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

Abstract

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.

Efficacy and Safety of Osilodrostat in Managing Cushing’s Syndrome: A Systematic Review and Meta-Analysis

“…[ 19 ] Simultaneous use of osilodrostat and oral contraceptives does not affect their half-life and metabolism. [ 20 ] Based on the available clinical data, the recommended dose of osilodrostat initiation to control hypercortisolism in CS is 2 mg twice daily, which is gradually up-titrated over several weeks with the aim to normalize 24-hour UFC on patients, without precipitating clinical and biochemical features of hypocortisolism like asthenia and hyperkalaemia among others. Commonly used maintenance dose is 4–14 mg twice daily with a maximum dose of 30 mg twice daily.…”

Aldosterone synthase inhibitor “Baxdrostat” for resistant hypertension: A clinical approach or futuristic idea?

“…It was soon discovered, nevertheless, that Osilodrostat also inhibits 11-beta hydroxylase (CYP11B1), which lowers serum cortisol levels. 7 Perhaps due to decreased cortisol levels, there were many reasons for the administration of Osilodrostat; thus, what was needed for the resistance was a selective aldosterone inhibitor, which was conceived and licensed by CinCor Pharma Inc. Baxdrostat, a drug in phase 2 clinical trials, exemplifies exceptional selective suppression of aldosterone synthase without blocking 11-beta hydroxylase. 8 Animal model studies conducted on cynomolgus monkeys suggested that this drug inhibits the production of aldosterone without influencing the increase in cortisol caused by adrenocorticotropic hormone.…”

“…It was soon discovered, nevertheless, that Osilodrostat also inhibits 11‐beta hydroxylase (CYP11B1), which lowers serum cortisol levels. 7 …”