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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: 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.

SUBMITTER: Auchus R

PROVIDER: S-EPMC6553349 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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Project description: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.

Project description:Abstract Background Relacorilant is a highly selective glucocorticoid receptor (GR) modulator in development for the treatment of endogenous Cushing syndrome (CS). Unlike the FDA-approved GR antagonist mifepristone, relacorilant lacks affinity for the progesterone and other receptors. In a phase 2 study in patients with CS (NCT02804750, Pivonello et al, 2021), relacorilant provided clinically meaningful changes in a number of cortisol-excess-related comorbidities, including hypertension and hyperglycemia, without undesirable antiprogesterone effects or drug-induced hypokalemia. Currently, 4 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 study (NCT03604198); and a phase 1b study in patients with adrenocortical carcinoma associated with glucocorticoid excess (NCT04373265). Here, we report safety results and liver function test (LFT) changes from open-label phase 1 and 2 studies of relacorilant in healthy and hepatically impaired adults and in adult patients with CS. Methods In a special population study, 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. In a phase 1 fixed-sequence drug-drug interaction study (NCT03512548), 28 healthy subjects received relacorilant (300 mg QD) for 10 days followed by 10 days of relacorilant (300 mg QD) combined with itraconazole (200 mg QD). Thirty-five patients with CS received relacorilant (100–400 mg QD) for up to 16 weeks in the phase 2 study. Results While relacorilant is eliminated primarily through the hepatic route, no apparent difference in relacorilant pharmacokinetics in subjects with moderate hepatic impairment vs matched controls was observed, with relacorilant exposures (as measured by area under the concentration-time curve [AUC] and maximum concentration [Cmax]) largely overlapping across both groups. In addition, reductions in LFTs were observed in this study. In healthy adults treated with 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 that includes a trend toward improved LFTs in volunteers and patients with normal and abnormal liver function. The findings of the hepatic impairment study support the use of relacorilant without dose adjustment in patients with moderate hepatic impairment. Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.

Project description:Somatostatin exhibits an inhibitory effect on pituitary hormone secretion, including inhibition of growth hormone and adrenocorticotropic hormone (ACTH), and it can have antisecretory and antitumor effects on neuroendocrine tumors (NETs) that express somatostatin receptors. Although the precise mechanism remains unclear, the finding that glucocorticoids downregulate somatostatin receptor subtype 2 (SSTR2) expression has been used to explain the lack of efficacy of traditional SSTR2-targeting analogs in patients with ACTH-secreting NETs. Glucocorticoid receptor (GR) antagonism with mifepristone has been shown to reverse the glucocorticoid-induced downregulation of SSTR2; however, the effects of GR modulation on SSTR2 expression in ACTH-secreting NETs, particularly corticotroph pituitary tumors, are not well known. The current study presents new insight from in vitro data using the highly selective GR modulator relacorilant, showing that GR modulation can overcome dexamethasone-induced suppression of SSTR2 in the murine At-T20 cell line. Additional data presented from clinical case observations in patients with ACTH-secreting NETs suggest that upregulation of SSTR2 via GR modulation may re-sensitize tumors to endogenous somatostatin and/or somatostatin analogs. Clinical, laboratory, and imaging findings from 4 patients [2 ACTH-secreting bronchial tumors and 2 ACTH-secreting pituitary tumors (Cushing disease)] who were treated with relacorilant as part of two clinical studies (NCT02804750 and NCT02762981) are described. In the patients with ectopic ACTH secretion, SSTR2-based imaging (Octreoscan and 68Ga-DOTATATE positron emission tomography) performed before and after treatment with relacorilant showed increased radiotracer uptake by the tumor following treatment with relacorilant without change in tumor size at computed tomography. In the patients with Cushing disease who received relacorilant prior to scheduled pituitary surgery, magnetic resonance imaging after a 3-month course of relacorilant showed a reduction in tumor size. Based on these findings, we propose that GR modulation in patients with ACTH-secreting NETs upregulates previously suppressed SSTR2s, resulting in tumor-specific antisecretory and anti-proliferative effects. The effect of relacorilant on pituitary corticotroph tumors is being investigated in an ongoing phase 3 study (NCT03697109; EudraCT 2018-003096-35).

Project description:BackgroundDespite the widespread use of glucocorticoids in inflammatory and autoimmune disorders, there is uncertainty about the safe cessation of long-term systemic treatment, as data from prospective trials are largely missing. Due to potential disease relapse or glucocorticoid-induced hypocortisolism, the drug is often tapered to sub-physiological doses rather than stopped when the underlying disease is clinically stable, increasing the cumulative drug exposure. Conversely, the duration of exposure to glucocorticoids should be minimized to lower the risk of side effects.MethodsWe designed a multicenter, randomized, triple-blinded, placebo-controlled trial to test the clinical noninferiority of abrupt glucocorticoid stop compared to tapering after ≥28 treatment days with ≥420 mg cumulative and ≥7.5 mg mean daily prednisone-equivalent dose. 573 adult patients treated systemically for various disorders will be included after their underlying disease has been stabilized. Prednisone in tapering doses or matching placebo is administered over 4 weeks. A 250 mg ACTH-test, the result of which will be revealed a posteriori, is performed at study inclusion; all patients are instructed on glucocorticoid stress cover dosing. Follow-up is for 6 months. The composite primary outcome measure is time to hospitalization, death, initiation of unplanned systemic glucocorticoid therapy, or adrenal crisis. Secondary outcomes include the individual components of the primary outcome, cumulative glucocorticoid doses, signs and symptoms of hypocortisolism, and the performance of the ACTH test in predicting the clinical outcome. Cox proportional hazard, linear, and logistic regression models will be used for statistical analysis.ConclusionThis trial aims to demonstrate the clinical noninferiority and safety of abrupt treatment cessation after ≥28 days of systemic glucocorticoid therapy in patients with stabilized underlying disease.Trial registrationClinicalTrials.gov Identifier: NCT03153527; EUDRA-CT: 2020-005601-48 https://clinicaltrials.gov/ct2/show/NCT03153527?term=NCT03153527&draw=2&rank=1.

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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)

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