KORLYM MECHANISM OF ACTION

Korlym® (mifepristone) is a cortisol receptor blocker indicated to control hyperglycemia secondary to hypercortisolism in adult patients with endogenous Cushing syndrome who have type 2 diabetes mellitus or glucose intolerance and have failed surgery or are not candidates for surgery. Do not use Korlym for the treatment of type 2 diabetes mellitus unrelated to endogenous Cushing syndrome.

Please note that mifepristone has potent antiprogestational effects and will result in the termination of pregnancy. Please see Important Safety Information, including Indication and Boxed Warning at the end of the video.

Cortisol is an essential hormone that helps to regulate many systems in the body. But when cortisol activity is chronically elevated, there can be wide ranging negative effects on those systems, such as impaired glucose tolerance, hypertension, osteoporosis, obesity, and cognitive issues. The release of cortisol is precisely controlled through a complex feedback mechanism.

Its release follows a diurnal rhythm, reaching its peak in the morning and its lowest at night.

Cortisol works by binding to and activating glucocorticoid receptors, or GR, which are present in most body tissues.

Endogenous hypercortisolism develops when tumors of pituitary, adrenal, or ectopic origin cause excess cortisol to be secreted. This leads to abnormally high levels of GR activation, and it's this excessive GR activation that causes the multisystemic dysfunction experienced by patients with hypercortisolism.

Korlym is a competitive GR antagonist that offers a unique approach to treatment. It acts directly on the GR, modulating, but not eliminating the effects of cortisol on this receptor. It does this by competing with the binding of cortisol to the GR in a dose dependent manner. With Korlym modulating cortisol activity at the GR, symptoms of hypercortisolism, such as high blood glucose, obesity, and cognitive issues, start to improve.

With Korlym, important physiological effects of cortisol are preserved, while negative effects of excessive exposure are reduced. It's important to note that Korlym does not bind to the mineralocorticoid receptor or MR.

Cortisol levels may rise during treatment with Korlym, which may lead to MR overstimulation and hypokalemia. Potassium levels should be carefully monitored in patients taking Korlym. In SEISMIC, the Phase III Pivotal Trial, most adverse events were mild or moderate in severity and no association was seen between common AEs and increasing dose.

Treatment with Korlym may result in symptoms of cortisol withdrawal, such as fatigue, nausea, and headache. Administration of Korlym requires careful and gradual titration and potassium monitoring. Positive effects of Korlym can be measured by assessing improvements in blood glucose levels, weight, and mental status.

Korlym is an FDA-approved competitive GR antagonist that has been shown to clinically improve measures that matter.