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

Abstract

Introduction/PurposeRelacorilant 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).Materials and MethodsA 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%).Results35 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.ConclusionsThe SGRM relacorilant provided clinical benefit to patients with CS without undesirable antiprogesterone effects or drug-induced hypokalemia.

Peripheral glucocorticoid receptor antagonism by relacorilant with modest HPA axis disinhibition

“…Copyright © 2022 Society for Endocrinology Downloaded from Bioscientifica.com at 12/05/2022 08:03:17AM via free access increase in serum ACTH and cortisol concentrations (Pivonello et al, 2021). In a novelty stress test in mice, we confirmed the strong disinhibition of the HPA axis by mifepristone treatment (Gaillard et al, 1984;Ratka et al, 1989).…”

Glucocorticoid Receptor Antagonism Upregulates Somatostatin Receptor Subtype 2 Expression in ACTH-Producing Neuroendocrine Tumors: New Insight Based on the Selective Glucocorticoid Receptor Modulator Relacorilant

“…Two patients with de novo Cushing disease due to pituitary macroadenomas received relacorilant 100 mg/day titrated to 200 mg/day as part of a phase 2 Cushing syndrome study prior to previously scheduled transsphenoidal pituitary surgery ( 35 ). Patient 3 was a 50-year-old woman with a pituitary macroadenoma measuring 10.01 × 6.29 × 4.91 mm on MRI (tumor volume 155 mm 3 ).…”

The Role of Glucocorticoid Receptor in the Pathophysiology of Pituitary Corticotroph Adenomas

“…On the contrary, the drug showed important benefits on blood pressure and no cases of hypokalemia were registered. Moreover, its molecular structure strongly reduces its affinity for PR avoiding anti-progesterone effect [ 77 ].…”