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

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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
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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; 2013.

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

Korlym should not be used in the treatment of patients with type 2 diabetes unless it is secondary to 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 non-hormonal 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.

Contraindications

Korlym is contraindicated in women who are pregnant. Pregnancy must be excluded before the initiation of treatment with Korlym or if treatment is interrupted for more than 14 days in females of reproductive potential. Nonhormonal contraceptives should be used during and one month after stopping treatment in all women of reproductive potential.

Korlym is contraindicated in patients taking simvastatin, lovastatin, and CYP3A substrates with narrow therapeutic ranges, such as cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, and tacrolimus, due to an increased risk of adverse events.

Korlym is contraindicated in patients who require concomitant treatment with systemic corticosteroids for serious medical conditions or illnesses (e.g., immunosuppression after organ transplantation) because Korlym antagonizes the effect of glucocorticoids.

Korlym is contraindicated in women with a history of unexplained vaginal bleeding and women with endometrial hyperplasia with atypia or endometrial carcinoma.

Korlym is contraindicated in patients with prior hypersensitivity reactions to mifepristone or to any of the product components.

Warnings and Precautions

Patients receiving mifepristone may experience adrenal insufficiency. Because serum cortisol levels remain elevated and may even increase during treatment with Korlym, serum cortisol levels do not provide an accurate assessment of hypoadrenalism in patients receiving Korlym. Patients should be closely monitored for signs and symptoms of adrenal insufficiency, including weakness, nausea, increased fatigue, hypotension, and hypoglycemia. If adrenal insufficiency is suspected, discontinue treatment with Korlym immediately and administer glucocorticoids without delay. High doses of supplemental glucocorticoids may be needed to overcome the glucocorticoid receptor blockade produced by mifepristone. Factors considered in deciding on the duration of glucocorticoid treatment should include the long half-life of mifepristone (85 hours). Treatment with Korlym at a lower dose can be resumed after resolution of adrenal insufficiency. Patients should also be evaluated for precipitating causes of hypoadrenalism (infection, trauma, etc.).

In a study of patients with Cushing's syndrome, hypokalemia was observed in 44% of subjects during treatment with Korlym. Hypokalemia should be corrected prior to initiating Korlym. During Korlym administration, serum potassium should be measured 1 to 2 weeks after starting or increasing the dose of Korlym and periodically thereafter. Hypokalemia can occur at any time during Korlym treatment. Mifepristone-induced hypokalemia should be treated with intravenous or oral potassium supplementation based on event severity. If hypokalemia persists in spite of potassium supplementation, consider adding mineralocorticoid antagonists.

Being an antagonist of the progesterone receptor, mifepristone promotes unopposed endometrial proliferation that may result in endometrium thickening, cystic dilatation of endometrial glands, and vaginal bleeding. Korlym should be used with caution in women who have hemorrhagic disorders or are receiving concurrent anticoagulant therapy. Women who experience vaginal bleeding during Korlym treatment should be referred to a gynecologist for further evaluation.

Mifepristone and its metabolites block IKr. Korlym prolongs the QTc interval in a dose-related manner. There is little or no experience with high exposure, concomitant dosing with other QT-prolonging drugs, or potassium channel variants resulting in a long QT interval. To minimize risk, the lowest effective dose should always be used.

Use of Korlym in patients who receive corticosteroids for other conditions (e.g., autoimmune disorders) may lead to exacerbation or deterioration of such conditions, as Korlym antagonizes the desired effects of glucocorticoid in these clinical settings. For medical conditions in which chronic corticosteroid therapy is life-saving (e.g., immunosuppression in organ transplantation), Korlym is contraindicated.

Korlym should be used with extreme caution in patients taking ketoconazole and other strong inhibitors of CYP3A, such as itraconazole, nefazodone, ritonavir, nelfinavir, indinavir, atazanavir, amprenavir, fosamprenavir, boceprevir, clarithromycin, conivaptan, lopinavir, posaconazole, saquinavir, telaprevir, telithromycin, or voriconazole, as these could substantially increase the concentration of mifepristone in the blood. The benefit of concomitant use of these agents should be carefully weighed against the potential risks. Mifepristone should be used in combination with strong CYP3A inhibitors only when necessary, and in such cases the dose should be limited to 300 mg per day.

Patients with endogenous Cushing's syndrome are at risk for opportunistic infections such as Pneumocystis jiroveci pneumonia during Korlym treatment. Patients may present with respiratory distress shortly after initiation of Korlym. Appropriate diagnostic tests should be undertaken and treatment for Pneumocystis jiroveci should be considered.

Korlym does not reduce serum cortisol levels. Elevated cortisol levels may activate mineralocorticoid receptors which are also expressed in cardiac tissues. Caution should be used in patients with underlying heart conditions including heart failure and coronary vascular disease.

Adverse Reactions

The most frequently reported adverse reactions (reported in ≥20% of patients, regardless of relationship to Korlym) were nausea, fatigue, headache, decreased blood potassium, arthralgia, vomiting, peripheral edema, hypertension, dizziness, decreased appetite, and endometrial hypertrophy. Drug-related adverse events resulted in dose interruption or reduction in study drug in 40% of patients.

Please see full Prescribing Information and Medication Guide.