Korlym (mifepristone) for Cushing’s disease
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What is Korlym for Cushing’s disease?
Korlym (mifepristone) is an oral therapy approved in the U.S. to lower high blood sugar levels, or hyperglycemia, in adults with endogenous Cushing’s syndrome, including Cushing’s disease.
Marketed by Corcept Therapeutics, the medication is indicated for people who have type 2 diabetes or glucose intolerance and for whom surgery is not an option or has failed to control their symptoms.
An application requesting the therapy’s approval in Europe was submitted in 2013, a year after Korlym was approved in the U.S. The therapy would have been marketed under the brand name Corluxin in the European Union, but the application was withdrawn in 2015 after a negative opinion from the European Medicines Agency’s Committee for Medicinal Products for Human Use.
Therapy Snapshot
| Brand Name: | Korlym |
| Chemical Name: | Mifepristone |
| Usage: | Treatment of high blood sugar in adults with endogenous Cushing’s syndrome who have type 2 diabetes or glucose intolerance and for whom surgery is not an option or has been ineffective |
| Administration: | Oral tablets |
How does Korlym work?
Endogenous Cushing’s syndrome refers to any disorder marked by excessive levels of the hormone cortisol in the body, including Cushing’s disease.
One of the many roles of cortisol — perhaps best known for regulating the body’s stress response — is the modulation of blood sugar or glucose levels. Too much cortisol can cause blood sugar levels to rise, which is called glucose intolerance. When glucose levels meet a certain high level, a person is said to have type 2 diabetes.
Cortisol exerts its numerous effects by binding to glucocorticoid receptors on the surface of cells. Korlym is a competitive glucocorticoid receptor antagonist, meaning it binds to these receptors, partially blocking cortisol’s access to them. Ultimately, this prevents the chain of signaling events that leads to high blood sugar in Cushing’s.
Who can take Korlym?
Korlym was approved by the U.S. Food and Drug Administration in 2012 to control high blood sugar levels in adults with endogenous Cushing’s syndrome with glucose intolerance or type 2 diabetes. It is indicated for patients who are ineligible for surgery or for whom surgery has failed to control their symptoms.
Importantly, the medication is only indicated for people with endogenous Cushing’s. It is not expected to be used to treat hyperglycemia or type 2 diabetes unrelated to Cushing’s.
Who should not take Korlym?
Korlym is contraindicated, or not recommended, for certain patients:
- People who are pregnant should not take Korlym, as the medication will cause pregnancy loss.
- Women with a history of unexplained vaginal bleeding, abnormal thickening of the uterine wall (endometrial hyperplasia), or endometrial carcinoma, a type of cancer of the lining of the uterus, are recommended not to take Korlym.
- Patients taking medications that are broken down by CYP3A, an enzyme whose activity is blocked by Korlym, should not take it for this indication. These are drugs such as:
- cholesterol-lowering medications (simvastatin or lovastatin)
- immunosuppressants (cyclosporine, sirolimus, or tacrolimus)
- migraine medications (dihydroergotamine and ergotamine)
- opioids (fentanyl)
- antipsychotics (pimozide)
- medicines to treat heart rhythm disorders (quinidine).
- Individuals receiving systemic corticosteroids for life-saving purposes, such as for immunosuppression following a transplant, should not take Korlym as it may block the effects of these medications.
- Those with a known allergy to mifepristone or other ingredients in Korlym should not take the medication.
The therapy’s prescribing information contains a boxed warning because of its potential for pregnancy termination. Due to its potent inhibition of progesterone, an important hormone for maintaining pregnancy, Korlym will result in pregnancy loss. Thus, pregnancy must be excluded in anyone planning to start treatment with the medication.
The medication should not be used by patients with severe liver impairments. It also should be used with caution in women with bleeding disorders or receiving blood thinning therapies.
Caution also is recommended regarding the therapy’s use in people with certain heart conditions, and among those receiving strong CYP3A inhibitors such as ketoconazole — which is sometimes used off label in people with Cushing’s. As these drugs may increase the levels of mifepristone in circulation, the potential benefits and risks of using them along with Korlym should be carefully weighed.
How is Korlym administered?
Korlym comes in the form of oral tablets containing 300 mg of mifepristone, the medication’s active ingredient. Tablets are oval in shape, light yellow to yellow in color, and engraved with “Corcept” on one side and “300” on the other.
The recommended starting dose is a single 300 mg tablet, taken once daily by mouth with a meal. The dose may be increased in 300 mg increments every two to four weeks up to a maximum daily dose of 1,200 mg, based on a person’s tolerability and clinical response. The maximum Korlym dose should never exceed 2o mg per kilogram of body weight per day, and dose changes should be determined by a healthcare professional under careful monitoring.
Patients with kidney impairments, mild-to-moderate liver impairments, or those taking certain medications may require different dose adjustments, as determined by a healthcare professional.
Korlym’s maximum dose should be limited to 600 mg in patients with kidney and mild-to-moderate liver impairments. For those on medications that strongly inhibit CYP3A and may increase the concentration of Korlym’s active ingredient in the body, the treatment’s maximum dose should not exceed 900 mg.
Grapefruit juice also may increase the amount of Korlym in the bloodstream and increase the risk of side effects. Thus, patients should not drink grapefruit juice while taking Korlym.
Korlym should always be taken with a meal. Tablets should be swallowed whole, and should not be split, crushed, or chewed.
Korlym in clinical trials
Korlym’s approval was largely based on data from a single open-label Phase 3 trial called SEISMIC (NCT00569582), which did not involve a placebo dose. In an open-label trial, both participants and researchers know what medication patients are receiving.
The trial enrolled 50 adults with endogenous Cushing’s syndrome — including 43 with Cushing’s disease — who had failed to respond to surgery or were not eligible for it.
SEISMIC trial
All patients in SEISMIC had either type 2 diabetes or glucose intolerance and/or high blood pressure. Participants were given Korlym at a dose ranging from 300 to 1,200 mg per day for 24 weeks, or about six months. This was followed by a six-week safety monitoring period.
Among patients with type 2 diabetes or glucose intolerance, 60% showed a clinically meaningful improvement in glucose control, as assessed by an oral glucose tolerance test, after six months. Other observed benefits included a lower use of antidiabetic medications, significant weight loss, and reductions in waist circumference.
For those with high blood pressure, 38% saw reductions in diastolic blood pressure — the pressure in the arteries while the heart rests between beats.
Overall, 87% of the trial participants were deemed by an independent review board to show clinical improvements. That board looked at a range of symptoms, including body weight and composition, Cushing’s physical features, and psychological symptoms.
A total of 30 trial participants then entered a long-term extension study (NCT00936741), in which all patients continued to receive treatment for up to three years. Results from the extension phase indicated that weight loss seen in the main trial was generally sustained for up to two years.
Phase 4 trial
A pilot Phase 4 trial (NCT01990560) evaluated Korlym in eight people with mild autonomous cortisol secretion (ACS), a subclinical form of Cushing’s syndrome in which patients, despite having high cortisol levels, do not exhibit overt symptoms of the condition.
Participants received 300 mg of Korlym once daily for six months. This treatment led to significant reductions in blood sugar and insulin resistance — a feature of diabetes marked by cells’ unresponsiveness to insulin, a hormone that controls how cells store and use glucose.
Ongoing trials
Corcept is sponsoring a Phase 4 trial called CATALYST (NCT05772169) to investigate the prevalence of hypercortisolism, or high cortisol levels, in people with difficult to control type 2 diabetes despite treatment, and to examine the safety and efficacy of Korlym in those patients. The study is expected to enroll about 1,000 participants in the U.S.
Common side effects of Korlym
The most common side effects associated with Korlym in clinical trials include:
- nausea
- fatigue
- headache
- low blood potassium levels (hypokalemia)
- joint pain
- vomiting
- swelling in the legs, ankles, feet, or hands (peripheral edema)
- high blood pressure (hypertension)
- dizziness
- decreased appetite
- endometrial enlargement (hypertrophy).
Adrenal insufficiency
Patients given Korlym may experience adrenal insufficiency, a potentially life-threatening condition that occurs when the adrenal glands don’t make enough of certain hormones, including cortisol. Symptoms of adrenal insufficiency may include weakness, nausea, fatigue, low blood pressure, and low blood sugar.
Individuals taking the therapy should be carefully monitored for signs and symptoms of adrenal insufficiency during treatment. If adrenal sufficiency is suspected, Korlym should be discontinued and patients should be treated with glucocorticoid medications immediately. Treatment may later be resumed at a lower dose at a doctor’s discretion.
Low blood potassium
Low blood potassium levels, known as hypokalemia, may occur at any time while a patient is taking Korlym. Thus, blood potassium levels should be measured and corrected as needed before starting Korlym, as well as assessed periodically throughout treatment.
Vaginal bleeding and endometrial changes
Korlym may result in a thickening of the lining of the uterus (endometrium), dilation of the endometrial glands, and vaginal bleeding. The medication should be used cautiously in women with bleeding disorders or in those receiving blood thinners. Women who experience vaginal bleeding while taking Korlym should be referred to a gynecologist for further evaluation.
Heart function abnormalities
Korlym may lead to QTc prolongation, an electrical disturbance in the heart that can cause heartbeat irregularities. To minimize that risk, patients should always be on the lowest effective dose of Korlym.
Worsening of conditions treated with corticosteroids
Patients receiving corticosteroids for other conditions, such as autoimmune diseases, may experience a worsening of those disorders when using Korlym. This is due to the medication blocking the receptors through which corticosteroids exert their effects. In cases in which corticosteroids are life-saving — for instance, in patients taking these medicines to suppress organ transplant rejection — Korlym should not be used.
Use of ketoconazole, other CYP3A inhibitors
Ketoconazole is an antifungal treatment sometimes used off-label to treat Cushing’s syndrome in the U.S. This and similar CYP3A inhibitors can change the way Korlym is absorbed in the body, leading to increased concentrations of mifepristone in the bloodstream.
Because both medications may be used simultaneously to treat Cushing’s patients, doctors should carefully evaluate the potential benefits and risks of using these medicines together, and the combination should only be used when necessary.
Pneumocystis jiroveci infection
Cushing’s patients using Korlym are at an increased risk of experiencing opportunistic infections, such as pneumocystis jiroveci pneumonia. If patients present with respiratory distress while on treatment with Korlym, appropriate tests and treatment for infection should be considered.
Elevated blood cortisol
While Korlym works to block the receptors through which cortisol exerts its effects, it does not lower cortisol levels in the bloodstream, and cortisol elevations may occur while patients are taking Korlym. High cortisol levels may lead to the activation of certain receptors in heart tissues. Thus, caution should be used in patients with underlying heart conditions, such as heart failure, who are given Korlym.
Use in pregnancy and breastfeeding
Korlym’s active ingredient is a potent blocker of progesterone, an important hormone for maintaining pregnancy. The use of Korlym will result in pregnancy loss. The therapy’s label comes with a boxed warning that it should never be taken by women who are pregnant or may become pregnant.
Women with reproductive potential must obtain a negative pregnancy test before starting treatment and again when restarting treatment after more than a two-week pause.
Female patients with the ability to become pregnant must use a medically acceptable, nonhormonal form of contraception during treatment. Korlym interferes with the effectiveness of hormonal forms of birth control, which typically contain progesterone and should not be used. Patients who suspect they may be pregnant while taking Korlym should contact their doctor immediately.
While the active ingredient in Korlym has been detected in human milk, there are no available data on the potential effects of the medication on a breastfed infant or on milk production during long-term treatment. Patients wishing to breastfeed while taking Korlym should discuss the potential benefits and risks with their doctor.
Cushing’s Disease News is strictly a news and information website about the disease. It does not provide medical advice, diagnosis, or treatment. This content is not intended to be a substitute for professional medical advice, diagnosis or treatment. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a medical condition. Never disregard professional medical advice or delay in seeking it because of something you have read on this website.
FAQs about Korlym
Korlym was approved by the U.S. Food and Drug Administration (FDA) in February 2012 as a treatment to help control high blood sugar levels in adults with endogenous Cushing’s syndrome. The FDA cleared the therapy for use in Cushing’s patients with type 2 diabetes or glucose intolerance who are not surgical candidates or failed to respond to surgery.
There are no known interactions between Korlym and alcohol. However, because drinking alcohol while on certain medications can sometimes lower their effectiveness or cause side effects, patients wishing to drink while using Korlym should discuss that with their healthcare providers.
In the SEISMIC trial that supported Korlym’s approval, significant reductions in blood sugar levels were observed in some patients as early as six weeks after starting treatment. However, each patient is unique and may respond differently to medications based on a number of different factors. Patients should talk to their doctors about how Korlym might benefit them.
The most common side effects associated with Korlym include nausea, fatigue, headache, low blood potassium, joint pain, vomiting, swelling, high blood pressure, dizziness, decreased appetite, and endometrial hypertrophy, or a thickening of the uterine wall. Patients should speak with their healthcare providers if they experience any unanticipated side effects from the medication, as dose adjustments or treatment discontinuation may be needed in some cases. The medication carries a boxed warning that notes that taking Korlym during pregnancy will result in pregnancy loss.
Korlym is not known to cause weight gain. On the contrary, the treatment was associated with significant reductions in body weight for people with Cushing’s syndrome in clinical trials. Patients who gain weight on Korlym or experience other unexpected side effects should let their healthcare team know.
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