63.6%) with hypertension and 6/12 patients (50%) with hyperglycemia achieved response. Common (≥20%) adverse events included back pain, headache, peripheral edema, nausea, pain at extremities, diarrhea, and dizziness. No drug-induced vaginal bleeding or hypokalemia occurred.
The SGRM relacorilant provided clinical benefit to patients with CS without undesirable antiprogesterone effects or drug-induced hypokalemia.