The somatostatin analogue pasireotide substantially reduced high cortisol levels in patients with Cushing’s disease, in a phase III clinical trial published in the March 8 issue of the New England Journal of Medicine.
This decline was accompanied by improvements in the signs and symptoms of Cushing’s disease and by increases in health-related quality of life scores, said Dr. Annamaria Colao of the department of molecular and clinical endocrinology and oncology, University of Naples (Italy) Federico II, and her associates.
However, hyperglycemia-related adverse events developed in 73% of patients, and glucose and glycated hemoglobin levels increased soon after the drug was initiated, requiring medical management. "Blood glucose should be monitored in pasireotide-treated patients, with special attention to patients with impaired glucose tolerance or diabetes mellitus," the researchers noted.
They assessed pasireotide in an industry-sponsored study of 162 adults who had moderate to very severe hypercortisolism. All the study subjects had persistent or recurrent Cushing’s disease, or they had newly diagnosed disease but were not candidates for surgery.
The study subjects were randomly assigned to receive subcutaneous pasireotide, beginning at a dose of 600 mcg (82 subjects) or 900 mcg (80 patients) twice daily for 3 months. Those who responded to the treatment continued with their randomly assigned injections in a double-blind fashion through another 3 months, while the others were unblinded and given dose increases of 300 mcg for that 3 months.
At 6 months, all the study subjects entered an open-label phase of the trial that lasted until month 12. During this time, dose escalations were permitted to improve treatment response.
The mean duration of treatment was 10.8 months, and 78 patients (48%) completed the full 12 months of therapy.
The primary end point of the study was normalization of the urinary free cortisol level at month 6 without any dose escalations. This was achieved in 12 of 82 (15%) of the patients receiving 600 mcg and in 21 of the 80 (26%) of those receiving 900 mcg, Dr. Colao and her colleagues said (N. Engl. J. Med. 2012;366:914-24).
The majority of the remaining patients had substantial (50% or greater) reductions in urinary free cortisol levels at month 6, even if they did not achieve normalization of those levels. Both these patients and the ones whose urinary cortisol levels normalized showed marked improvement in the signs and symptoms of Cushing’s syndrome, "suggesting that a reduction in the cortisol level may be associated with a long-term clinical benefit," the researchers said.
These changes included a mean decrease of 6.1 mm Hg in blood pressure, a mean decrease of 3.7 mm Hg in diastolic blood pressure, a mean decrease of 2 mg/dL in triglycerides, a mean decrease of 15 mg/dL in LDL cholesterol, and a mean decrease of 6.7 kg in weight. Facial rubor and supraclavicular and dorsal fat pads also diminished.
Pituitary tumor volume on MRI decreased by a mean of 9% in the lower-dose group and by 44% in the higher-dose group.
Concomitantly, scores for health-related quality of life on the Cushing quality of life questionnaire increased by 11 points, reflecting an 11% improvement.
The treatment effect occurred rapidly, with 50% reductions in urinary free cortisol noted within 2 months and remaining stable for the duration of treatment. And 90% of patients whose hypercortisolism was uncontrolled at 2 months still had hypercortisolism at 12 months. This indicates that clinicians should be able to identify patients who are unlikely to respond to pasireotide within the first few months of therapy, Dr. Colao and her associates said.
Hyperglycemia developed in 13% of patients, including 6% who discontinued pasireotide because of this adverse event. Diabetes mellitus developed in 7%. And 118 patients (73%) experienced a hyperglycemia-related adverse event.
Adverse events related to hypocortisolism occurred in 13 patients (8%). And of 137 patients who had undergone gallbladder ultrasonography at baseline, 9 developed "detectable sludge" and 27 developed gallstones at their most recent follow-up. Six of these patients have undergone cholecystectomy to date.
This study was funded by Novartis Pharma. Dr. Colao’s associates reported ties to Corcept Therapeutics, Ipsen, and Pfizer.