Category: Pituitary Disorders/Neuroendocrinology
Objective : Secondary endpoints in SONICS include investigator-assessed clinical signs and symptoms and patient-reported outcomes for the treatment of endogenous Cushing’s syndrome (CS).
Methods : In a phase 3, multicenter, open-label, dose-titration study, adults with confirmed CS and mean 24-hour urinary free cortisol (mUFC) ≥1.5 × upper limit of normal (ULN) were treated with levoketoconazole in 3 phases: 2- to 21-week dose-titration phase (150 to 600 mg BID, as needed, to target mUFC normalization), 6-month maintenance (M) phase (primary endpoint), and 6-month extended evaluation phase. The end of M phase (EoM) findings focused on reductions in mUFC and safety have been presented (Fleseriu M, et al. Presented at ENEA; 2018). Secondary endpoints include changes from baseline (BL) to EoM in investigator-assessed CS clinical signs and symptoms (acne score [range: 0-44]; hirsutism score [women only; range: 0-36]; and peripheral edema score [range: 0-12]), and patient-reported outcomes of quality-of-life (QoL; Cushing QoL questionnaire score [range: 0-100]) and depression (Beck Depression Inventory II score [range: 0-63]). Hormones including free testosterone levels were also assessed. Statistical significance of the mean changes from BL to EOM for all measures was inferred from paired t-tests.
Results : 94 patients were enrolled and treated with ≥1 dose of levoketoconazole; 77 entered M phase (secondary endpoint population). The majority of enrolled patients were female (82%) and white (96%), mean (SD) age 44 (13) years, and mean BL mUFC 243.3 μg/day (4.9 × ULN). Significant mean improvements from BL to EoM were observed in acne (mean BL score: 2.8; ∆ -1.8; P=0.0063 vs BL), hirsutism (women only; mean BL score: 7.8; ∆ -2.6; P=0.0008 vs BL), and peripheral edema (mean BL score: 1.0; ∆ -0.4; P=0.0295 vs BL) scores. Significant mean improvements were observed from BL to EoM in QoL (mean BL score: 44.3; ∆ +10.6 [+∆ = improvement]; P<0.0001 vs BL) and depression (mean BL score: 17.1; ∆ -4.3; P=0.0043 vs BL). Mean free testosterone levels increased non-significantly from BL to EoM in men (5.1 to 5.8 ng/dL; reference: 4.6-22.4 ng/dL) and decreased significantly in women (0.3 to 0.1 ng/dL; P<0.0001; reference: 0.02-0.5 ng/dL). Overall, 33 patients (35%) discontinued by EoM; 12 (13%) due to adverse events.
Conclusion : Clinical signs and symptoms of CS including acne, hirsutism, and peripheral edema, and patient-reported outcomes of QoL and symptoms of depression improved following 6 months of levoketoconazole therapy. Improvements in biochemical markers of efficacy including reduction in urinary cortisol and free testosterone (in women) were also observed.
Maria Fleseriu– Professor of Medicine and Neurological Surgery, Oregon Health and Science University
Rosario Pivonello– Professor, Dipartimento di Medicina Clinica e Chirurgia, Sezione di Endocrinologia, Università Federico II di Napoli, Naples, Italy
Atanaska Elenkova– Assoc. Professor Clinical Centre of Endocrinology and Gerontology, Medical University Sofia
Roberto Salvatori– Professor of Medicine, Johns Hopkins University
Richard Auchus– Professor of Internal Medicine; Professor of Pharmacology, University of Michigan Medical School
Richard Feelders– Associate Professor of Endocrinology, Erasmus Medical Center
Eliza Geer– Medical Director, Pituitary & Skull Base Tumor Center, Memorial Sloan Kettering Cancer Center
Yona Greenman– Senior Deputy Director, Institute of Endocrinology and Metabolism, Tel Aviv University
Przemyslaw Witek– Associate Professor of Endocrinology and Diabetes, Military Institute of Medicine
Beverly Biller– Professor of Medicine, Harvard Medical School, Massachusetts General Hospital
Fredric Cohen– Professor of Medicine, Harvard Medical School, Massachusetts General Hospital
Professor of Medicine and Neurological Surgery
Oregon Health and Science University
Maria Fleseriu, MD, FACE is a Professor of Medicine and Neurological Surgery and Director of the Northwest Pituitary Center at Oregon Health & Science University in Portland, Oregon, USA.
Dr. Fleseriu has a long-standing clinical and research interest in the pathophysiology and treatment of pituitary and adrenal disorders. She is a frequent guest speaker at national and international meetings on treatment of pituitary tumors (especially Cushing’s disease and acromegaly), is the principal investigator in clinical trials, and has authored over 150 manuscripts and book chapters.
Dr. Fleseriu is President Elect of the Pituitary Society, serves on the Board of Directors and chairs its Physician Education Committee. She serves on several committees for the Endocrine Society, Pituitary Society, and the American Association of Clinical Endocrinology and she chaired the Endocrine Society Guidelines Committee and the Hypopituitarism task force.
Dr. Fleseriu is Chief Editor of Pituitary Endocrinology for Frontiers in Endocrinology, Section Head for Pituitary and Neuroendocrine F 1000, Senior Editor for Endocrinology, Diabetes and Metabolism CR and a member of the editorial board of Pituitary, Endocrine, and Reviews in Endocrinology and Metabolism. She has been involved in leadership positions of educational programs sponsored by the Endocrine Society, the Pituitary Society, and patient advocacy groups to teach physicians and patients about pituitary tumors and neuroendocrine disorders. She has served on multiple scientific advisory boards and participated in study design for Cushing’s and acromegaly.
Professor, Dipartimento di Medicina Clinica e Chirurgia, Sezione di Endocrinologia
Università Federico II di Napoli
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.
Assoc. Professor Clinical Centre of Endocrinology and Gerontology
Medical University Sofia
Assoc. Prof. Atanaska Elenkova, MD, PhD, graduated from the Medical University, Sofia in 1994. She is a specialist in Internal Medicine (since 1999) and Endocrinology & Metabolic Disorders (since 2002). In 2013, she defended her doctoral thesis entitled: “Some current aspects in diagnostics and treatment of patients with prolactinomas”. Dr Elenkova has been working at the Clinical Center of Endocrinology, USHATE “Acad.Ivan Penchev” since 1999. Currently she is the Head of the Clinic of Hypothalamic, Pituitary, Adrenal&Gonadal Diseases at this hospital. Her main scientific interests are in the areas of neuroendocrinology, endocrine hypertension, pituitary and adrenal tumorogenesis.
Professor of Medicine
Johns Hopkins University
Dr. Roberto Salvatori graduated summa cum laude with honors from Catholic University School of Medicine in Rome, Italy. He trained in Internal Medicine at the Montefiore Medical Center of the Albert Einstein University in the Bronx, NY and completed fellowships in Endocrinology and Metabolism at Cornell University in New York and at the Johns Hopkins University School of Medicine. He joined the Johns Hopkins faculty in 1998 and is currently a Professor of Medicine.
One of the founders of the Johns Hopkins Pituitary Tumor Center, Dr. Salvatori focuses his clinical practice on the diagnosis and treatment of pituitary and adrenal tumors and pituitary dysfunction, with a particular interest in growth hormone excess (acromegaly) and deficiency, and on cortisol excess (Cushing) and deficiency (adrenal insufficiency).
Dr. Salvatori is the director of the Johns Hopkins endocrinology fellowship training program.
Professor of Internal Medicine; Professor of Pharmacology
University of Michigan Medical School
Dr. Richard Auchus is a professor of Internal Medicine, Division of Metabolism, Endocrinology & Diabetes (MEND) and Chief of the Endocrinology Section at the Ann Arbor VA Medical Center. He received his medical degree and Ph.D. in pharmacology from Washington University in St. Louis. Then Dr. Auchus completed a residency at the University of Iowa and an endocrinology fellowship at UTHSC-San Antonio/Wilford Hall Medical Center. Dr. Auchus came to UMHS from the Graduate School of Biomedical Sciences in Southwestern Medical School, University of Texas, where he was a Professor of Internal Medicine - Endocrinology.
Dr. Auchus is a steroid biologist with expertise both in basic science and clinical/translational science. His work has included translational research into: molecular and genetic mechanisms of human hypertension, improved diagnostic studies and management in primary aldosteronism and Cushing syndromes, modifier genes in 21-hydroxylase deficiency, cardiovascular disease in polycystic ovary syndrome, and the endocrinology of traumatic brain injury.
Associate Professor of Endocrinology
Erasmus Medical Center
Richard Feelders, MD, PhD Erasmus Medical Center, Rotterdam, The Netherlands. Richard Feelders is an Associate Professor of Endocrinology at the Erasmus University Medical Center, Rotterdam, The Netherlands. He trained in Internal Medicine at the Maasstad Hospital, Rotterdam and the Erasmus Medical Center, Rotterdam (1993-1999, followed by an endocrinology fellowship, also at the Erasmus Medical Center (1999-2001). In 1999 Dr. Feelders completed his thesis on endocrine changes in the acute phase response. In Erasmus Medical Center he is chair of the Pituitary Center Rotterdam and coordinator of the ENETS GEP-Neuroendocrine Tumor Center Rotterdam. In 2012-2013 Dr. Feelders works as Visiting Professor at the National Institutes of Health, Bethesda, USA. Dr. Feelders main fields of patient care and scientific interest are neuroendocrinology and neuroendocrine tumors. His research is focused on the pathophysiology and treatment of (non-)functional pituitary adenomas, adrenal and neuroendocrine tumors. A main topic in this respect involves diagnosis and medical treatment of Cushing's syndrome. Another research area concerns determinants of glucocorticoid sensitivity in health and disease.
Medical Director, Pituitary & Skull Base Tumor Center
Memorial Sloan Kettering Cancer Center
I am an endocrinologist who specializes in caring for people with pituitary and neuroendocrine diseases. I am the Medical Director of Memorial Sloan Kettering’s Multidisciplinary Pituitary & Skull Base Tumor Center, located at Memorial Hospital in Manhattan. At this center, we bring together experts from many areas — including neurosurgery, head and neck surgery, endocrinology, radiation oncology, and medical oncology — to offer comprehensive care for people with pituitary and skull base tumors.
Senior Deputy Director, Institute of Endocrinology and Metabolism
Tel Aviv University
Dr. Yona Greenman received her medical degree from the Sackler Faculty of Medicine at the Tel Aviv University in 1986. After completion of her Endocrine Fellowship at the Institute of Endocrinology at the Tel Aviv Medical Center in 1991 she did a research fellowship at Cedars Sinai Medical Center, Los Angeles, under the orientation of Prof. Shlomo Melmed. Since her return to Israel in 1995 she has worked as senior faculty at the Institute of Endocrinology and Metabolism at the Tel Aviv Medical Center and has been appointed as its senior deputy director since 2012. Dr. Greenman is a Senior Lecturer in Internal Medicine at the Tel Aviv University School of Medicine since 2008. Her main research areas include clinical aspects of pituitary tumors, and more recently, the interface between stress and eating behavior. She founded and was the first president of the G. Ouakine Israel Pituitary Association, a support group for patients with pituitary disorders. She was a member of the clinical initiatives committee of the Pituitary Society in 2002, and of the executive committee of the European Neuroendocrine association from 2004-2008. In 2009 she chaired the exams committee for certification in endocrinology from the Israel Medical Association. She is currently a member of the Editorial Board of Clinical Endocrinology and a member of the executive committee of the Israel Endocrine Society.
Associate Professor of Endocrinology and Diabetes
Military Institute of Medicine
Przemysław Witek MD, PhD is specialist in internal medicine (2005), endocrinology (2009), and diabetes (2012). He worked in the Department of Endocrinology at the Center of Postgraduate Medical Education, where, in 2011, he received a PhD in medical sciences based on his doctoral dissertation on assessing the predictive factors for curative surgery in Cushing’s disease.
Since the beginning of his professional career Przemysław Witek has been engaged in the topic of pituitary tumors, especially Cushing disease and acromegaly. Currently, he is Associate Professor of Endocrinology and Diabetes and works at Military Institute of Medicine in Warsaw, where he collaborates with the Neurosurgery Clinic on establishing a team which would provide comprehensive care for pituitary adenoma patients. Przemysław Witek has been particularly interested in the metabolic and cardiovascular complications of Cushing disease and acromegaly.
He is an author of a number of original and review articles as well as case reports on pituitary adenomas, both in Polish and foreign journals. He is also the author of chapters on this topic in Polish endocrinology handbooks. Currently, Professor Witek is the Head of the Gastroenterology, Endocrinology, and Internal Medicine Department and a member of the Scientific Board at Military Institute of Medicine in Warsaw.
Professor of Medicine, Harvard Medical School
Massachusetts General Hospital
Beverly MK Biller, MD is an endocrinologist in the Massachusetts General Hospital (MGH) Neuroendocrine and Pituitary Tumor Clinical Center. She is a faculty member in the Neuroendocrine Unit at MGH and a Professor of Medicine at Harvard Medical School. Dr. Biller's major clinical and research interests include the diagnosis and treatment of Cushing's disease, prolactinomas, acromegaly, other pituitary tumors and sellar masses, and pituitary hormone deficiencies in adults.