Endocrine Abstracts

Background: Relacorilant is a highly selective glucocorticoid receptor (GR) modulator in development for the treatment of endogenous Cushing syndrome (CS). Unlike the GR antagonist mifepristone, relacorilant lacks affinity for the progesterone and other receptors. In a phase 2 study in patients with CS (Pivonello et al, 2021), relacorilant provided clinically meaningful changes in several cortisol-excess-related comorbidities, including hypertension and hyperglycemia, without undesirable antiprogesterone effects or drug-induced hypokalemia. Four clinical studies of relacorilant in patients with CS are ongoing: GRACE (NCT03697109), a phase 3 trial enrolling patients with endogenous CS of all etiologies; GRADIENT (NCT04308590), a phase 3 trial focusing on hypercortisolism due to adrenal adenomas or hyperplasia; a phase 2/3 long-term extension trial (NCT03604198); and a phase 1b trial in patients with adrenocortical carcinoma and glucocorticoid excess (NCT04373265). Here, we report data from open-label phase 1 and 2 studies of relacorilant in healthy and hepatically impaired adults and in adult patients with CS.

Methods: Data from 3 studies are reported: a study including subjects with hepatic impairment in which 9 subjects with moderate hepatic impairment (Child-Pugh Class B) and 9 matched controls with normal hepatic function received relacorilant (300 mg QD) for 10 days; a phase 1 fixed-sequence drug-drug interaction study (NCT03512548) in which 28 healthy subjects received relacorilant (300 mg QD) for 10 days followed by 10 days of relacorilant (300 mg QD) + itraconazole (200 mg QD); and a phase 2 study in which 35 patients with endogenous CS received relacorilant (100–400 mg QD) for up to 16 weeks (NCT02804750).

Results: While relacorilant is eliminated primarily hepatically, no apparent difference in relacorilant pharmacokinetics in subjects with moderate hepatic impairment vs matched controls was observed, with relacorilant exposures largely overlapping across both groups. Reductions in liver function tests (LFTs) were also observed in this study. In healthy adults receiving relacorilant followed by relacorilant + itraconazole (an agent with reported liver toxicity), a similar trend toward reduced LFTs was seen throughout the study. In the phase 2 study in patients with CS, reductions in LFTs were also observed, including normalization of LFTs in some patients with abnormal values at baseline.

Conclusions: These results suggest that relacorilant has a favorable liver safety profile, including a trend toward improved LFTs in volunteers and patients with normal and abnormal liver function. The hepatic impairment study results support relacorilant use without dose adjustment in patients with moderate hepatic impairment.