Osilodrostat Is a Potential Novel Steroidogenesis Inhibitor for the Treatment of Cushing Syndrome: An In Vitro Study

Creemers, Sara G; Feelders, Richard A; Jong, Frank H. de; Franssen, Gaston J H; Rijke, Yolanda B. de; Koetsveld, Peter M. van; Hofland, Leo J.

doi:10.1210/jc.2019-00217

Cited by 40 publications

(29 citation statements)

References 31 publications

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“…Osilodrostat potently inhibits the adrenal enzymes aldosterone synthase, which is responsible for the conversion of corticosterone to aldosterone, and 11β-hydroxylase, which is responsible for the conversion of 11-deoxycortisol to cortisol and of 11-deoxycorticosterone to corticosterone, therefore inducing a decrease in glucocorticoid and mineralocorticoid production and secretion (74). In particular, an experimental direct comparison of osilodrostat with metyrapone and ketoconazole, two classical adrenal steroidogenesis inhibitors, has shown that osilodrostat inhibits in vitro cortisol production more potently than both metyrapone (IC 50 0.0347 µM vs. 0.0678 µM) and ketoconazole (IC 50 0.0347 µM vs. 0.621 µM) in human adrenocortical HAC15 cell cultures, suggesting that lower doses of osilodrostat compared to metyrapone and ketoconazole may be sufficient to reach the same efficacy, despite the variable results observed in human adrenal cell cultures deriving from cortisol-producing adrenal hyperplasias, adrenal adenomas, and ACC (75). Moreover, osilodrostat has shown a longer half-life compared with both metyrapone (4 vs. 2 h) and ketoconazole (4 vs. 3.3 h), allowing therefore a twice-daily administration (4,76,77).…”

Section: Osilodrostatmentioning

confidence: 97%

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: Osilodrostatmentioning

confidence: 97%

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

et al. 2020

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“…A new 11-hydroxylase inhibitor with improved potency and a longer half-life than metyrapone, called Osilodrostat (R) or LCI 699, is currently being developed for use in Cushing's disease (221,222,223). This compound is remarkably effective in Cushing's disease, including forms with severe hypercortisolism (222,223).…”

Section: (B) Specific Treatments: Personalized Medicinementioning

confidence: 99%

MANAGEMENT OF ENDOCRINE DISEASE: Cushing’s syndrome due to ectopic ACTH secretion: an expert operational opinion

Young

Haissaguerre

Viera-Pinto

et al. 2020

European Journal of Endocrinology

139

186

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Ectopic ACTH syndrome (EAS) is rare but is frequently a severe condition because of the intensity of the hypercortisolism that may be dissociated from the tumoral condition. EAS should often be considered as an endocrine emergency requiring an emergency response both in terms of diagnostic procedures and therapeutic interventions. Patient management is complex and necessitates dual skills, in the diagnosis and treatment of CS and in the specific management of neuroendocrine tumors (NET). Therefore, initial management should be performed ideally by experienced endocrinology teams in collaboration with specialized hormonal laboratory, modern imaging platforms and intensive care units. Diagnostic procedures vary according to the endocrine and tumoral contexts but should be reduced to a minimum in intense hypercortisolism. Preventive and curative treatments of cortisol-induced comorbidities, non-specific management of hypercortisolism and etiological treatments should be considered simultaneously. Therapeutic strategies vary according to (1.) the intensity of hypercortisolism, the general condition of the patient and associated comorbidities and (2.) the tumoral status, ranging from resectable ACTH secreting tumors to non-resectable metastatic endocrine tumors or occult tumors. The ideal treatment is complete excision of the ACTH-secreting tumor that can be performed rapidly or after preoperative preparation using cortisol-lowering drugs. When this is not possible, the therapeutic strategy should be discussed by a multidisciplinary experienced team in a personalized perspective and include variable combinations of pharmacological agents, bilateral adrenalectomy and non-specific tumoral interventions. Here we discuss the diagnosis and therapeutic strategies including the modern, currently available tools and emphasize on the operational effectiveness of care.

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“…The effects of the following selected steroid enzyme inhibitors were examined alone (basal conditions) or with ACTH (1 nM, stimulated conditions): Abiraterone acetate (1 μM), Osilodrostat (1 μM), and Efavirenz (10 μM). Treatment concentrations were selected based on pilot experiments testing doses of 1 and 10 μM which have previously been reported to inhibit steroidogenesis in vitro [9,[19][20][21] and the lowest dose showing an effect on steroidogenesis was chosen. Additionally, doseresponse effect was examined for Abiraterone acetate (1 and 10 μM) and Osilodrostat (1 and 10 μM) under basal conditions.…”

Section: Ex Vivo Culture Treatmentsmentioning

confidence: 99%

The effects of selected inhibitors on human fetal adrenal steroidogenesis differs under basal and ACTH-stimulated conditions

Melau

Riis

Nielsen

et al. 2021

BMC Med

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Background Disordered fetal adrenal steroidogenesis can cause marked clinical effects including virilization of female fetuses. In postnatal life, adrenal disorders can be life-threatening due to the risk of adrenal crisis and must be carefully managed. However, testing explicit adrenal steroidogenic inhibitory effects of therapeutic drugs is challenging due to species-specific characteristics, and particularly the impact of adrenocorticotropic hormone (ACTH) stimulation on drugs targeting steroidogenesis has not previously been examined in human adrenal tissue. Therefore, this study aimed to examine the effects of selected steroidogenic inhibitors on human fetal adrenal (HFA) steroid hormone production under basal and ACTH-stimulated conditions. Methods This study used an established HFA ex vivo culture model to examine treatment effects in 78 adrenals from 50 human fetuses (gestational weeks 8–12). Inhibitors were selected to affect enzymes critical for different steps in classic adrenal steroidogenic pathways, including CYP17A1 (Abiraterone acetate), CYP11B1/2 (Osilodrostat), and a suggested CYP21A2 inhibitor (Efavirenz). Treatment effects were examined under basal and ACTH-stimulated conditions in tissue from the same fetus and determined by quantifying the secretion of adrenal steroids in the culture media using liquid chromatography-tandem mass spectrometry. Statistical analysis was performed on ln-transformed data using one-way ANOVA for repeated measures followed by Tukey’s multiple comparisons test. Results Treatment with Abiraterone acetate and Osilodrostat resulted in potent inhibition of CYP17A1 and CYP11B1/2, respectively, while treatment with Efavirenz reduced testosterone secretion under basal conditions. ACTH-stimulation affected the inhibitory effects of all investigated drugs. Thus, treatment effects of Abiraterone acetate were more pronounced under stimulated conditions, while Efavirenz treatment caused a non-specific inhibition on steroidogenesis. ACTH-stimulation prevented the Osilodrostat-mediated CYP11B1 inhibition observed under basal conditions. Conclusions Our results show that the effects of steroidogenic inhibitors differ under basal and ACTH-stimulated conditions in the HFA ex vivo culture model. This could suggest that in vivo effects of therapeutic drugs targeting steroidogenesis may vary in conditions where patients have suppressed or high ACTH levels, respectively. This study further demonstrates that ex vivo cultured HFAs can be used to evaluate steroidogenic inhibitors and thereby provide novel information about the local effects of existing and emerging drugs that targets steroidogenesis.

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Osilodrostat Is a Potential Novel Steroidogenesis Inhibitor for the Treatment of Cushing Syndrome: An In Vitro Study

Cited by 40 publications

References 31 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

MANAGEMENT OF ENDOCRINE DISEASE: Cushing’s syndrome due to ectopic ACTH secretion: an expert operational opinion

The effects of selected inhibitors on human fetal adrenal steroidogenesis differs under basal and ACTH-stimulated conditions

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