AUTHOR=Fleseriu Maria , Iweha Chioma , Salgado Luiz , Mazzuco Tania Longo , Campigotto Federico , Maamari Ricardo , Limumpornpetch Padiporn 

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

JOURNAL=Frontiers in Endocrinology

VOLUME=10

YEAR=2019

URL=https://www.frontiersin.org/journals/endocrinology/articles/10.3389/fendo.2019.00436

DOI=10.3389/fendo.2019.00436

ISSN=1664-2392

ABSTRACT=<p><bold>Introduction:</bold> 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 (<ext-link ext-link-type="uri" xlink:href="https://www.clinicaltrials.gov/" xmlns:xlink="http://www.w3.org/1999/xlink">clinicaltrials.gov</ext-link>, identifier: NCT01582061).</p><p><bold>Methods:</bold> Adults with active CD previously untreated with pasireotide were enrolled; pasireotide sc was initiated at 600 μg twice daily (bid; EU countries) or 900 μg bid (non-EU countries; 600 μg bid in patients with impaired glucose metabolism). Pasireotide dose could be adjusted in 300 μg increments/decrements to a maximum of 900 μg bid or minimum of 300 μg 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.</p><p><bold>Results:</bold> One hundred and four patients received pasireotide: female, <italic>n</italic> = 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 × 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 (<italic>n</italic> = 26, 25.0%) and adverse events (AEs; <italic>n</italic> = 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 (<italic>n</italic> = 12, 11.5%) and hyperglycemia (<italic>n</italic> = 8, 7.7%). All patients experienced ≥1 AE and most (<italic>n</italic> = 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 normalized mUFC levels. Clinical signs/symptoms and QoL were also improved.</p><p><bold>Conclusions:</bold> 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 ~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 &lt;6% of patients discontinuing treatment because of these events.</p>