Category: Pituitary Disorders/Neuroendocrinology

EFFICACY AND SAFETY OF THE SELECTIVE GLUCOCORTICOID RECEPTOR MODULATOR, RELACORILANT (UP TO 400 MG/DAY), IN PATIENTS WITH ENDOGENOUS HYPERCORTISOLISM: RESULTS FROM AN OPEN-LABEL PHASE 2 STUDY

Saturday, Apr 27
10:15 AM – 10:30 AM

Objective : Relacorilant (RELA) is a potent selective glucocorticoid receptor modulator being investigated for the treatment of all etiologies of endogenous hypercortisolism (Cushing syndrome, CS). RELA has no activity at the progesterone or mineralocorticoid receptors (PR, MR). A phase 2, multicenter, open-label study was conducted to assess RELA’s efficacy and safety.


Methods : Patients (pts, N=35) with confirmed CS plus hyperglycemia (n=25) and/or hypertension (HTN; n=23) were enrolled in 1 of 2 dose groups, both with 50-mg dose escalation every 4 weeks (wks). A low-dose group (LD, n=17, 12 wks) received once-daily doses of 100 mg/d, followed by 150 mg/d and then 200 mg/d. A high-dose group (HD, n=18, 16 wks) received 250 mg/d, followed by 300 mg/d, 350 mg/d, and then 400 mg/d. Hyperglycemia response criterion was improvement in glucose tolerance demonstrated by: ≥0.5% decrease in HbA1c, normalization or ≥50 mg/dL decrease in 2-hr OGTT glucose, or decrease in daily dose of insulin (≥25%) or sulfonylurea (≥50%). HTN response criterion was ≥5 mmHg drop in mean systolic or diastolic blood pressure (BP).


Results :

In pts with hyperglycemia, 15.4% (2/13) in the LD group and 50% (6/12) in the HD group were responders at last observed visit. In pts with HTN, 41.7% (5/12) in the LD group and 63.6% (7/11) in the HD group were responders at last BP measurement. Considered as one group, pts demonstrated statistically significant improvements in hypercoagulopathy, liver function, fructosamine, cognitive function, depression, and Cushing quality of life score. 42.9% (15/35) of pts lost weight. In those who did, mean loss was 2.2 kg (LD group, 6/17) and 5.1 kg (HD group, 9/15). No PR-related (vaginal bleeding) adverse events or drug-induced hypokalemia occurred. The most common treatment-emergent adverse events (TEAEs) were back pain, edema, headache, pain in extremities, and nausea. Five serious TEAEs were reported in 4 pts.


Discussion : Ptsdemonstrated improvements in endpoints related to excess cortisol activity. RELA was generally well tolerated. There were no PR-related adverse events. Because cortisol and ACTH levels did not increase significantly, no pts experienced drug-induced hypokalemia (a MR-mediated effect). The most common TEAEs were possibly associated with cortisol withdrawal; serious TEAES were likely related to unmasking of pre-existing conditions previously suppressed by hypercortisolism.


Conclusion : RELA may offer clinical benefit of potent glucocorticoid modulation without undesirable PR- (e.g., termination of pregnancy, vaginal bleeding) or MR- (e.g., hypokalemia) mediated effects. A phase 3 trial is underway.

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Rosario Pivonello

Professor, Dipartimento di Medicina Clinica e Chirurgia, Sezione di Endocrinologia
Università Federico II di Napoli
Naples, Italy

Rosario Pivonello is Professor at the Department of Molecular and Clinical Endocrinology and Oncology of the “Federico II” University of Naples, Italy. In 1994, he got the University Degree in Medicine and Surgery with a vote of “Summa cum Laude” and Honourable Mention for the University Carreer with a thesis focused on “GH deficiency in adulthood”. In 1999, he got the Specialization Degree in Endocrinology and Metabolism with a vote of “Summa cum Laude”, and a thesis focused on diabetes insipidus. From 1998 to 2000, he was Research Fellow at the Department of Internal Medicine, directed by professor Steven WJ Lamberts, of the Erasmus Medical Center in Rotterdam, The Netherlands, with a research project on the role of dopaminergic system in the hypothalamus-pituitary-adrenal axis. In 2003, he got the Doctorate Degree in Neuropsychopharmacology and Toxicology at the Federico II University of Naples, with “Optimum” score and a thesis focused on the role of dopamine receptors in pituitary and adrenal tumors. In 2005, he got the Doctorate Degree in Neuroendocrinology at the Erasmus University of Rotterdam, The Netherlands with a thesis entitled “Dopamine receptor expression and function in the normal and pathological hypothalamuspituitary-adrenal axis”. In 2010, he became Assistant Professor at the Federico II University of Naples. In 2005 and in 2009, he won the Italian Society of Endocrinology Award for Young Investigators for the Scientific Carrer. He is author of more than 180 publications in peer-reviewed international journals, several chapters for national and international books, and he was presenter and invited lecturer in several national and international conference, meeting and courses. He is expert in the field of pituitary and adrenal diseases, mainly on Cushing’s syndrome.

Atil Y. Kargi

Associate Professor of Clinical Medicine, Division of Endocrinology, Diabetes, and Metabolism
University of Miami Miller School of Medicine
Miami, Florida

Dr. Kargi is an Associate Professor of Clinical Medicine and J. Maxwell McKenzie Fellowship Program Director at University of Miami Miller School of Medicine. Dr. Kargi obtained his medical degree in Izmir, Turkey. In 2008 Dr. Kargi joined the faculty at the University of Miami, Miller School of Medicine in the clinical educator career track. He is coordinator of the medical school endocrine and reproductive systems course, director of the UMH and Jackson Memorial inpatient endocrinology consultation service, and co-director of University of Miami Endocrine Testing Center. Dr. Kargi's clinical research interests include the diagnosis of growth hormone deficiency, treatment of male hypogonadism, and tumors of the adrenal and pituitary glands.

Noel Ellison

Senior Biostatistician
Trialwise, Inc
Boise, Idaho

Noel Ellison received her MS in Statistics from Brigham Young University, where she also held positions as Research Assistant and Statistical Consultant. Ms. Ellison is currently Senior Biostatistician at Trialwise, Inc, Houston, TX, and has worked as a statistical consultant and SAS programmer for several firms, including Viritec, Ivoclar Viadent, Pentara, and Corcept Therapeutics.

Andreas Moraitis

Senior Medical Director
Corcept Therapeutics
Menlo Park, California

Dr. Andreas G. Moraitis is Senior Medical Director at Corcept Therapeutics in Menlo Park, CA, where he is involved in research, development, and clinical assessment of treatments for Cushing’s syndrome and other endocrine disorders. He received his MD from the National and Kapodistrian University of Athens, Athens, Greece, where his focus was on adrenal tumors, endocrine hypertension, and Cushing's syndrome. Dr. Moraitis completed a fellowship in adult and reproductive endocrinology at the US National Institutes of Health, Bethesda, MD, and was Assistant Professor of Endocrine Oncology at the University of Michigan Medical School, Ann Arbor, MI before coming to Corcept Therapeutics.

Massimo Terzolo

Professor, Department of Clinical and Biological Sciences
Internal Medicine 1 - San Luigi Gonzaga Hospital, University of Turin
Orbassano, Italy

Prof. Massimo Terzolo is Professor of Internal Medicine and Director of the Division of Internal Medicine 1 at the San Luigi Hospital, Orbassano, Italy, and Deputy Director of the Department of Clinical and Biological Sciences at the University of Turin, where he earned his MD and postgraduate degree in Endocrinology.

Prof. Terzolo has extensive experience in the clinical management of patients with adrenal tumors and in conducting clinical trials. His clinical interests focus mainly on adrenal and pituitary disorders. He leads a research team that is active in research projects such as basic pharmacologic studies of novel therapeutic approaches for adrenocortical carcinoma, translational and clinical investigation in disorders of the adrenals, tumors and Addison’s, and pituitary, Cushing’s and acromegaly. He is currently the head of ENSAT, the European Network for the Study of Adrenal Tumors. Prof. Terzolo is also active in physician and nurse training and education.

Rosario Pivonello

Professor, Dipartimento di Medicina Clinica e Chirurgia, Sezione di Endocrinologia
Università Federico II di Napoli
Naples, Italy

Rosario Pivonello is Professor at the Department of Molecular and Clinical Endocrinology and Oncology of the “Federico II” University of Naples, Italy. In 1994, he got the University Degree in Medicine and Surgery with a vote of “Summa cum Laude” and Honourable Mention for the University Carreer with a thesis focused on “GH deficiency in adulthood”. In 1999, he got the Specialization Degree in Endocrinology and Metabolism with a vote of “Summa cum Laude”, and a thesis focused on diabetes insipidus. From 1998 to 2000, he was Research Fellow at the Department of Internal Medicine, directed by professor Steven WJ Lamberts, of the Erasmus Medical Center in Rotterdam, The Netherlands, with a research project on the role of dopaminergic system in the hypothalamus-pituitary-adrenal axis. In 2003, he got the Doctorate Degree in Neuropsychopharmacology and Toxicology at the Federico II University of Naples, with “Optimum” score and a thesis focused on the role of dopamine receptors in pituitary and adrenal tumors. In 2005, he got the Doctorate Degree in Neuroendocrinology at the Erasmus University of Rotterdam, The Netherlands with a thesis entitled “Dopamine receptor expression and function in the normal and pathological hypothalamuspituitary-adrenal axis”. In 2010, he became Assistant Professor at the Federico II University of Naples. In 2005 and in 2009, he won the Italian Society of Endocrinology Award for Young Investigators for the Scientific Carrer. He is author of more than 180 publications in peer-reviewed international journals, several chapters for national and international books, and he was presenter and invited lecturer in several national and international conference, meeting and courses. He is expert in the field of pituitary and adrenal diseases, mainly on Cushing’s syndrome.