Efficacy and safety of osilodrostat in patients with Cushing's disease (LINC 3): a multicentre phase III study with a double-blind, randomised withdrawal phase

Pivonello, Rosario; Fleseriu, Maria; Newell‐Price, John; Bertagna, Xavier; Findling, James W.; Shimatsu, Akira; Gu, Feng; Auchus, Richard J.; Leelawattana, Rattana; Lee, Mi Kyung; Kim, Jung Hee; Lacroix, André; Laplanche, Audrey; O'Connell, Paul; Tauchmanovà, Libuse; Pedroncelli, Alberto; Biller, Beverly M. K.

doi:10.1016/s2213-8587(20)30240-0

Cited by 126 publications

(158 citation statements)

References 28 publications

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“…Regarding clinical profile, at week 48, a decrease in body weight, blood pressure, total and LDL cholesterol, fasting serum glucose, and HbA1c, with a minor decrease in high-density lipoprotein (HDL) cholesterol, together with improvement of quality of life and depression status, was observed; the clinical improvement mainly occurred in the first 12 weeks. Considering patients with measurable tumor at pituitary MRI both at baseline and at 24 weeks, 20 (30.3%) and 19 (28.9%) of 66 patients had a ≥20% increase and decrease, respectively, in tumor volume at 24 weeks; similar evidences were reported in patients with measurable tumor at pituitary MRI both at baseline and at 48 weeks, when 24 (37.5%) and 21 (32.8%) of 64 patients had a ≥20% increase and decrease, respectively, in tumor volume (82). Regarding safety profile, the most frequently reported AEs were nausea (41.6%), headache (33.6%), and fatigue (28.5%), together with hirsutism (11.3%), acne (11.3%), and hyperthrychosis (0.9%) in women.…”

Section: Osilodrostatsupporting

confidence: 76%

“…An increase in testosterone levels was observed in the whole cohort in the first 12 weeks, whereas in the subsequent study periods no further increases were observed. In women, mean testosterone levels increased from the normal range to the ULN, whereas in men, testosterone levels increased from the lower limit of normal range at baseline to the mid-normal range during treatment, with men with hypogonadism at baseline reaching normal testosterone levels throughout the study (82). Regarding clinical profile, at week 48, a decrease in body weight, blood pressure, total and LDL cholesterol, fasting serum glucose, and HbA1c, with a minor decrease in high-density lipoprotein (HDL) cholesterol, together with improvement of quality of life and depression status, was observed; the clinical improvement mainly occurred in the first 12 weeks.…”

Section: Osilodrostatmentioning

confidence: 92%

“…A phase III, double-blind, randomized-withdrawal following an open-label, single-arm period, multicenter clinical trial the LINC3 study (clinicaltrials.gov code: NCT02180217), was started to assess the efficacy and safety of osilodrostat treatment on a large population of CD patients for a period of 48 weeks (82). Osilodrostat was orally administered in a twice-daily schedule.…”

Section: Osilodrostatmentioning

confidence: 99%

“…Treatment discontinuation occurred in 24 (17.5%) patients, because of AEs in 15 (10.9%) patients. Noteworthy, no treatment discontinuation because of lack of efficacy occurred (82).…”

Section: Osilodrostatmentioning

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: Osilodrostatsupporting

confidence: 76%

Section: Osilodrostatmentioning

confidence: 92%

Section: Osilodrostatmentioning

confidence: 99%

“…Treatment discontinuation occurred in 24 (17.5%) patients, because of AEs in 15 (10.9%) patients. Noteworthy, no treatment discontinuation because of lack of efficacy occurred (82).…”

Section: Osilodrostatmentioning

confidence: 99%

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

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“…Osilodrostat is a potent, oral, reversible inhibitor of 11β-hydroxylase. In a phase 3 trial, osilodrostat maintained a complete response in 53% of 137 patients without up-titration after week 12 [8]. Common side effects were nausea, headache, fatigue, and adrenal insufficiency.…”

Section: Novel Drugs For Cushing's Diseasementioning

confidence: 99%

Best Achievements in Pituitary and Adrenal Diseases in 2020

Ahn

Kim

2021

Endocrinol Metab

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Significant progress in pituitary and adrenal diseases was made in 2020. This review presents major translational and clinical advances in research on pituitary and adrenal diseases, encompassing their epidemiology, pathogenesis, diagnosis, and clinical management. We address the controversy regarding the nomenclature of pituitary neuroendocrine tumors, omics-based molecular classification of pituitary adenomas, and novel drugs for Cushing’s disease in the field of pituitary diseases. In the field of adrenal diseases, we cover big data-driven epidemiology of adrenal tumors, steroid profiling as a new diagnostic tool, and the utility of scoring systems in the decision-making process of managing primary aldosteronism. This brief article will broaden readers’ understanding of pituitary and adrenal diseases.

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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 osilodrostat in patients with Cushing's disease (LINC 3): a multicentre phase III study with a double-blind, randomised withdrawal phase

Abstract: This is a repository copy of Efficacy and safety of osilodrostat in patients with Cushing's disease (LINC 3) : a multicentre phase III study with a doubleblind, randomised withdrawal phase.

Cited by 126 publications

References 28 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

Best Achievements in Pituitary and Adrenal Diseases in 2020

Cushing Syndrome

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