Abstract
Background: Clinical trials have shown that subcutaneous (sc) pasireotide effectively decreases urinary free cortisol (UFC), improves signs/symptoms and has a favorable safety profile in patients with Cushing’s disease (CD). We describe interim long-term safety and efficacy results of an ongoing multicenter observational study of pasireotide sc in real-world clinical practice for CD (NCT02310269). Methods: This study aims to enroll 100-200 adults with CD for whom surgery has failed or is not an option. Eligible patients could have started pasireotide before (prior use) or at (new use) study entry. Primary endpoint: incidence of pasireotide-related adverse events (AEs) and serious AEs (SAEs) over a 3-year observation period. Secondary endpoint: proportion of patients with mean UFC (mUFC) not exceeding the upper limit of normal (ULN) at months 1, 3, 6, 12, 24 and 36. Results: As of October 1, 2017, 127 patients had received ≥1 dose of pasireotide. Median (range) exposure to pasireotide was 30.5 months (1.9-118.4) in the 96 prior-use patients (12.0 months [0.3-14.6] on study) and 3.4 months (0.1-18.4) in the 31 new-use patients. Median (range) daily dose was 1.2 mg/day (0.2-2.2). Pasireotide was discontinued early in 44 (45.8%) prior-use and 22 (71.0%) new-use patients; 15 (15.6%) prior-use and 12 (38.7%) new-use patients discontinued because of AEs. Of 123 patients (92 prior use, 31 new use) with ≥1 safety assessment, 98 (79.7%) experienced ≥1 AE. Drug-related AEs were recorded in 37 (40.2%) prior-use and 24 (77.4%) new-use patients. The most common were: nausea, recorded in 7 (7.6%) prior-use and 10 (12.9%) new-use patients; hyperglycemia, recorded in 5 (5.4%) prior-use and 9 (29.0%) new-use patients; diarrhea, recorded in 8 (8.7%) prior-use and 5 (16.1%) new-use patients. Except for hyperglycemia, drug-related AEs were reported in similar proportions between cohorts. Drug-related SAEs occurred in 10 (10.9%) prior-use and 7 (22.6%) new-use patients, of which hyperglycemia was the most common, experienced by 3 (9.7%) new-use and no prior-use patients. Overall, hyperglycemia-related AEs were recorded in 16 (17.4%) prior-use and 16 (51.6%) new-use patients. Of patients with evaluable UFC assessments, mUFC was ≤ULN at baseline and months 6, 12, 24 and 36, respectively, in 28/43 (65%), 27/40 (68%), 27/33 (82%), 12/19 (63%) and 2/2 (100%) prior-use patients, and 1/16 (6%), 4/8 (50%), 1/3 (33%), 0/0 and 0/0 new-use patients. Conclusion: Pasireotide sc was generally well tolerated in this real-world study; AEs were expected based on findings from previous clinical trials, with no new safety signals observed. Sustained suppression of mUFC was observed with pasireotide. A lower incidence of hyperglycemia was found in prior versus new users, which suggests that pasireotide-induced hyperglycemia does not worsen over time if appropriately managed at onset.