General Information

Korlym (mifepristone) is a small-molecule progesterone and glucocorticoid antagonist. It blocks the binding of cortisol to its receptor. It does not decrease cortisol production but reduces the effects of excess cortisol, such as high blood sugar levels.

Korlym was specifically approved to control hyperglycemia secondary to hypercortisolism in adults with endogenous Cushing's syndrome who have type II diabetes mellitus or glucose intolerance and have failed surgery or are not candidates for surgery.

Mechanism of Action

Korlym (mifepristone) is a small-molecule progesterone and glucocorticoid antagonist. It is a selective antagonist of the progesterone receptor at low doses and blocks the glucocorticoid receptor (GR-II) at higher doses. Mifepristone has high affinity for the GR-II receptor but little affinity for the GR-I (MR, mineralocorticoid) receptor. In addition, mifepristone appears to have little or no affinity for estrogen, muscarinic, histaminic or monoamine receptors.

Side Effects

Adverse events associated with the use of Korlym may include, but are not limited to, the following:

Nausea

Fatigue

Headache

Decreased blood potassium

Arthralgia

Vomiting

Peripheral edema

Hypertension

Dizziness

Decreased appetite

Endometrial hypertrophy

Dosage/Administration

Korlym is supplied as a tablet for oral administration. The recommended initial dose is a single dose of 300 mg orally once daily. The daily dose of Korlym may be increased in 300 mg increments. The dose of Korlym may be increased to a maximum of 1200 mg once daily but should not exceed 20 mg/kg per day. Increases in dose should not occur more frequently than once every two to four weeks.

Clinical Trial Results

FDA approval of Korlym was based on an uncontrolled, open-label, 24-week, multicenter clinical study. The study enrolled 50 subjects with clinical and biochemical evidence of hypercortisolemia despite prior surgical treatment and radiotherapy. The subjects were placed in one of two cohorts: a diabetes cohort and a hypertension cohort and were evaluated separately. Korlym treatment was started at a dose of 300 mg once a day. The study protocol allowed an increase in dose to 600 mg after two weeks, and then by additional 300 mg increments every four weeks to a maximum of 900 mg per day for patients <60 kg or 1200 mg per day for patients >60 kg.

Diabetes Cohort
The primary efficacy analysis for the diabetes cohort was an analysis of responders. A responder was defined as a subject who had a ≥25% reduction from baseline in glucose AUC. Fifteen of 25 subjects (60 percent) were treatment responders.

Hypertension Cohort
There were no changes in mean systolic and diastolic blood pressures at the end of the trial relative to baseline.