Drugs in the medical treatment of Cushing's syndrome – an update on mifepristone and pasireotide

Keywords::

• Cushing's syndrome
• persistent Cushing's
• pituitary suppression
• receptor antagonist

Cushing's syndrome is a complex endocrine condition resulting in excessive cortisol secretion with potential serious complications if untreated or inadequately treated, such as cardiovascular mortality, skeletal fractures, limiting proximal muscle weakness, insulin-resistant hyperglycemia, depression and persistent cognitive deficits. There are several types depending on whether adrenocorticotropic hormone (ACTH) is the mediating mechanism for the hypercortisolemia. Pituitary ACTH-dependent type, also known as Cushing's disease, accounts for 70% of all cases, the majority of them being caused by a microadenoma measuring less than 10 mm. These adenomas can be detected by magnetic resonance imaging (MRI) or in case of questionable MRI imaging, by inferior petrosal sinus (IPS) sampling. Macroadenomas, measuring more than 10 mm may extend into the supra or parasellar areas and invade the cavernous sinus. Syndromes of ectopic ACTH and/or corticotropin-releasing hormone (CRH) secretion can be characterized by high ACTH and cortisol levels and associated hypokalemia but frequently resemble the clinical picture of pituitary ACTH-dependent disease. Non-pituitary neoplasms secreting ACTH may be located in the head (paranasal sinus tumors), neck (medullary thyroid cancer), chest (oat-cell lung cancer, malignant thymomas, bronchial carcinoids) or abdomen (islet cell tumors, paragangliomas). They are distinguished from pituitary tumors by lack of central to peripheral gradients of ACTH during IPS sampling. A primary adrenal etiology is identified by the finding of elevated cortisol with suppressed ACTH levels, and the discovery on adrenal imaging of a unilateral adrenal mass or bilateral micro- or macronodular hyperplasia. The benign or malignant nature of unilateral adrenal masses can be suspected on the basis of size and lipid content. Masses larger than 5 cm have a greater probability of being malignant, and lipid-rich masses have higher probability of being benign. Bilateral primary adrenocortical hyperplasia can be part of Carney's complex or result from expression of G protein-bound ectopic receptors.

Treatment of Cushing's syndrome depends on its etiologic subtype but the ultimate objective is to decrease cortisol levels or block its action. The primary treatment for pituitary ACTH-dependent disease is transsphenoidal resection of a pituitary adenoma and occasionally, hypophysectomy. Resection of the primary tumor is the treatment for ectopic ACTH syndrome, and resection of the adrenal tumor or unilateral or bilateral adrenalectomy, the treatment for ACTH-independent disease.

Transsphenoidal surgery (TSS) with resection of a pituitary adenoma is successful in 75–80% of patients with pituitary ACTH-dependent disease, but approximately 20–25% show persistence of Cushing's syndrome, and a similar proportion may experience recurrence within 4 years post-op. Rarely these recurrences may occur much later, but the possibility exists in these cases of a newly developed pituitary adenoma. When surgery fails to reverse the hypercortisolemia, medical treatment can temporarily suppress excessive cortisol production and ameliorate its clinical manifestations while more definitive therapy becomes effective [1].

Drugs currently used to suppress cortisol secretion are mostly inhibitors of steroidogenesis. Ketoconazole, metyrapone, mitotane and etomidate are in that category. Drugs that suppress ACTH secretion such as cabergoline [2], peroxisome proliferator-activated receptor (PPAR)-γ agonists [3-6] have been tested in limited clinical trials but they are only partially effective in normalizing cortisol secretion. A third category of drugs is glucocorticoid receptor (GCR) antagonists. We recently reviewed in detail the published experience with the use of these drugs [7]. This editorial updates this experience by focusing on two recently completed Phase III clinical trials: one with mifepristone, a GCR antagonist and the other with pasireotide, a somatostatin (sst) receptor agonist [8,9].

Mifepristone (Corcept Therapeutics Inc. 149 Commonwealth Dr, Menlo Park CA, 94025) is a GC and progesterone receptor antagonist. It is highly bound to α1-acid glycoprotein (AAG) and approaches saturation at doses of 100 mg or more. There are several mifepristone metabolites which also bind to albumin and distribute to various tissues, including the central nervous system. After single-dose administration, peak plasma concentrations of the parent compound occurred between 1 and 2 h. Ninety percent of a dose, as measured by the administration of radiolabeled compound, is recovered in the feces, and biliary excretion is the primary route of elimination. As GC receptor antagonists, mifepristone and its metabolites have greater affinity for the GCR (mifepristone100%, metabolites 45 – 61%) than either dexamethasone (23%) or cortisol (9%). Mifepristone had been tried in individual cases of Cushing's syndrome with amelioration of the clinical manifestations of hypercortisolism [10] and has been used in the treatment of patients with psychotic depression [11].

In a Phase III, 24-week, open-label clinical trial (Seismic trial), 50 patients with Cushing's syndrome were studied (Table 1). The majority had persistent or recurrent Cushing's disease and a few patients had cortisol-secreting adrenal cancer and ectopic ACTH syndrome. The two primary end points were > 25% improvement in glucose control in patients with impaired glucose tolerance or diabetes and a decrease of at least 5 mm Hg diastolic blood pressure in patients with hypertension without glucose intolerance. Secondary end points were changes in weight and fat distribution, waist circumference, neuropsychiatric symptoms and global clinical improvement as determined by a three-member panel independent data review board.

Table 1. Drugs under development for treatment of Cushing's syndrome.

Compound	Company	Structure	Indication	Stage of development	Class
Mifepristone (Corlux)	Corcept Therapeutics	Butanoic acid,4-[[1-[[(4 aminobutyl)amino]carbonyl]-3-methylbutyl]amino]-4	Psychotic major depression, Cushing's syndrome	Completed Phase III clinical trial in Cushing's disease Received FDA approval	GCR type II antagonist
Mifepristone (Mifedren)	HRA Pharma	Estra-4,9-dien-one,11-[4-(dimethylamino)phenyl]-17-hydroxy-17-(1-propynyl)-, (11β,17β) [CAS 84371-65-3]	Cushing's syndrome	Phase III clinical trial	GCR antagonist
Pasireotide	Novartis	Cyclo[(4R)-4-(2-aminoethylcarbamoyloxy)-l-propyl-l-phenylglycyl-d-tryptophyl-l-lysyl-4-o-benzyl-l-tyrosyl-l-phenylalanyl-]	Acromegaly, carcinoid tumors, Cushing's syndrome	Completed Phase III clinical trial	sst receptor agonist with binding ability to sst1, sst2, sst3 and sst5 receptors
Dopastatin	Ipsen	A chimeric molecule; specific structure not available	Acromegaly, hyperprolactinemia, Cushing's disease	Preclinical studies on pituitary tumors.Phase II clinical trial for acromegaly	Combined sst and D2 receptor agonist

D₂: Dopamine; GCR: Glucocorticoid receptor; sst: Somatostatin.

Of the patients with diabetes or impaired glucose tolerance, 60% responded with decreases of > 25% in the area under the curve in a glucose tolerance test; decreases in the daily dose of insulin for insulin-requiring patients > 50% and the mean hemoglobin A1c from 7.43 to 6.29%. Of the patients with hypertension, 38% showed improved blood pressure readings. Patients lost weight and improved body composition with a decrease in waist circumference (abdominal obesity) of 6.8 cm in women and 8.4 cm in men; 87% showed global improvement in the clinical features of Cushing's syndrome.

Significant side effects of treatment included hypokalemia in 28%, adrenal insufficiency in 14% and metrorrhagia in 10% of patients. As a GCR blocker mifepristone does not decrease cortisol levels but actually increase them by negative feedback in patient with pituitary ACTH-dependent disease. The higher cortisol levels saturate 11β-hydroxysteroid dehydrogenase type 2 and inhibit the conversion of cortisol to cortisone, making cortisol more available for binding to mineralocorticoid renal receptors. This leads to hypokalemia. The addition of mineralocorticoid receptor antagonist such as spironolactone or eplerenone and potassium supplementation reverses the hypokalemia. Adrenal insufficiency was diagnosed in a few patients on mifepristone and was reversed by interruption of treatment and the administration of dexamethasone. Mifepristone is also a progesterone receptor antagonist and can cause endometrial hyperplasia and metrorrhagia but this complication was seen in few patients.

Overall, mifepristone was effective in reversing many of the clinical features of Cushing's syndrome and is a valuable treatment option in patients with recurrent or persistent Cushing's disease after TSS and are not candidates for repeat TSS, adrenalectomy or other adrenal inhibitors. It is also a good temporary treatment choice in patients with severe metabolic complications of Cushing's in preparation for more definite therapy. By ameliorating severe clinical and metabolic complications of Cushing's syndrome, patients may become better candidates for surgery. Mifepristone is also an excellent choice for patients with metastatic cortisol-secreting adrenal cortical carcinoma or occult ectopic ACTH syndrome. Based on the results of this clinical trial, the Food and Drug Administration (FDA) has recently approved mifepristone for the treatment of Cushing's syndrome and the drug will be commercially available.

The majority of pituitary adenomas causing Cushing's disease express sst5 and/or dopamine (D₂) receptors [12]. A sst receptor agonist, pasireotide, binds to sst 1, 2, 3 and 5 and inhibits CRH-stimulated ACTH secretion in vitro acting mainly through the sst5 receptor [13]. This sst analog has been tested in a Phase II, open-label, single arm multicenter clinical trial in patients with persistent or recurrent Cushing's disease but the results were insufficient and only a small percentage of patients normalized their cortisol level [14]. A Phase III multicenter clinical trial (PASPORT-CUSHINGS trial) (Novartis) has recently been completed. The trial involved 162 patients with persistent/recurrent Cushing's disease (135 patients) and 27 de novo patients ineligible for surgery. Patients were randomly assigned to either 600 or 900 μg twice-daily injections of pasireotide for 6 months. Primary end point was urinary free cortisol (UFC) without dose up-titration. At 6 months, 14.6% of patients in the 600 μg dose group and 26.3% in the 900 group met the primary end point. Values were essentially the same at 12 months. Some patients only had a decrease in urinary cortisol without normalization. Median decrease at 6 months was 47.6% for both groups and at 12 months, 67.6% in the 600 group and 62.4% in the 900 group. Side effects consisted of diarrhea in 58% of patients, nausea in 46%, hyperglycemia in 38.9% and cholelithiasis in 29.6%. These side effects are similar to those observed with sst treatment and are caused by suppression of insulin secretion (hyperglycemia) and inhibition of gastrointestinal motility.

The major indication of a drug like pasireotide is patients with ACTH-secreting pituitary adenomas. Only a minority of these patients normalized their cortisol levels and it is not certain if the effect would have continued beyond the 12-month trial period. Almost two-third of patients experienced improvement in their cortisol levels but those who did not normalize would have required additional drugs for treatment. Anecdotal reports suggest that combining pasiroetide with other drugs helped normalize cortisol levels but few clinical trials are available to validate these treatment approaches. Side effects with pasireotide were significant and the need for injections twice daily a major inconvenience but a new Phase III clinical trial under way with pasireotide LAR (long-acting release) may make the administration of the drug more appealing.

Mifepristone and pasireotide are promising drugs for treating selective cases of Cushing's syndrome but it is likely they will need to be used in combination with inhibitors of steroidogenesis whose efficacy and safety have been well validated over the years. Ketoconazole [15] is the most commonly used while metyrapone [16] is available in the USA only on a compassionate use basis. Mitotane [17] is an adrenalytic drug that causes adrenocortical necrosis and can be used to induce a chemical adrenalectomy. Its main use is in patients with adrenal cortical carcinoma because of its antitumor effects. Etomidate [18,19] is an anesthetic drug that can promptly cause suppression of cortisol secretion when administered intravenously but can only be used with close monitoring in an inpatient setting (Table 2). All of these drugs have dose-dependent toxicity that may limit their use. Ketoconazole may cause hepatotoxicity when given in doses greater than 1000 mg/day and mitotane is associated with gastrointestinal and neurological side effects as the dose is increased.

Table 2. Drug treatment of Cushing's syndrome.

Drug	Main mechanism of drug action
Ketoconazole	↓ 17-hydroxylase, 11β-hydroxylase, cholesterol SCC
Metyrapone	↓ 11β-hydroxylase
Mitotane	Formation of acyl chloride, binding to bionucleophiles
Etomidate	↓ 11β-hydroxylase
Cabergoline	D2 agonist
sst analogs	sst receptor agonists
Glitazones	PPAR-γ agonists
Mifepristone	Type II GCR antagonist

D₂: Dopamine; GCR: Glucocorticoid receptor; PPAR: Peroxisome proliferator-activated receptor; SCC: Side-chain cleavage; sst: Somatostatin.

Expert opinion

While surgical treatment has the best probability of cure, medical treatment with drugs alone offers only temporary relief of the clinical manifestations of Cushing's syndrome. Monotherapy with inhibitors of steroidogenesis like ketoconazole is sufficiently effective to render most patients eucortisolemic for long periods. In cases of persistent pituitary corticotrope adenomas, suppression of cortisol may lead to rising ACTH levels and tumor growth causing Nelson's syndrome. In other cases, cortisol levels are only partially suppressed but low level active Cushing's persists. It is in those patients that combined drug treatment directed to the adrenal, the pituitary or both may have its place. At the pituitary level, there is reported enhanced response of patients with Cushing's disease to combination of cabergoline and pasireotide. Pituitary adenomas may express both D₂ and sst5 receptors and combination of these two drugs could be effective in suppressing ACTH secretion. Novel chimeric molecules with D₂ and sst receptor agonist activity may be promising. Similarly, neuroendocrine tumors secreting ACTH ectopically may also express sst and D₂ receptors. In cases where surgery is unable to totally eradicate these tumors, pharmacological treatment with D₂ and sst agonists may be an effective option in controlling excessive ACTH secretion. Combinations of inhibitors of ACTH release and suppressors of steroidogenesis might be able to more effectively reverse the clinical manifestations of Cushing's syndrome. Combination treatment with inhibitors of steroidogenesis like ketoconazole and mifepristone may be useful in reversing the clinical manifestations of cortisol excess but drug–drug interaction with ketoconazole may limit the use of this combination. Mifepristone is principally metabolized via CYP3A4 that is strongly inhibited by ketoconazole and dose adjustments may be necessary when the drugs are given together.

Declaration of interest

The author has received clinical trial support from Corcept Therapeutics.