LCI699, a Potent 11β-hydroxylase Inhibitor, Normalizes Urinary Cortisol in Patients With Cushing's Disease: Results From a Multicenter, Proof-of-Concept Study

Bertagna, Xavier; Pivonello, Rosario; Fleseriu, Maria; Zhang, Yiming; Robinson, Paul; Taylor, Ann E.; Watson, Catherine E.; Maldonado, Mario; Hamrahian, Amir H.; Boscaro, Marco; Biller, Beverly M. K.

doi:10.1210/jc.2013-2117

Cited by 164 publications

(161 citation statements)

References 20 publications

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“…In a phase II proof of concept study of LCI699, rapid UFC normalization in 11 out of 12 patients with CD, all achieving O50% reduction in baseline UFC, was observed. Doses ranged from 4 to 100 mg/day for 10 weeks (Bertagna et al 2014). As expected, ACTH increased; 45% of cases had ACTH more than twice that of baseline.…”

Section: Lci699mentioning

confidence: 53%

Treatment of Cushing's disease: a mechanistic update

Cuevas‐Ramos¹,

Fleseriu²

2014

Journal of Endocrinology

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Cushing's disease (CD) is characterized by an ACTH-producing anterior corticotrope pituitary adenoma. If hypothalamus-pituitary-adrenal (HPA) axis physiology is disrupted, ACTH secretion increases, which in turn stimulates adrenocortical steroidogenesis and cortisol production. Medical treatment plays an important role for patients with persistent disease after surgery, for those in whom surgery is not feasible, or while awaiting effects of radiation. Multiple drugs, with different mechanisms of action and variable efficacy and tolerability for controlling the deleterious effects of chronic glucocorticoid excess, are available. The molecular basis and clinical data for centrally acting drugs, adrenal steroidogenesis inhibitors, and glucocorticoid receptor antagonists are reviewed, as are potential novel molecules and future possible targets for CD treatment. Although progress has been made in the understanding of specific corticotrope adenoma receptor physiology and recent clinical studies have detected improved effects with a combined medical therapy approach, there is a clear need for a more efficacious and better-tolerated medical therapy for patients with CD. A better understanding of the molecular mechanisms in CD and of HPA axis physiology should advance the development of new drugs in the future.

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Section: Lci699mentioning

confidence: 53%

Treatment of Cushing's disease: a mechanistic update

Cuevas‐Ramos¹,

Fleseriu²

2014

Journal of Endocrinology

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“…Safety concerns regarding the hepatotoxicity of KTZ have led to limited availability in many countries (5). At the same time, there is a potential for new inhibitors to enter clinical practice over the next few years (10). Outside this class of agents, there are limited new alternatives.…”

Section: Introductionmentioning

confidence: 99%

THERAPY OF ENDOCRINE DISEASE: Steroidogenesis enzyme inhibitors in Cushing's syndrome

Daniel

Newell‐Price

2015

European Journal of Endocrinology

111

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Steroidogenesis enzyme inhibitors are the mainstay of medical therapy in Cushing's syndrome (CS). Ketoconazole (KTZ) and metyrapone are the most commonly used agents. Although there is considerable experience of their use in individual specialist centres, these drugs have not been rigorously tested in prospective clinical trials. Clinicians face uncertainties and concerns with respect to the safety profile of these agents, and best means to monitor effect. We review steroidogenesis inhibitors in the management of CS, including older agents (KTZ, metyrapone, etomidate and mitotane) and those currently under development (LCI699, non-racemic KTZ), and offer a practical approach for their use in clinical practice.

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“…Pituitarydirected approaches include the dopamine agonist cabergoline (18) and the multi-receptor somatostatin-analogue pasireotide (19). Inhibitors of steroidogenesis that inhibit cytochrome P450 enzymes include metyrapone, ketoconazole and LCI699 (20,21). Hypercortisolism can also be controlled by the adrenolytic agent mitotane (22,23,24) and by the glucocorticoid receptor antagonist mifepristone (25).…”

Section: Introductionmentioning

confidence: 99%

A critical reappraisal of bilateral adrenalectomy for ACTH-dependent Cushing's syndrome

Reincke

Ritzel

Oßwald

et al. 2015

European Journal of Endocrinology

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Objective: Our aim was to review short-and long-term outcomes of patients treated with bilateral adrenalectomy (BADx) in ACTH-dependent Cushing's syndrome. Methods: We reviewed the literature and analysed our experience with 53 patients treated with BADx since 1990 in our institution. Results: BADx is considered if ACTH-dependent Cushing's syndrome is refractory to other treatment modalities. In Cushing's disease (CD), BADx is mainly used as an ultima ratio after transsphenoidal surgery and medical therapies have failed. In these cases, the time span between the first diagnosis of CD and treatment with BADx is relatively long (median 44 months). In ectopic Cushing's syndrome, the time from diagnosis to BADx is shorter (median 2 months), and BADx is often performed as an emergency procedure because of life-threatening complications of severe hypercortisolism. In both situations, BADx is relatively safe (median surgical morbidity 15%; median surgical mortality 3%) and provides excellent control of hypercortisolism; Cushing's-associated signs and symptoms are rapidly corrected, and co-morbidities are stabilised. In CD, the quality of life following BADx is rapidly improving, and long-term mortality is low. Specific long-term complications include the development of adrenal crisis and Nelson's syndrome. In ectopic Cushing's syndrome, long-term mortality is high but is mostly dependent on the prognosis of the underlying malignant neuroendocrine tumour. Conclusion: BADx is a relatively safe and highly effective treatment, and it provides adequate control of long-term co-morbidities associated with hypercortisolism.European Journal of Endocrinology (2015) 173, M23-M32 Invited Author's profile Prof. Martin Heinrich Reincke is Director of the Medizinische Klinik and Poliklinik IV, Ludwig-MaximiliansUniversität München, and Chair of the Department of Endocrinology and Diabetology. His research specialities include adrenal physiology and pathophysiology, endocrine hypertension, pituitary disease, mineralocorticoid and glucocorticoid action and stress research. Professor Reincke heads a research team that specifically explores the prevalence and relevance of Cushing's syndrome at the epidemiological, clinical, genetic and molecular levels. The research teams of his clinic have particular expertise in assay development and validation for endocrine disease and in the development of genetically manipulated animals as models for human adrenal disease.

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LCI699, a Potent 11β-hydroxylase Inhibitor, Normalizes Urinary Cortisol in Patients With Cushing's Disease: Results From a Multicenter, Proof-of-Concept Study

Abstract: LCI699 was efficacious and well tolerated in patients with Cushing's disease enrolled in this proof-of-concept study.

Cited by 164 publications

References 20 publications

Treatment of Cushing's disease: a mechanistic update

Treatment of Cushing's disease: a mechanistic update

THERAPY OF ENDOCRINE DISEASE: Steroidogenesis enzyme inhibitors in Cushing's syndrome

A critical reappraisal of bilateral adrenalectomy for ACTH-dependent Cushing's syndrome

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