|Other names||Osilodrostat phosphate, LCI-699|
|Drug class||Steroidogenesis inhibitor|
|Main uses||Cushing's disease|
|Side effects||Adrenal insufficiency, headache, vomiting, tiredness, swelling|
|Typical dose||2 to 30 mg BID|
|Chemical and physical data|
|Molar mass||227.242 g·mol−1|
|3D model (JSmol)|
Common side effects are adrenal insufficiency, headache, vomiting, tiredness, and swelling. QTc prolongation, low potassium, and high blood pressure may also occur. Safety is unclear in pregnancy and use in breastfeeding is not recommended. It works by inhibiting the enzyme 11-beta-hydroxylase which makes cortisol.
Osilodrostat was approved for medical use in Europe and the United States in 2020. In the United Kingdom a month of 10 mg twice per day costs about £6700 as of 2021. In the United States this amount costs about 32,200 USD.
Mechanism of action
Osilodrostat is an orally active, nonsteroidal corticosteroid biosynthesis inhibitor which was developed by Novartis for the treatment of Cushing's syndrome and pituitary ACTH hypersecretion (a specific subtype of Cushing's syndrome). It specifically acts as a potent and selective inhibitor of aldosterone synthase (CYP11B2) and at higher dosages of 11β-hydroxylase (CYP11B1).
In October 2014, an orphan designation was granted by the European Commission for osilodrostat for the treatment of Cushing's syndrome.
Osilodrostat's safety and effectiveness for treating Cushing's disease among adults was evaluated in a study of 137 adult subjects (about three-quarters women) with a mean age of 41 years. The majority of subjects either had undergone pituitary surgery that did not cure Cushing's disease or were not surgical candidates. In the 24-week, single-arm, open-label period, all subjects received a starting dose of 2 milligrams (mg) of osilodrostat twice a day that could be increased every two weeks up to 30 mg twice a day. At the end of this 24-week period, about half of subjects had cortisol levels within normal limits. After this point, 71 subjects who did not need further dose increases and tolerated the drug for the last 12 weeks entered an eight-week, double-blind, randomized withdrawal study where they either received osilodrostat or a placebo (inactive treatment). At the end of this withdrawal period, 86% of subjects receiving osilodrostat maintained cortisol levels within normal limits compared to 30% of subjects taking the placebo.
The U.S. Food and Drug Administration (FDA) approved osilodrostat based on the evidence from one clinical trial (NCT02180217) of 137 subjects with Cushing's disease. The trial was conducted at 66 sites across 19 countries (United States, Argentina, Austria, Bulgaria, Canada, China, Columbia, Germany, Spain, France, Great Britain, India, Italy, Japan, Korea, Netherlands, Russia, Thailand, and Turkey).
There was one trial of 48 weeks duration that assessed the benefits and side effects of osilodrostat. The trial enrolled subjects with Cushing's disease for whom pituitary gland surgery was not an option or did not work. The trial was divided in four periods. Subjects received osilodrostat two times a day in all four periods. After the first two periods (24 weeks), the benefit of osilodrostat was assessed by the percentage of subjects who had 24-hour urinary free cortisol levels within normal limits.
In the third period (which lasted eight weeks), half of the subjects who had normal urinary free cortisol levels after 24 weeks of treatment continued taking osilodrostat and the other half was switched to placebo. Neither the subjects nor the healthcare providers know which treatment was given during this period. The benefit of osilodrostat was assessed on the percentage of subjects who had normal cortisol levels at the end of this period versus the subjects who received placebo.
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