Mifepristone in Cushing's Disease: Long-term Results

Kathleen Louden

July 23, 2014

More than 70% of patients with Cushing's disease (CD) receiving long-term treatment with mifepristone (Korlym, Corcept Therapeutics) experienced at least a 2-fold elevation in plasma adrenocorticotropic hormone (ACTH) levels, a new study finds.

The ACTH elevations, however, stabilized in most patients, appeared to produce no adverse health effects, and did not correlate with tumor growth, Maria Fleseriu, MD, associate professor and director of the Northwest Pituitary Center at Oregon Health & Science University in Portland, and first author, told Medscape Medical News.

"As far as we know now, elevated ACTH does not seem to be an issue," said Dr. Fleseriu, "but we need to study the long-term safety of mifepristone in more patients and for a longer time."

Dr. Fleseriu and colleagues reported their findings from 27 patients enrolled in the long-term extension of the Study of the Efficacy and Safety of Mifepristone in the Treatment of Endogenous Cushing's Syndrome (SEISMIC LTE) in an article published July 11 in the Journal of Clinical Endocrinology and Metabolism. The authors called the trial the longest prospective study to date of mifepristone as adjunctive medical treatment in CD, with a median treatment duration of 11.3 months.

Mifepristone, also called "the abortion pill" (RU-486), is a glucocorticoid receptor antagonist. It was approved in 2012 to control hyperglycemia in adults with endogenous CD who are not candidates for surgery or who have not responded to surgery.

During the original 6-month SEISMIC trial published in 2012, investigators noted improved metabolic and clinical status in most patients with CD who received mifepristone at doses of 300 to 1200 mg/day. However, 27 (62.8%) of the 43 patients with CD had a 2-fold or greater increase in ACTH levels, which correlated with increases in 24-hour urinary free cortisol, serum cortisol, and late-night salivary cortisol.

The planned extension study enrolled 27 of the 31 patients with CD who completed SEISMIC, according to the new article. For inclusion, patients had to have type 2 diabetes, impaired glucose tolerance, or a diagnosis of hypertension.

After a 6-week off-drug period, patients received a starting dose of mifepristone that was the same as their previous final dose. Dose increases were allowed up to the maximum dose of 1200 mg/day. Dr. Fleseriu said approximately 50% of patients required the maximum dose in the main study. Treatment duration ranged from 2 weeks to 42 months.

Study participants underwent monitoring of their ACTH levels and pituitary MRI to check for tumor changes. Adrenal-gland imaging was not performed, but Dr. Fleseriu said no adrenal-gland enlargement was reported.

ACTH and MRI Findings

Concentrations of ACTH rose within the first few weeks of treatment, reached a plateau on average beginning at month 18 of the LTE and returned to near-baseline levels after discontinuation of therapy, the authors report. Mean peak ACTH (± standard deviation) was 182.8 ± 126.7 pg/mL during the entire LTE study course vs 71.6 ± 53.9 at entry into the LTE, a significant difference (P < .001).

ACTH level directly correlated with mifepristone dose (analysis of variance; P < .001), and increases in ACTH levels occurred independently of prior pituitary radiation therapy, according to the article.

The authors reported MRI findings for all 36 patients from SEISMIC and SEISMIC LTE who had baseline and follow-up MRIs. All 27 patients who entered the LTE study were included in the analysis, Dr. Fleseriu said.

Tumors remained stable in 30 of the 36 patients, regressed in 2 patients, and progressed in 4 patients. Seven of the tumors were macroadenomas 10 mm or larger. Of these macroadenomas, 3 tumors remained stable, 1 regressed (after radiation therapy), and 3 continued to grow; however, Dr. Fleseriu said 1 of the 3 progressive macroadenomas was very aggressive before treatment.

Furthermore, she reported that ACTH increases did not predict corticotroph tumor progression, and ACTH increases in the 4 cases with tumor progression were similar to those in nonprogressive cases.

"The overall lack of tumor progression was reassuring because corticotroph tumor progression was expected to be similar to cases after bilateral adrenalectomy. However, macroadenomas will need close imaging follow-up," Dr. Fleseriu said.

Prior reports indicate that tumors also progressed after medical therapies that reduced the negative feedback of cortisol at the hypothalamus and pituitary, the authors note.

Differing Views of Tumor Results

However, the lack of tumor growth seen in most patients is likely because of the natural history of these pituitary tumors, contended Shlomo Melmed, MB. ChB., an Endocrine Society spokesperson and dean of the medical faculty at Cedars-Sinai Medical Center, Los Angeles, California, when asked by Medscape Medical News to comment.

"There is no evidence that the drug targets the pituitary tumor," said Dr. Melmed, who was not involved in the study.

In the overwhelming majority of patients, rising ACTH does not equal tumor progression. Dr. John Carmichael

On the other hand, the study shows that mifepristone does not cause pituitary tumor growth, John Carmichael, MD, codirector of the Keck Medical Center University of Southern California Pituitary Center, Los Angeles, told Medscape Medical News.

Dr. Carmichael, who also did not participate in SEISMIC LTE, said, "It's a little premature to say we wouldn't see tumor growth anymore because there is a possibility of it."

He continued, "Before this study, we didn't know what happened to ACTH with long-term treatment with mifepristone. In the overwhelming majority of patients, rising ACTH does not equal tumor progression. It's reassuring."

Dr. Melmed also said physicians should not be alarmed by the rising levels of plasma ACTH with mifepristone treatment. "Because the drug blocks the peripheral action of cortisol, there is little likelihood of a deleterious effect of a high ACTH level," he said.

Role of Mifepristone in CD Treatment

The US Food and Drug Administration has designated mifepristone an orphan drug and estimates approximately 5000 patients are eligible for therapy.

CD is a rare but debilitating disease that has few effective treatments, according to Dr. Melmed.

"These are very sick patients. Any help we can get for them is good," he said.

Although surgery remains the first-line treatment of CD, it will not cure some patients.

Dr. Fleseriu said mifepristone could be a useful medication to control blood glucose levels in adult patients with uncontrolled CD who have no contraindications to the drug. For all other cases, she suggested that clinicians consider using mifepristone before referring patients with CD for a bilateral adrenalectomy.

Major disadvantages of mifepristone include high cost and potential for pregnancy loss because of its antiprogestational effects. According to the label, women who could become pregnant must have a pregnancy test before starting treatment and should use a nonhormonal form of contraception during and 1 month after stopping treatment.

Injectable pasireotide (Signifor, Novartis) is approved for the treatment of adults with CD for whom pituitary surgery is not an option or has not been curative. The drug is also expensive and can cause hyperglycemia, Dr. Melmed said.

Other medications are used off-label to treat surgery-refractory CD, including ketoconazole, available as a low-cost generic, but according to the FDA, has the potential for hepatotoxicity.

This study was funded by Corcept Therapeutics. Dr. Fleseriu disclosed that her institution has received research funding for this and other clinical trials from Corcept Therapeutics and Novartis, and that she has been a paid ad hoc scientific consultant for Novartis. Drs. Melmed and Carmichael have reported no relevant financial relationships.

J Clin Endocrinol Metab. Published online July 11, 2014. Abstract


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