Is Korlym (mifepristone) safe and effective for treating hypercortisolism, particularly in patients with Cushing's syndrome who have failed or are intolerant to other treatments?

Is Korlym (Mifepristone) Safe and Effective for Hypercortisolism?

Korlym (mifepristone) is effective for controlling hyperglycemia in Cushing's syndrome patients who have failed surgery or are not surgical candidates, but it requires expert management due to the inability to monitor cortisol levels biochemically and significant safety concerns including hypokalemia, hypertension, and adrenal insufficiency. 1, 2

FDA-Approved Indication and Efficacy

• Mifepristone is FDA-approved specifically 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 2
• It should NOT be used for type 2 diabetes unrelated to Cushing's syndrome 2

Clinical efficacy is well-documented: In clinical studies, 38% of patients with diabetes or glucose intolerance showed significant improvement in glucose control, 38% with hypertension achieved ≥5 mm Hg reduction in diastolic blood pressure, and patients experienced improvements in insulin resistance, weight, waist circumference, and quality of life 1

Critical Safety Limitations Requiring Expert Management

Inability to Monitor Biochemically

• The most significant limitation is that cortisol levels remain elevated during mifepristone treatment because it blocks the glucocorticoid receptor rather than reducing cortisol production 1, 3, 4
• No reliable biochemical markers exist for monitoring treatment efficacy or detecting adrenal insufficiency—only clinical features can guide management 1, 3, 4
• This makes mifepristone fundamentally different from other medical therapies where urinary free cortisol and late-night salivary cortisol can be monitored 1

Serious Adverse Events Requiring Close Monitoring

Hypokalemia and hypertension from mineralocorticoid receptor activation:

• Twelve patients in the pivotal study showed increased blood pressure, including 9 with hypokalemia requiring spironolactone treatment 1
• Hypokalemia should be corrected prior to treatment initiation and monitored closely during therapy 2
• This occurs because elevated cortisol levels activate mineralocorticoid receptors 1

Adrenal insufficiency:

• Seven patients in clinical studies required dexamethasone for signs and symptoms of adrenal insufficiency 1
• The long half-life of mifepristone complicates management, requiring several days of stress-dose glucocorticoid replacement, preferably dexamethasone 3
• Patients must be closely monitored for clinical signs of adrenal insufficiency since laboratory values are unreliable 2

Endometrial and hormonal effects:

• Endometrial hypertrophy and irregular menstrual bleeding occur due to anti-progesterone activity 1, 2
• Mifepristone is contraindicated in women with unexplained vaginal bleeding, endometrial hyperplasia with atypia, or endometrial carcinoma 2
• Pregnancy must be excluded before initiation and prevented during treatment with non-hormonal contraception 2

Thyroid function changes:

• Thyroid function should be closely monitored and thyroid hormone replacement adjusted as needed 1, 3

Tumor progression concerns:

• In a long-term extension study, 3 patients with macroadenomas showed tumor volume progression up to 25 months from baseline, though this did not correlate with ACTH increases 1

Extensive Drug-Drug Interactions

• All concomitant medications must be carefully reviewed given potential interactions with multiple cytochrome P450 enzymes 1, 2
• Mifepristone is contraindicated with drugs metabolized by CYP3A with narrow therapeutic ranges (e.g., simvastatin, lovastatin) 2
• When used with strong CYP3A inhibitors (ketoconazole, itraconazole, ritonavir, clarithromycin), the maximum mifepristone dose should be limited to 900 mg daily 2
• Do not use with CYP3A inducers 2
• Hormonal contraceptives should not be used with mifepristone 2

Dosing and Administration

• Starting dose: 300 mg orally once daily with a meal 2
• May increase in 300 mg increments every 2-4 weeks based on clinical response and tolerability 2
• Maximum dose: 1200 mg once daily, not to exceed 20 mg/kg per day 2
• In renal impairment or mild-to-moderate hepatic impairment: do not exceed 600 mg daily 2
• Do not use in severe hepatic impairment 2

Position in Treatment Algorithm

Mifepristone should NOT be first-line medical therapy for Cushing's disease. The 2021 Endocrine Society guideline recommends that adrenal steroidogenesis inhibitors (osilodrostat, metyrapone, ketoconazole) are usually used first given their reliable effectiveness and ability to monitor cortisol levels 1, 3

Specific scenarios where mifepristone may be preferred:

• Patients with severe hyperglycemia as the dominant manifestation of hypercortisolism 1
• Men who need to avoid hypogonadism (unlike ketoconazole, mifepristone does not cause hypogonadism) 3
• As bridge therapy while awaiting effects of radiation or during surgical delays 5
• When other medical therapies have failed or are not tolerated 1, 6

For severe disease requiring rapid cortisol normalization: Osilodrostat and metyrapone are preferred because they work within hours and allow biochemical monitoring 1, 7

Pediatric Use

• Mifepristone is NOT currently approved for pediatric use 1
• Effects and safety are being evaluated in a phase II trial in children 1
• In children and adolescents, medical therapy should be confined to normalizing cortisol levels in preparation for surgery or while awaiting response to radiotherapy, not as long-term treatment 1

Clinical Expertise Requirement

Mifepristone should only be prescribed by clinicians with extensive experience in Cushing's disease management 3, 4

The inability to use biochemical markers for monitoring increases the risk of unrecognized adrenal insufficiency and requires sophisticated clinical judgment to balance efficacy against safety 3, 4

Contraindications

• Pregnancy (will cause termination) 2
• Patients taking CYP3A substrates with narrow therapeutic ranges 2
• Patients receiving systemic corticosteroids for life-saving purposes 2
• Women with unexplained vaginal bleeding, endometrial hyperplasia with atypia, or endometrial carcinoma 2
• Known hypersensitivity to mifepristone 2