Osilodrostat — an emerging drug for the medical management of Cushing’s disease

Witek, Przemysław; Mehlich, Anna; Stasiewicz, A; Jawiarczyk-Przybyłowska, Aleksandra; Bolanowski, Marek

doi:10.5603/ep.a2022.0009

Cited by 7 publications

(20 citation statements)

References 25 publications

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“…However, osilodrostat was found to have limited efficacy in hypertensive patients while it decreased cortisol levels, thereby shifting the interest towards its development as a potential treatment of CD. 22 Osilodrostat has a longer half-life (4 h) than metyrapone (2 h) and has a higher potency than metyrapone in inhibiting 11-beta-hydroxylase in vitro. 21 Osilodrostat is mostly excreted in the urine (91%).…”

Section: Pharmacokinetics/pharmacodynamics (Phase I Ii) -Linc 1 Andmentioning

confidence: 99%

“…Adrenal insufficiency was reported in 28% among LINC 4 participants. [20][21][22]25,27 After the 48th week, patients who showed benefit from osilodrostat at the end of the study period had the opportunity to enroll in a multicenter, extension phase lasting up to 72 weeks. The average exposure to osilodrostat was 130 weeks.…”

Section: Phase III (Linc 3 and 4) -Clinical Efficacy And Safetymentioning

confidence: 99%

Section: Pharmacokinetics/pharmacodynamics (Phase I Ii) – Linc 1 Andmentioning

confidence: 99%

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Clinical Utility of Osilodrostat in Cushing’s Disease: Review of Currently Available Literature

Perosevic¹,

Tritos²

2023

DDDT

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Cushing's disease (CD) is caused by endogenous hypercortisolism as a result of adrenocorticotropin (ACTH) secretion from a pituitary tumor. The condition is associated with multiple comorbidities and increased mortality. First-line therapy for CD is pituitary surgery, performed by an experienced pituitary neurosurgeon. Hypercortisolism may often persist or recur after initial surgery. Patients with persistent or recurrent CD will generally benefit from medical therapy, often administered to patients who underwent radiation therapy to the sella and are awaiting its salutary effects. There are three groups of medications directed against CD, including pituitary-targeted medications that inhibit ACTH secretion from tumorous corticotroph cells, adrenally-directed medications that inhibit adrenal steroidogenesis and a glucocorticoid receptor (GR) antagonist. The focus of this review is osilodrostat, a steroidogenesis inhibitor. Osilodrostat (LCI699) was initially developed to lower serum aldosterone levels and control hypertension. However, it was soon realized that osilodrostat also inhibits 11-beta hydroxylase (CYP11B1), leading to a reduction in serum cortisol levels. The focus of drug development then shifted from treatment of hypertension to treatment of hypercortisolism in CD. In a series of studies (LINC 1 through 4), osilodrostat was shown to be effective in normalizing 24-h urinary free cortisol (UFC) in the majority of treated patients and was approved for patients with CD who have failed surgery or are not surgical candidates. Further study is needed to examine the role of combination therapy as well as long-term outcomes of treated patients. Osilodrostat was shown to have an overall good safety profile. Most common adverse effects include nausea, headache, fatigue, arthralgias, dizziness, prolonged QT c interval, hypokalemia. In females, the drug can cause hirsutism and acne. Osilodrostat is administered twice daily, making it a good choice for patients with difficulty adhering to more complex regimens. Osilodrostat has an important, albeit adjunctive, role in the management of patients with CD.

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Section: Pharmacokinetics/pharmacodynamics (Phase I Ii) -Linc 1 Andmentioning

confidence: 99%

Section: Phase III (Linc 3 and 4) -Clinical Efficacy And Safetymentioning

confidence: 99%

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Clinical Utility of Osilodrostat in Cushing’s Disease: Review of Currently Available Literature

Perosevic¹,

Tritos²

2023

DDDT

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“…The untreated CD is associated with excessive mortality and morbidity as well as decreased quality of life (6,7). The clinical picture of CD consists of weight gain, central obesity with facial fat redistribution, skin changes, depression, cognitive impairment, susceptibility to infections, menstrual irregularities in women, and decreased libido in men (8,9). Patients with CD commonly develop multiple systemic and metabolic complications, including insulin resistance, prediabetes, diabetes mellitus (DM), dyslipidemia, hypertension, and hypercoagulability.…”

Section: Introductionmentioning

confidence: 99%

Medical treatment of Cushing’s disease with concurrent diabetes mellitus

et al. 2023

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Cushing’s disease (CD) is a severe endocrine disorder characterized by chronic hypercortisolaemia secondary to an overproduction of adrenocorticotropic hormone (ACTH) by a pituitary adenoma. Cortisol excess impairs normal glucose homeostasis through many pathophysiological mechanisms. The varying degrees of glucose intolerance, including impaired fasting glucose, impaired glucose tolerance, and Diabetes Mellitus (DM) are commonly observed in patients with CD and contribute to significant morbidity and mortality. Although definitive surgical treatment of ACTH-secreting tumors remains the most effective therapy to control both cortisol levels and glucose metabolism, nearly one-third of patients present with persistent or recurrent disease and require additional treatments. In recent years, several medical therapies demonstrated prominent clinical efficacy in the management of patients with CD for whom surgery was non-curative or for those who are ineligible to undergo surgical treatment. Cortisol-lowering medications may have different effects on glucose metabolism, partially independent of their role in normalizing hypercortisolaemia. The expanding therapeutic landscape offers new opportunities for the tailored therapy of patients with CD who present with glucose intolerance or DM, however, additional clinical studies are needed to determine the optimal management strategies. In this article, we discuss the pathophysiology of impaired glucose metabolism caused by cortisol excess and review the clinical efficacy of medical therapies of CD, with particular emphasis on their effects on glucose homeostasis.

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“…Alternatively, rapidacting oral steroidogenesis inhibitors, such as ketoconazole, metyrapone, or osilodrostat, might be considered in SH management. Osilodrostat is a novel adrenostatic agent that inhibits the activity of 11-β-hydroxylase as well as 18-hydroxylase enzyme (suppressing cortisol and also aldosterone synthesis) [17][18][19][20][21]. Recent reports show that osilodrostat can control SH relatively quickly [22][23][24].…”

Section: Introductionmentioning

confidence: 99%

Cushing’s syndrome: a combined treatment with etomidate and osilodrostat in severe life-threatening hypercortisolemia

Dzialach

Sobolewska

Respondek³

et al. 2022

Hormones

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Endogenous Cushing’s syndrome (CS) is associated with increased morbidity and mortality. Early diagnosis and initiation of therapy are essential, but effective treatment remains a challenge. In a long-term follow-up, biochemical control of hypercortisolemia, especially when severe, is difficult to achieve. Life-threatening hypercortisolemia is difficult to control due to the limitations of pharmacotherapy, including its side effects, and may require etomidate infusion in the intensive care unit (ICU) to rapidly lower cortisol levels. The effectiveness of hypercortisolemia management can be increased by a dual blockade of cortisol production. We report the efficacy, safety, and tolerability of combined therapy with two steroidogenesis inhibitors, etomidate, and osilodrostat, in a 32-year-old woman diagnosed with severe ACTH-dependent hypercortisolemia, subsequently maintaining a stable level of cortisol with osilodrostat monotherapy. This approach enabled achievement of relatively rapid control of the hypercortisolemia while using an etomidate infusion and concomitant increasing doses of oral osilodrostat applying a “titrations strategy.” Our experience shows that it is worth taking advantage of the synergistic anticortisolic action of etomidate with osilodrostat.

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Osilodrostat — an emerging drug for the medical management of Cushing’s disease

Abstract: thermore, central obesity with facial fat redistribution, skin changes, as well as depression and cognitive impairment reflect long-term physical and psychological abnormalities in patients with CD, which negatively affect the quality of life [3,7].

Cited by 7 publications

References 25 publications

Clinical Utility of Osilodrostat in Cushing’s Disease: Review of Currently Available Literature

Clinical Utility of Osilodrostat in Cushing’s Disease: Review of Currently Available Literature

Medical treatment of Cushing’s disease with concurrent diabetes mellitus

Cushing’s syndrome: a combined treatment with etomidate and osilodrostat in severe life-threatening hypercortisolemia

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