Study demonstrates potential of long-acting pasireotide in Cushing’s disease
A once-a-month intramuscular injection of pasireotide has shown promise in reducing cortisol levels in patients with pituitary-related Cushing’s disease, a recent phase III study found.
“This study substantiates the efficacy and safety of pasireotide in patients with Cushing’s disease, with the long-acting formulation providing a convenient monthly administration schedule,” said the researchers.
“Normalization of cortisol concentration represents a key treatment goal in patients with Cushing’s disease, which can improve the mortality rate towards that of the general population,” they said.
Patients in this multinational (57 sites in 19 countries) trial were aged ≥18 years (n=150, mean age 38.5 years, 79 percent female, mean time since diagnosis 22.3 months) with persistent, recurrent, or de novo Cushing’s disease and with a pituitary source of Cushing’s syndrome, mean urinary free cortisol (mUFC) levels of 1.5–5.0 times the upper limit of normal (ULN; 166.5 nmol/24 hours obtained in three 24-hour samples within 2 weeks of study onset), and normal or greater than normal morning plasma adrenocorticotropic hormone (ACTH) concentration. The patients were randomized to receive intramuscular injections of pasireotide 10 mg (n=74) or 30 mg (n=76) every 4 weeks for 12 months.
In the absence of intolerability, up-titration from 10 to 30 mg or from 30 to 40 mg was allowed at month 4 if mUFC >1.5 x ULN, or at month 7, 9, or 12 if mUFC >1.0 x ULN.
Thirty-one patients in each group met the primary endpoint, ie, an mUFC concentration of ≤ULN at month 7 (41.9 and 40.8 percent of patients on 10 and 30 mg pasireotide, respectively); of which 28.4 and 31.6 percent, respectively, did so without dose up-titration. [Lancet Diabetes Endocrinol 2017;doi:10.1016/S2213-8587(17)30326-1]
The mUFC concentration of ≤ULN was maintained in 35.1 and 25 percent of patients on 10 and 30 mg, respectively, at month 12.
At months 7 and 12, median mUFC concentrations reduced by 47.9 and 52.5 percent from baseline in the 10 mg group and by 48.5 and 51.9 percent in the 30 mg group.
Patients with lower mUFC concentrations had better response rates. Patients in both groups demonstrated sustained reductions in median morning plasma ACTH and late-night salivary cortisol concentration, as well as improvements in blood pressure, waist circumference, weight, BMI, and quality of life.
Seventy-two and 82 percent of patients on 10 and 30 mg, respectively, experienced hyperglycaemia. Elevations in mean fasting plasma glucose concentrations were observed in both groups (rising from 93.9 mg/dL at baseline to 113.5 mg/dL at month 1 [10 mg] and from 95.8 to 138.5 mg/dL [30 mg]) as were elevations in mean HbA1c levels (from 5.7 percent in each group at baseline to 6.9 and 7.0 percent among patients on 10 and 30 mg, respectively, at month 12).
“Blood glucose concentration should be monitored closely in patients treated with pasireotide and action taken – including initiation of glucose-lowering therapy – if necessary,” said the researchers.
Other adverse events experienced by patients in both groups were diarrhoea, cholelithiasis, diabetes mellitus, and nausea.
Serious adverse events suspected to be treatment-related occurred in 11 and 5 percent of patients in the 10 and 30 mg groups, respectively. There were two deaths in the 30 mg group, neither of which was attributed to the study drug.
When done by an expert pituitary surgeon, “surgical resection of the causative pituitary adenoma”, the first-line treatment for most cases of Cushing’s disease, leads to remission in more than three-quarters of patients, said the researchers. Nonetheless, disease can recur years after remission, and not all patients are candidates for surgery.
“[S]second-line treatments have been problematic,” said Professor Ashley Grossman from the University of Oxford, UK, in a commentary. [Lancet Diabetes Endocrinol 2017;doi:10.1016/S2213-8587(17)30341-8]
“[R]epeat surgery cures a lower proportion of patients than does initial surgery and can lead to partial or complete hypopituitarism, radiotherapy of any type ... can take several years to become effective and also induces some loss of pituitary function, and bilateral adrenalectomy induces life-long hypoadrenalism and raises the spectre of Nelson’s syndrome,” he said.
Furthermore, other medical therapies that act on the adrenal cortex do not directly act upon the pituitary tumour, Grossman added.
Based on the results of a previous phase III trial, the US FDA* approved the use of twice-daily subcutaneous injections for patients with Cushing’s disease in whom surgery is not an option or has been unsuccessful. [N Engl J Med 2012;366:914-924; US FDA, https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/200677lbl.pdf]
“[A] once-monthly administration schedule could allow greater convenience and adherence to treatment,” said the researchers.