Safety and Efficacy of Subcutaneous Pasireotide in Patients With Cushing's Disease: Results From an Open-Label, Multicenter, Single-Arm, Multinational, Expanded-Access Study

Introduction: The efficacy and safety of subcutaneous (sc) pasireotide have been evaluated in a Phase III trial. Here, we report safety and efficacy results from a multinational, expanded-access study of pasireotide sc in patients with Cushing's disease (CD) in a real-world setting (clinicaltrials. gov, identifier: NCT01582061). Methods: Adults with active CD previously untreated with pasireotide were enrolled; pasireotide sc was initiated at 600 mu g twice daily (bid; EU countries) or 900 mu g bid (non-EU countries; 600 mu g bid in patients with impaired glucosemetabolism). Pasireotide dose could be adjusted in 300 mu g increments/decrements to amaximumof 900 mu g bid or minimum of 300 mu g bid for sustained urinary free cortisol (UFC) normalization/tolerability issues. Primary objective: document the safety of pasireotide sc in patients with CD. Key secondary objectives: assess the proportion of patients with mean UFC (mUFC) not exceeding the upper limit of normal (ULN) and changes from baseline in clinical signs/symptoms and quality of life (QoL) to weeks 12, 24, and 48. Results: One hundred and four patients received pasireotide: female, n = 84 (80.8%); median duration of pasireotide exposure, 25.1 weeks; median (range) baseline mUFC, 321.2 nmol/24 h (142-10,920; 2.3 x ULN [1.0-79.2]). Forty (38.5%) patients completed the study. The most common reasons for premature discontinuation of pasireotide were unsatisfactory therapeutic effect (n = 26, 25.0%) and adverse events (AEs; n = 20, 19.2%). Drug-related grade 3/4 AEs or drug-related serious AEs (primary endpoint) were documented in 42 (40.4%) patients, most commonly diabetes mellitus (n = 12, 11.5%) and hyperglycemia (n = 8, 7.7%). All patients experienced >= 1 AE and most (n = 102; 98.1%) reported >= 1 drug-related AE; six (5.8%) patients discontinued treatment because of hyperglycemia-related AEs. At weeks 12, 24, and 48, respectively, 36/66 (54.5%), 22/46 (47.8%), and 9/21 (42.9%) evaluable patients had normalizedmUFC levels. Clinical signs/symptoms and QoL were also improved. Conclusions: In an international, real-world, clinical-practice setting, pasireotide sc was generally well-tolerated (no new safety signals were identified), effectively reduced UFC (normalization in similar to 50% of evaluable patients) and improved clinical signs and QoL in patients with CD. While hyperglycemia-related AEs were common, consistent with previous studies, most were manageable, with < 6% of patients discontinuing treatment because of these events.