Background: Twice-daily formulation of pasireotide, a pituitary-directed therapy, is approved for treatment of Cushings disease. Here we present data from a phase III study designed to evaluate the more convenient once-monthly long-acting release (LAR) formulation of pasireotide (approved for acromegaly) in patients with Cushings disease.
Methods: Patients with persistent, recurrent, or de novo Cushings disease (not candidates for surgery) and baseline mean UFC (mUFC) ≥1.5-≤5×ULN (mean of three 24-h UFC collections) were randomised (double-blind) to pasireotide LAR 10 mg or 30 mg; at month 4, dose could be increased to 30 mg or 40 mg, respectively, if mUFC>1.5×ULN. Patients (N=150; baseline median mUFC 2.4×ULN) were stratified for analysis by screening mUFC: stratum 1 (mUFC ≥1.5-<2×ULN) and stratum 2 (mUFC 2-5×ULN). The primary efficacy endpoint was the proportion of patients with mUFC≤ULN at month 7, regardless of dose titration.
Results: The primary efficacy response rate was 41.9% (95%CI, 30.553.9%) and 40.8% (95%CI, 29.752.7%) in 10 mg (n=74) and 30 mg (n=76) dose groups, respectively. In stratum 1 (milder disease), 52% (13/25) patients in both 10 mg and 30 mg groups had mUFC≤ULN. In stratum 2, 36.7% (18/49) and 35.3% (18/51) patients in 10 mg and 30 mg groups, respectively, had mUFC≤ULN. Median percentage decrease in mUFC from baseline to month 7 was 48% in both dose groups. Two deaths reported in the 30 mg group (cardiorespiratory failure and pulmonary artery thrombosis) were not considered drug-related. The safety profile of pasireotide LAR was consistent with that of twice-daily pasireotide. Fifty (68%) and 61 (80%) patients experienced hyperglycaemia-related adverse events in the 10 mg and 30 mg groups, respectively; of these 2 (2.7%) and 3 (3.9%) patients discontinued.
Conclusions: Results from this phase III study in patients with Cushings disease show that pasireotide LAR treatment effectively lowers UFC levels with a tolerability profile similar to the twice-daily subcutaneous formulation, and provides a convenient monthly administration schedule.