Abstract
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 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.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 × 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 normalized mUFC 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 ~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.
Highlights
The efficacy and safety of subcutaneous pasireotide have been evaluated in a Phase III trial
Bilateral adrenalectomy can result in complete resolution of hypercortisolism, but it renders patients glucocorticoid and mineralocorticoid deficient and may lead to corticotroph tumor progression (Nelson’s syndrome), which is characterized by pituitary tumor expansion coupled with high adrenocorticotropic hormone (ACTH) concentrations [11]
Patients must have had active disease, as evidenced by: mean of three 24 h UFC samples collected during a 3-week screening period above the upper limit of normal (ULN; 137.95 nmol/24 h), which was determined from a central laboratory reference; morning plasma ACTH within or above the normal range; and confirmed pituitary source of the disease
Summary
The efficacy and safety of subcutaneous (sc) pasireotide have been evaluated in a Phase III trial. 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). Cushing’s disease is a rare and serious endocrine disorder characterized by a pituitary tumor (corticotropinoma) that secretes an excess of adrenocorticotropic hormone (ACTH), with consequent overproduction of cortisol from the adrenal glands [1]. Current medical therapies used for the treatment of Cushing’s disease include adrenal-directed agents such as ketoconazole, metyrapone (both approved in the EU) and mitotane, the glucocorticoid receptor antagonist mifepristone (approved in the USA for the management of hyperglycemia associated with Cushing’s syndrome), and the pituitary-targeted drugs cabergoline and pasireotide, of which the latter (twicedaily [bid] subcutaneous [sc] formulation) is approved in both the USA and the EU [5, 12]. A longacting formulation of pasireotide suitable for once-monthly administration has been approved in the EU, Japan, Canada, and the USA
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