Tijmen Moll1, Max Gentenaar1, Iris Waardijk1, Hazel Hunt2, Onno Meijer1, Jan Kroon1
(1) Department of Medicine, Division of Endocrinology, Leiden University Medical Center, Leiden, The Netherlands.
(2) Corcept Therapeutics, Redwood City, California, USA.
Mifepristone is currently the only clinically approved glucocorticoid receptor (GR) antagonist. It effectively alleviates hypercortisolism-associated symptoms, e.g. in Cushing’s syndrome. A drawback is that mifepristone strongly increases plasma cortisol levels, presumably by interference with GR-mediated negative feedback in the hypothalamic-pituitary-adrenal (HPA) axis. Relacorilant is a selective GR modulator in phase 3 clinical development that improves hypertension and hyperglycemia in patients with hypercortisolism, but does not significantly increase cortisol levels. Here, we aimed to characterize the effect of relacorilant on HPA axis activity in mice.
Mice were treated with vehicle, mifepristone or relacorilant (both 60 mg/kg/day) by daily oral gavage for 1, 3 or 12 days. We evaluated endogenous basal corticosterone levels and tested HPA-axis reactivity in response to novelty-induced stress. Mifepristone induced acute disinhibition of basal HPA axis activity. This was normalized after 3 days, but recurred after 12 days of treatment. Strong mifepristone-induced disinhibition of HPA axis activity in response to novelty-induced stress was evident at all timepoints. Relacorilant strongly lowered basal corticosterone levels at day 1, 3 and 12, while relacorilant-treated mice increased corticosterone levels in response to novelty-induced stress, similar to vehicle-treated mice. These differences between mifepristone and relacorilant were not associated with changes in adrenal cortex size or total pituitary ACTH content.
We conclude that selective GR modulation with relacorilant provides benefit over the use of mifepristone by lacking HPA axis disinhibition.