Maria Fleseriu, M.D.,
Cushing’s syndrome (CS) is a severe endocrine disorder. Cushing’s disease (CD) is the most frequent cause of CS (with the exception of exogenous glucocorticoids) due to a pituitary tumor. If inadequately treated, due to prolonged exposure to high cortisol concentrations, CS is associated with significant morbidity and a 3.8- to 5-fold higher mortality than the general population.
While transsphenoidal surgery is the initial treatment of choice for Cushing’s disease, it is not always successful in all cases; if successful, the disease can return in a number of cases, even up to decades later. Repeat surgeries or radiation can be useful, though both have clear efficacy limitations. Certain medications (e.g., Ketoconazole, Mitotane) have been used off-label; however, drugs of this type do not target the underlying pituitary tumor, and dose adjustments to maintain effectiveness may be required.
Until recent clinical trials—including studies at the OHSU Northwest Pituitary Center — there had not been a Federal Drug Administration (FDA)-approved drug to treat hyperglycemia associated with CS.
Mifepristone clinical trials
OHSU was the largest subject enroller during a multicenter, open-label phase 3 trial to evaluate the safety and efficacy of Korlym (mifepristone), a glucocorticoid receptor antagonist, in endogenous CS. Korlym has been granted FDA orphan designation to treat hyperglycemia caused by hypercortisolism in adults with refractory CS who have type 2 diabetes mellitus or glucose intolerance.
Subjects completed 24 weeks of 300-1200 mg daily mifepristone treatment under the study and continued treatment in an extension study. Participants included 50 adults with endogenous CS associated with type 2 diabetes mellitus/impaired glucose tolerance or a diagnosis of hypertension alone.
Of the 29 patients enrolled in the study who were glucose intolerant, 60 percent experienced a 25 percent or greater reduction in blood sugar level. Of the 12 patients taking insulin at baseline, seven cut their daily dose by at least 50 percent. Many patients lost weight and reported an improved quality of life.
Side effects observed in the study were consistent with the safety profile of mifepristone, with fatigue and nausea being the ones most commonly reported, but hypokalemia and adrenal insufficiency were also seen. Korlym is contraindicated for pregnancy, type 2 diabetes mellitus not caused by CS, long-term corticosteroid use and women with endometrial hyperplasia with atypia or endometrial carcinoma.
The results of this study, as published in The Journal of Clinical Endocrinology and Metabolism1,? demonstrated that patients with refractory CS receiving Korlym experienced significant clinical improvement with an acceptable risk-benefit profile over 6 months.?
Pasireotide clinical trials
OHSU has also played a pivotal role in several clinical trials with a pituitary targeted therapy, pasireotide (new somatostatin analogue). Pasireotide was recently approved for Cushing’s disease in Europe as Signifor and in November 2012 the US FDA’s Endocrinologic and Metabolic Drugs Advisory Committee voted unanimously in support of the use of Signifor? (pasireotide) for the treatment of patients with Cushing's disease who require medical therapeutic intervention.
The phase 3 study was an international collaborative effort2: 162 subjects with persistent, recurrent or de novo Cushing’s disease were randomized to receive pasireotide 600 mcg or 900 mcg subcutaneously twice daily for 12 months. After 12 months of treatment, 68 percent and 62 percent of the patients receiving 600 and 900 mcg doses respectively normalized their UFC levels.
Improvements in biochemical control were accompanied by clinical improvements in blood pressure, weight and quality of life. Pituitary tumor volume as assessed on magnetic resonance imaging decreased by a mean of nine percent in the lower-dose group and by 44 percent in the higher-dose group.
Adverse effects were similar to other somatostatin analogues with the exception of the degree of hyperglycemia. Blood glucose should be monitored in pasireotide-treated patients, with special attention to patients with impaired glucose tolerance or diabetes mellitus.
Another study with pasireotide for Cushing’s disease is ongoing at OHSU.
About the OHSU Northwest Pituitary Center
The OHSU Northwest Pituitary Center is a regional leader in neuroendocrine and pituitary surgery care.
Our team has decades of accumulated expertise in the clinical, teaching and research realms, and we provide comprehensive, streamlined care for patients with hypothalamic/pituitary abnormalities, including pituitary tumors and pituitary hormone dysfunction. The Center is led by Maria Fleseriu, M.D., FACE, who has a longstanding clinical and research interest in the pathophysiology and treatment of pituitary and adrenal diseases.
1 Fleseriu M et al, Mifepristone, a Glucocorticoid Receptor Antagonist, Produces Clinical and Metabolic Benefits in Patients with Cushing's Syndrome. J Clin Endocrinol Metab , 2012, Jun;97(6):2039-49
2 Colao A et al, A 12-Month Phase 3 Study of Pasireotide in Cushing's Disease. New England Journal of Medicine , 2012, 366:914-924.