PATIENT SITE

Study of the Efficacy and Safety of Mifepristone in the Treatment of Endogenous Cushing's Syndrome (SEISMIC): A Phase 3 Pivotal Trial

Study design1,2

  • An uncontrolled, open-label, 24-week, multicenter clinical study was conducted to evaluate the safety and efficacy of Korlym in the treatment of endogenous Cushing's syndrome1,2
  • 50 subjects with Cushing's syndrome received 300 mg to 1200 mg of Korlym per day for up to 24 weeks. The subjects were divided into 2 groups1:
    • Those with diabetes mellitus type 2 and/or glucose intolerance
    • Those with a diagnosis of hypertension but without diabetes and/or glucose intolerance during enrollment
Chart Image

Source: Fleseriu M, et al.1

This study enrolled 50 subjects with clinically significant hypercortisolism. Forty-three patients had Cushing's disease and all except one had previously undergone pituitary surgery. Four patients had ectopic ACTH secretion, and 3 had adrenal carcinoma. The population was 26 to 71 years of age; 70% were female. Forty-six of the 50 subjects received at least 30 days of dosing during the 24-week study period and were included in a mITT analysis. Pre-existing antidiabetic and antihypertensive medications were continued at the start of Korlym treatment.1,2

Korlym: Primary end point

Patients with Cushing's syndrome and diabetes mellitus1

  • Responders were defined as those subjects who had at least a 25% decrease from baseline in AUCglucose at Week 24.1
  • The study used the measurement of blood glucose as a primary end point because hyperglycemia is highly prevalent in patients with Cushing's syndrome2
  • Because the measurement of cortisol levels is not an indicator of the efficacy of Korlym and because AUCglucose is a quantitative measure of a main comorbid condition of Cushing's syndrome, AUCglucose is a logical marker to determine the effects of Korlym3
  • Results1:
  • 60% of patients were responders, with a ≥25% reduction from baseline in AUCglucose (95% CI lower bound, 42%)
    • Because the lower bound of the 95% CI was greater than 20%, this response rate of 60% was statistically significant

Patients with Cushing's syndrome and hypertension*

  • Responders were defined as those subjects who had at least a 5 mm Hg reduction from baseline in diastolic blood pressure (DBP) at Week 24.1
  • As a group, patients in the hypertension cohort had normotensive DBP measurements at the start of the study (mean DBP: 82.9 mm Hg), as many patients were controlled on BP medicine1
  • Results2:
  • 38.1% of patients responded with at least a 5 mm Hg reduction from baseline in DBP at Week 24. Results were not statistically significant1
  • There were no changes in mean systolic BP and DBP the end of the trial relative to baseline in the modified ITT population (mITT) (n=21)1
  • Korlym is not indicated to treat hypertension in patients with Cushing's syndrome

Extension Trial

  • 88% of patients who completed the trial chose to enroll in the extension trial3

1. Fleseriu M, Biller BM, Findling JW, Molitch ME, Schteingart DE, Gross C; on behalf of the SEISMIC Study Investigators. Mifepristone, a glucocorticoid receptor antagonist, produces clinical and metabolic benefits in patients with Cushing's syndrome. J Clin Endocrinol Metab. 2012;97(6):2039-2049.

2. Korlym full Prescribing Information. Corcept Therapeutics Incorporated; May 2017.

3. Data on file, Corcept Therapeutics Incorporated. March 31, 2013.

INDICATIONS AND USAGE

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

Important Limitations of Use

Do not use for the treatment of type 2 diabetes mellitus unrelated to endogenous Cushing's syndrome.

IMPORTANT SAFETY INFORMATION

WARNING: TERMINATION OF PREGNANCY

Mifepristone is a potent antagonist of progesterone and cortisol via the progesterone and glucocorticoid (GR-II) receptors, respectively. The antiprogestational effects will result in the termination of pregnancy. Pregnancy must therefore be excluded before the initiation of treatment with Korlym and prevented during treatment and for one month after stopping treatment by the use of a nonhormonal medically acceptable method of contraception unless the patient has had a surgical sterilization, in which case no additional contraception is needed. Pregnancy must also be excluded if treatment is interrupted for more than 14 days in females of reproductive potential.

DOSAGE AND ADMINISTRATION

Administer once daily orally with a meal. The recommended starting dose is 300 mg once daily. Renal impairment: Do not exceed 600 mg once daily. Mild-to-moderate hepatic impairment: Do not exceed 600 mg once daily. Do not use in severe hepatic impairment. Based on clinical response and tolerability, the dose may be increased in 300-mg increments to a maximum of 1200 mg once daily. Do not exceed 20 mg/kg per day.

Concomitant use of Korlym with a strong CYP3A inhibitor resulted in a 38% increase in mean plasma concentration of mifepristone. For patients already being treated with a strong CYP3A inhibitor, start with a Korlym dose of 300 mg per day and titrate to a maximum of 600 mg per day if clinically indicated. When a strong CYP3A inhibitor is administered to patients already receiving Korlym, adjust the dose as follows: For patients receiving a daily dose of 600 mg, reduce the daily dose to 300 mg. Titrate to a maximum of 600 mg per day if clinically indicated. For patients receiving a daily dose of either 900 mg or 1200 mg, reduce the daily dose to 600 mg.

CONTRAINDICATIONS

Pregnancy; use of simvastatin or lovastatin and CYP3A substrates with narrow therapeutic range; concurrent long-term corticosteroid use; women with history of unexplained vaginal bleeding; women with endometrial hyperplasia with atypia or endometrial carcinoma.

WARNINGS AND PRECAUTIONS

Adrenal insufficiency: Patients should be closely monitored for signs and symptoms of adrenal insufficiency.

Hypokalemia: Hypokalemia should be corrected prior to treatment and monitored for during treatment.

Vaginal bleeding and endometrial changes: Women may experience endometrial thickening or unexpected vaginal bleeding. Use with caution if the patient also has a hemorrhagic disorder or is on anticoagulant therapy.

QT interval prolongation: Avoid use with QT interval-prolonging drugs, or in patients with potassium channel variants resulting in a long QT interval.

Use of Strong CYP3A Inhibitors: Concomitant use increases mifepristone plasma levels. Adjust Korlym dose as described in Dosage and Administration. Use only when necessary and do not exceed a Korlym dose of 600 mg.

ADVERSE REACTIONS

Most common adverse reactions in Cushing's syndrome (≥20%): nausea, fatigue, headache, decreased blood potassium, arthralgia, vomiting, peripheral edema, hypertension, dizziness, decreased appetite, endometrial hypertrophy.

DRUG INTERACTIONS

Drugs metabolized by CYP3A: Administer drugs that are metabolized by CYP3A at the lowest dose when used with Korlym.

CYP3A inhibitors: Caution should be used when Korlym is used with strong CYP3A inhibitors. Adjust Korlym dose as described in Dosage and Administration. Use only when necessary, and do not exceed a Korlym dose of 600 mg.

CYP3A inducers: Do not use Korlym with CYP3A inducers.

Drugs metabolized by CYP2C8/2C9: Use the lowest dose of CYP2C8/2C9 substrates when used with Korlym.

Drugs metabolized by CYP2B6: Use of Korlym should be done with caution with bupropion and efavirenz.

Hormonal contraceptives: Do not use with Korlym.

USE IN SPECIFIC POPULATIONS

Nursing mothers: Discontinue drug or discontinue nursing.

Please see accompanying full Prescribing Information and Medication Guide.