Pasireotide can induce sustained decreases in urinary cortisol and provide clinical benefit in patients with Cushing's disease: results from an open-ended, open-label extension trial

Abstract

Purpose: Report the efficacy and safety of pasireotide sc in patients with Cushing's disease during an open-ended, open-label extension to a randomized, double-blind, 12-month, Phase III study.

Methods: 162 patients entered the core study. 58 patients who had mean UFC ≤ ULN at month 12 or were benefiting clinically from pasireotide entered the extension. Patients received the same dose of pasireotide as at the end of the core study (300-1,200 μg bid). Dose titration was permitted according to efficacy or drug-related adverse events.

Results: 40 patients completed 24 months' treatment. Of the patients who entered the extension, 50.0% (29/58) and 34.5% (20/58) had controlled UFC (UFC ≤ ULN) at months 12 and 24, respectively. The mean percentage decrease in UFC was 57.3% (95% CI 40.7-73.9; n = 52) and 62.1% (50.8-73.5; n = 33) after 12 and 24 months' treatment, respectively. Improvements in clinical signs of Cushing's disease were sustained up to month 24. The most frequent drug-related adverse events in patients who received ≥1 dose of pasireotide (n = 162) from core baseline until the 24-month cut-off were diarrhea (55.6%), nausea (48.1%), hyperglycemia (38.9%), and cholelithiasis (31.5%). No new safety issues were identified during the extension.

Conclusions: Reductions in mean UFC and improvements in clinical signs of Cushing's disease were maintained over 24 months of pasireotide treatment. The safety profile of pasireotide is typical for a somatostatin analogue, except for the frequency and degree of hyperglycemia; patients should be monitored for changes in glucose homeostasis. Pasireotide represents the first approved pituitary-targeted treatment for patients with Cushing's disease.

Trial registration: ClinicalTrials.gov NCT00434148.

Figures

Fig. 1

Proportion of patients with UFC ≤ ULN at time points up to month 24 in the 58 patients who entered the open-ended extension. The numbers shown above each bar represent the total number of patients in each treatment group with UFC ≤ ULN at the specific time point. Patients with missing data are classed as non-responders at the given time point; patients who discontinued are classed as non-responders at subsequent time points. The pasireotide 600 and 900 µg dose groups represent the randomly assigned treatment at core baseline; patients were not necessarily receiving their randomized dose at each time point

Fig. 2

Mean (±SE) a UFC, b serum cortisol, and c plasma ACTH levels from baseline up to month 24 in the 58 patients who entered the open-ended extension. The total numbers of patients with evaluable measurements for UFC, serum cortisol, and plasma ACTH are shown beneath each graph

Fig. 3

Mean UFC (±SE) and a systolic blood pressure, b diastolic blood pressure, and c weight up to month 24 in the 58 patients who entered the open-ended extension. The total numbers of patients included in the analyses of mean UFC level and mean signs and symptoms scores are shown beneath each graph. DBP diastolic blood pressure, SBP systolic blood pressure

Fig. 4

Mean (±SE) a HbA1c and b fasting plasma glucose over time from baseline up to 24-month data cut-off in the 162 patients who received at least one dose of pasireotide