Efficacy and safety of levoketoconazole in the treatment of endogenous Cushing's syndrome (SONICS): a phase 3, multicentre, open-label, single-arm trial

Fleseriu, Maria; Pivonello, Rosario; Еленкова, Атанаска; Salvatori, Roberto; Auchus, Richard J.; Feelders, Richard A; Geer, Eliza B.; Greenman, Yona; Witek, Przemysław; Cohen, Fredric J.; Biller, Beverly M. K.

doi:10.1016/s2213-8587(19)30313-4

Cited by 70 publications

(120 citation statements)

References 26 publications

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“…LNSC levels significantly decreased from baseline to the end of maintenance period, although normalization occurred only in four (4.2%) patients, whereas, in CD patients, plasma ACTH levels increased during up-titration period and remained elevated throughout the study. Moreover, mean testosterone levels significantly decreased in women, whereas in men a slight, although non-significant, increase was observed (88). Regarding clinical profile, after the 6 months of the maintenance period, a significant decrease in body weight, total, LDL, and HDL cholesterol, fasting serum glucose, and HbA1c, as well as an improvement in quality of life and depressive status, in peripheral oedema, and in acne and hirsutism in women, were observed (88).…”

Section: Levoketoconazolementioning

confidence: 79%

“…Moreover, mean testosterone levels significantly decreased in women, whereas in men a slight, although non-significant, increase was observed (88). Regarding clinical profile, after the 6 months of the maintenance period, a significant decrease in body weight, total, LDL, and HDL cholesterol, fasting serum glucose, and HbA1c, as well as an improvement in quality of life and depressive status, in peripheral oedema, and in acne and hirsutism in women, were observed (88). Levoketoconazole effects on pituitary tumor in CD patients were not evaluated in this study.…”

Section: Levoketoconazolementioning

confidence: 79%

“…A first phase III, open-label, multicenter clinical trial, the SONICS study (clinicaltrials.gov code: NCT01838551), was started to assess the efficacy and safety of levoketoconazole treatment in CS patients for a period ranging from 12.5 to 16.8 months according to the initial up-titration period duration (88). Levoketoconazole was orally administered in a twice-daily schedule.…”

Section: Levoketoconazolementioning

confidence: 99%

“…Regarding safety profile, the most frequently reported AEs were nausea (32%), headache (28%), and peripheral oedema (19%). Hypertension was reported in 16 (17%) patients, although no increase in mean systolic and diastolic blood pressure was observed (88). AEs were also grouped in categories of special interest, including liver related-AEs (7.4%), QT prolongation (5.3%), and AI (3.2%).…”

Section: Levoketoconazolementioning

confidence: 99%

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Medical Treatment of Cushing's Disease: An Overview of the Current and Recent Clinical Trials

et al. 2020

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Cushing's disease (CD) is a serious endocrine disorder characterized by chronic hypercortisolism, or Cushing's syndrome (CS), caused by a corticotroph pituitary tumor, which induces an excessive adrenocorticotropic hormone (ACTH) and consequently cortisol secretion. CD presents a severe clinical burden, with impairment of the quality of life and increase in mortality. Pituitary surgery represents the first-line therapy, but it is non-curative in one third of patients, requiring additional treatments. Among second-line treatments, medical therapy is gradually gaining importance, although the current medical treatments are unable to reach optimal efficacy and safety profile. Therefore, new drugs and new formulations of presently available drugs are currently under clinical investigation in international clinical trials, in order to assess their efficacy and safety in CD, or in the general population of CS. Among pituitary-directed agents, pasireotide, in the twice-daily subcutaneous formulation, has been demonstrated to be an effective treatment both in clinical trials and in real-world studies, and extension studies of the phase II and III clinical trials reported evidence of long-term efficacy with general good safety profile, although associated with frequent hyperglycemia, which requires monitoring of glucose metabolism. Moreover, the most recent once-monthly intramuscular formulation, pasireotide long-acting release (LAR), showed similar efficacy and safety, but associated with potential better compliance profile in CD. Roscovitine is an experimental drug currently under investigation. Among adrenal-directed agents, metyrapone is the only historical agent currently under investigation in a prospective, multicenter, international clinical trial, that would likely clarify its efficacy and safety in a large population of patients with CS. Osilodrostat, a novel agent with a mechanism of action similar to metyrapone, seems to offer a rapid, sustained, and effective disease control of CD, according to recently completed clinical trials, whereas levoketoconazole, a different chemical formulation of the historical agent ketoconazole, is still under investigation in clinical trials, with preliminary evidences showing an effective and safe control of CS. ATR-101 is an experimental drug currently under investigation. Among glucocorticoid receptor-directed drugs, mifepristone has been demonstrated to improve clinical syndrome and comorbidities, especially hypertension and impairment of glucose metabolism, but the occurrence of hypokalemia and in women uterine disorders, due to the concomitant action on progestin receptor, requires caution, whereas the preliminary evidence on relacorilant, characterized by high selectivity for glucocorticoid receptor, suggested good efficacy in the control of hypertension and impairment of glucose metabolism, as well as a good safety profile, in CS. Finally, a limited experience has demonstrated that combination therapy might be an interesting approach in the management of CD. The current review provides a summary of the available evidences from current and recent clinical trials on CD, with a specific focus on preliminary data.

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Section: Levoketoconazolementioning

confidence: 79%

Section: Levoketoconazolementioning

confidence: 79%

Section: Levoketoconazolementioning

confidence: 99%

Section: Levoketoconazolementioning

confidence: 99%

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Medical Treatment of Cushing's Disease: An Overview of the Current and Recent Clinical Trials

et al. 2020

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“…Phase III trials Levoketoconazole, the 2S,4R-enantiomer of ketoconazole, was studied in a recently published phase III, multicenter, open-label, non-randomized, single-arm study [149]. The primary end point of the study, UFC normalization without dose increase and without imputing any missing data was achieved in 31 % of patients; when missing data was computed, similar with other studies for comparison, 42 % of patients had normal UFC.…”

Section: Novel Steroidogenesis Inhibitors Currently Evaluated In Clinmentioning

confidence: 92%

Updates in the Medical Treatment of Pituitary Adenomas

2019

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Pituitary adenomas represent approximately 15% of brain tumors; incidence is significantly on the increase due to widespread use of magnetic resonance imaging. Surgery remains the first-line treatment for most tumors overall. The role of dopaminergic agonists (DAs) and somatostatin receptor ligands (SRLs) in the treatment of pituitary adenomas is quite well established for prolactinomas and growth hormone (GH) excess. However, over the last decade new multi-receptor binding SRLs are increasingly used for treatment of acromegaly and Cushing’s disease. SRLs/DA chimeric compounds seem to have enhanced potency and efficacy when compared to that of individual SRLs or DA receptor agonists according to preclinical data. However, following negative results, more research is needed to determine if this interesting mechanism will translate into positive clinical effects for acromegaly patients. Furthermore, new agents that block adrenal steroidogenesis have been developed in phase III clinical trials for Cushing’s disease and several new compounds working at the pituitary level and/or blocking the glucocorticoid receptor are also in development. Combination therapy of drugs with similar or different mechanisms (possibly synergistic) are also on the increase. A growing awareness regarding all mechanisms involved in both control of pituitary secretion and cellular proliferation might allow for sole medical treatment of pituitary adenomas, especially macroadenomas, rather than surgery and/or radiation therapy, in the future. Moreover, the underlying decision on how to treat patients with pituitary adenomas should be individualized on a case-by-case basis with not only a goal of tumor shrinkage and biochemical control, but also of improving patients’ quality of life.

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Cushing Syndrome

Reincke

Fleseriu

2023

JAMA

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ImportanceCushing syndrome is defined as a prolonged increase in plasma cortisol levels that is not due to a physiological etiology. Although the most frequent cause of Cushing syndrome is exogenous steroid use, the estimated incidence of Cushing syndrome due to endogenous overproduction of cortisol ranges from 2 to 8 per million people annually. Cushing syndrome is associated with hyperglycemia, protein catabolism, immunosuppression, hypertension, weight gain, neurocognitive changes, and mood disorders.ObservationsCushing syndrome characteristically presents with skin changes such as facial plethora, easy bruising, and purple striae and with metabolic manifestations such as hyperglycemia, hypertension, and excess fat deposition in the face, back of the neck, and visceral organs. Cushing disease, in which corticotropin excess is produced by a benign pituitary tumor, occurs in approximately 60% to 70% of patients with Cushing syndrome due to endogenous cortisol production. Evaluation of patients with possible Cushing syndrome begins with ruling out exogenous steroid use. Screening for elevated cortisol is performed with a 24-hour urinary free cortisol test or late-night salivary cortisol test or by evaluating whether cortisol is suppressed the morning after an evening dexamethasone dose. Plasma corticotropin levels can help distinguish between adrenal causes of hypercortisolism (suppressed corticotropin) and corticotropin-dependent forms of hypercortisolism (midnormal to elevated corticotropin levels). Pituitary magnetic resonance imaging, bilateral inferior petrosal sinus sampling, and adrenal or whole-body imaging can help identify tumor sources of hypercortisolism. Management of Cushing syndrome begins with surgery to remove the source of excess endogenous cortisol production followed by medication that includes adrenal steroidogenesis inhibitors, pituitary-targeted drugs, or glucocorticoid receptor blockers. For patients not responsive to surgery and medication, radiation therapy and bilateral adrenalectomy may be appropriate.Conclusions and RelevanceThe incidence of Cushing syndrome due to endogenous overproduction of cortisol is 2 to 8 people per million annually. First-line therapy for Cushing syndrome due to endogenous overproduction of cortisol is surgery to remove the causative tumor. Many patients will require additional treatment with medications, radiation, or bilateral adrenalectomy.

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Efficacy and safety of levoketoconazole in the treatment of endogenous Cushing's syndrome (SONICS): a phase 3, multicentre, open-label, single-arm trial

Cited by 70 publications

References 26 publications

Medical Treatment of Cushing's Disease: An Overview of the Current and Recent Clinical Trials

Medical Treatment of Cushing's Disease: An Overview of the Current and Recent Clinical Trials

Updates in the Medical Treatment of Pituitary Adenomas

Cushing Syndrome

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