Treatment of patients with refractory Cushing's syndrome using the glucocorticoid receptor antagonist mifepristone led to improvements in global clinical response, a post-hoc analysis found.
By week 24 of treatment, 88% of patients showed improvements on a global clinical assessment (GCA) score that reflected multiple disease domains including glucose, lipids, blood pressure, appearance, strength, psychiatric/cognitive symptoms, and quality of life, according to Laurence Katznelson, MD, of Stanford University in California, and colleagues.
The specific disease manifestations that showed the strongest effects on the GCA score in a multivariate analysis were diastolic blood pressure (P<0.0001), weight (P<0.0001), glucose concentration 2 hours after oral glucose challenge (P=0.0003), and Cushingoid appearance (P=0.022), the researchers reported online in Clinical Endocrinology.
Surgery improves many of the potentially serious manifestations of Cushing's syndrome, but up to half of patients continue to have elevated levels of cortisol.
"Medical therapy is usually relegated to an adjuvant role following incomplete surgical extirpation or recurrence of the tumoral source of hormonal excess; the drugs employed have typically consisted of agents that lower cortisol secretion and have variable efficacy and tolerability," explained Katznelson and colleagues.
Mifepristone, formerly known as RU-486 and used in medical abortions, blocks the effects of cortisol in tissues at the level of the receptor. It was approved in 2012 for use in Cushing's disease following an open-label multicenter study that showed it significantly improved the glucose area under the curve (AUC) in patients with Cushing's syndrome and diabetes and lowered diastolic blood pressure in those with hypertension. The drug is marketed as Korlym for the Cushing's indication.
To further explore the effects of treatment, Katznelson and colleagues analyzed secondary endpoints from that 24-week trial that included 46 adult patients.
The oral drug was given in initial doses of 300 mg per day and could be increased to 1,200 mg per day, balancing efficacy with tolerance.
Three independent raters judged patients' clinical status at weeks six, 10, 16, and 24 as +1, meaning clinically meaningful improvement; 0, representing no change; and -1, deterioration from baseline.
"The methodology used to determine GCR was chosen to integrate multiple clinical variables into a single rating to provide a clinically relevant assessment of response to therapy (e.g., to simulate clinical judgment in a practice situation," the researchers explained.
Raters' agreement was assessed using an intraclass correlation coefficient, which ranges from -1 to 1, with scores of 0.01 to 0.2 being "slight" agreement and 0.81 to 100 being "almost perfect" agreement.
A total of 70% of the patients were women, mean age was 45, and most were white. Mean body weight at baseline was 99.5 kg (220 lb), and 98% had Cushingoid appearance.
Among the 46 patients included, 25 had type 2 diabetes or impaired fasting glucose, 21 had hypertension, and 19 had both comorbidities.
At baseline, men and women were similar in the number of signs and symptoms, with a median of four, and no differences were seen in the frequency of high body weight, proximal muscle weakness, Cushingoid appearance, low bone mass, hirsutism/acne, or psychiatric symptoms.
Men had higher levels of urinary free cortisol, but the difference wasn't statistically significant.
Response rates overall reached 80% by week 16, but symptom improvement occurred more slowly among the women (P=0.02), so longer treatment may be needed for women, the researchers suggested.
Positive GCA scores were seen in 83% of patients at the study termination visit and in 80% at the last evaluated visit, with the last observation carried forward.
Percentages of positive GCA scores were similar at the study termination visit and the last evaluated visit in patients who had previously had pituitary radiation and those who had not.
There was 100% agreement among the raters in three-quarters of all study visits, and the intraclass correlation coefficient for rater agreement was 0.652 (P<0.001).
In the multiple regression analysis, quality of life overall wasn't associated with positive GCA scores, but there were improvements in the physical composite score and in several domains of the Short Form 36.
"In conclusion, treatment of Cushing's syndrome with mifepristone results in early and progressive clinical improvement in most patients," they wrote.
Limitations of the analysis included its post-hoc nature and the original study's open-label design.
Primary source: Clinical Endocrinology
Source reference: Katznelson L, et al "Global clinical response in Cushing's syndrome patients treated with mifepristone" Clin Endocrinol 2013; DOI: 10.1111/cen.12332.
The study was sponsored by Corcept Therapeutics.
Katznelson and several co-authors have received grants and act as consultants to Corcept Therapeutics, and one co-author is an employee of the company.