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by Kristen Monaco, Staff Writer, MedPage Today LOS ANGELES -- An investigational therapy improved quality of life and reduced disease symptoms for patients with endogenous Cushing's syndrome, according to new findings from the phase III SONICS study. Patients taking oral levoketoconazole twice daily had significant reductions in mean scores for acne (-1.8), peripheral edema (-0.4), and hirsutism (-2.6), all secondary endpoints of the pivotal trial (P<0.03 for all), reported Maria Fleseriu, MD, of Oregon Health and Science University in Portland. "We're looking forward to see the results of further studies and to add this therapy to the landscape of Cushing's," Fleseriu said here during a presentation of the findings at AACE 2019, the annual meeting of the American Association of Clinical Endocrinologists. "We have a newer medication and still we cannot make a dent in the outcomes of Cushing's, especially for patient-reported outcomes." Free testosterone levels significantly decreased in women taking levoketoconazole (a ketoconazole stereoisomer and potent steroidogenesis inhibitor), from an average of 0.32 ng/dL down to 0.12 ng/dL (0.011 to 0.004 nmol/L, P<0.0001). Men had a non-significant increase: 5.1 ng/dL up to 5.8 ng/dL (0.177 to 0.202 nmol/L). There were no significant changes from baseline to the end of maintenance for other secondary endpoints in the analysis: moon facies, facial plethora, striae, bruising, supraclavicular fat, irregular menstruation, and dysmenorrhea. However, significant improvements after 6 months of therapy were seen in patient-reported quality of life compared with baseline (mean 10.6 change on the Cushing QOL questionnaire) as well as a significant reduction in depressive symptoms (mean -4.3 change on the Beck Depression Inventory II). The open-label, multicenter SONICS (Study of Levoketoconazole in Cushing's Syndrome) trial included 94 adult men and women with a confirmed diagnosis of Cushing's syndrome and elevated 24-hour mean urinary free cortisol (mUFC) levels at least 1.5 times the upper limit of normal. In the dose-titration phase of the study (weeks 2 to 21), patients were titrated up to a max dose of 600 mg levoketoconazole twice daily until mUFC normalization. A 6-month maintenance phase followed with no dose increases, but decreases were allowed if adverse events emerged. An additional 6-month extended evaluation phase followed thereafter. The study met it's previously reported primary endpoint, with 30% of patients achieving normalized mUFC levels after 6 months of maintenance therapy without a dose increase (95% CI 21%-40%, P=0.0154). Levoketoconazole was well tolerated, with only 12.8% of patients discontinuing treatment due to adverse events. The most commonly reported adverse events were nausea (31.9%), headache (27.7%), peripheral edema (19.1%), hypertension (17%), and fatigue (16%), some of which were expected due to steroid withdrawal, Fleseriu said. Serious adverse events were reported in 14 patients, including prolonged QTc interval in two patients, elevated liver function in one patient, and adrenal insufficiency in another, events similar to those seen with ketoconazole (Nizoral) therapy. Fleseriu explained that drug-drug interaction is a problem in Cushing's, as all of the available medications prolong QT interval. She noted that in SONICS, QT prolongation with levoketoconazole was observed in few patients. It's still a "concern," said Fleseriu, especially for patients on other drugs that prolong QT. Although not yet approved, levoketoconazole has received orphan drug designation from the FDA and the European Medicines Agency for endogenous Cushing's syndrome. The tentative brand name is Recorlev. The study was supported by Strongbridge Biopharma. Fleseriu reported relationships with Strongbridge, Millendo Therapeutics, and Novartis. Co-authors also disclosed relevant relationships with industry. Primary Source American Association of Clinical Endocrinologists Source Reference: Fleseriu M, et al "Levoketoconazole in the treatment of endogenous Cushing's syndrome: Improvements in clinical signs and symptoms, patient-reported outcomes, and associated biochemical markers in the phase 3 SONICS study" AACE 2019; Poster 369. From https://www.medpagetoday.com/meetingcoverage/aace/79465
The effects of obesity on the diagnosis of Cushing’s syndrome and strategies to alter the traditional approaches have been addressed in a new review study. The study, “Diagnosis and Differential Diagnosis of Cushing’s Syndrome,” appeared in The New England Journal of Medicine. The author was Dr. Lynn D. Loriaux, MD and PhD, and a professor of medicine at the Division of Endocrinology, Diabetes and Clinical Nutrition at the School of Medicine, Oregon Health & Science University (OHSU), in Portland, Oregon. Traditionally, exams of patients with glucocorticoid excess focused on the presence of changes in anabolism (the chemical synthesis of molecules). Given the increase in obesity in the general population, changes in anabolism can no longer distinguish Cushing’s syndrome from metabolic syndrome. However, analyses of anti-anabolic changes of cortisol – including osteopenia (lower bone density), thin skin, and ecchymoses (injury that causes subcutaneous bleeding) – are an effective way to make this distinction. The worldwide prevalence of metabolic syndrome in obese people is estimated at about 10%. Conversely, the incidence of undiagnosed Cushing’s syndrome is about 75 cases per 1 million people. Cushing’s and metabolic syndrome share significant clinical similarities, including obesity, hypertension, and type 2 diabetes. Therefore, “making the diagnosis is the least certain aspect in the care of patients with [Cushing’s],” Loriaux wrote. Regarding a physical examination, patients with osteoporosis, reduced skin thickness in the middle finger, and three or more ecchymoses larger than 1 cm in diameter and not associated with trauma are more likely to have Cushing’s. Researchers estimate the probability of people with all three of these symptoms having Cushing’s syndrome is 95%. Measuring 24-hour urinary-free cortisol levels allows the assessment of excess glucocorticoid effects, typical of Cushing’s syndrome. The test, which should be done with the most stringent techniques available, averages the augmented secretion of cortisol in the morning and the diminished secretion in the afternoon and at night. Dexamethasone suppression is one of the currently used screening tests for Cushing’s syndrome. Patients with obesity and depression should not show decreased plasma cortisol levels when dexamethasone is suppressed. However, given its low estimated predictive value (the proportion of positive results that are “true positives”), “this test should not influence what the physician does next and should no longer be used” to screen for Cushing’s, the author wrote. Some patients may show evidence of Cushing’s syndrome at a physical examination, but low urinary free cortisol excretion. This may be due to glucocorticoids being administered to the patient. In this case, the glucocorticoid must be identified and discontinued. Periodic Cushing’s assessments that measure urinary free cortisol should be performed. The opposite can also occur: no clinical symptoms of Cushing’s, but elevated urinary free cortisol excretion and detectable plasma levels of the hormone corticotropin. In these patients, the source of corticotropin secretion, which can be a tumor or the syndrome of generalized glucocorticoid resistance, must be determined. The disease process can be corticotropin-dependent or independent, depending on whether the hormone is detectable. Corticotropin in Cushing’s syndrome can come from the pituitary gland (eutopic) or elsewhere in the body (ectopic). Loriaux recommends that the source of corticotropin secretion be determined before considering surgery. Up to 40% of patients with pituitary adenomas have nonfunctioning tumors (the tumor does not produce any hormones) and the corticotropin source is elsewhere. If misdiagnosed, patients will likely undergo an unnecessary surgery, with a mortality rate of 1%. Patients with an ectopic source of corticotropin should undergo imaging studies in the chest, followed by abdominal and pelvic organs. If these tests fail to detect the source, patients should undergo either the blockade of cortisol synthesis or an adrenalectomy (removal of adrenal glands). However, corticotropin-independent Cushing’s is usually caused by a benign adrenal tumor that uniquely secretes cortisol. “Such tumors can be treated successfully with laparoscopic adrenalectomy,” Loriaux wrote. If the tumor secretes more than one hormone, it is likely malignant. Surgical to remove the tumor and any detectable metastases should be conducted. Overall, “the treatment for all causes of [Cushing’s syndrome], other than exogenous glucocorticoids, is surgical, and neurosurgeons, endocrine surgeons, and cancer surgeons are needed,” Loriaux wrote in the study. “This level of multidisciplinary medical expertise is usually found only at academic medical centers. Thus, most, if not all, patients with [Cushing’s syndrome] should be referred to such a center for treatment.” From https://cushingsdiseasenews.com/2017/10/24/diagnosing-cushings-syndrome-amid-challenge-of-obesity-and-strategies-to-improve-methods/