Pasireotide can induce sustained decreases in urinary cortisol and provide clinical benefit in patients with Cushing’s disease: results from an open-ended, open-label extension trial

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Abstract

Purpose

Report the efficacy and safety of pasireotide sc in patients with Cushing’s disease during an open-ended, open-label extension to a randomized, double-blind, 12-month, Phase III study.

Methods

162 patients entered the core study. 58 patients who had mean UFC ≤ ULN at month 12 or were benefiting clinically from pasireotide entered the extension. Patients received the same dose of pasireotide as at the end of the core study (300–1,200 μg bid). Dose titration was permitted according to efficacy or drug-related adverse events.

Results

40 patients completed 24 months’ treatment. Of the patients who entered the extension, 50.0 % (29/58) and 34.5 % (20/58) had controlled UFC (UFC ≤ ULN) at months 12 and 24, respectively. The mean percentage decrease in UFC was 57.3 % (95 % CI 40.7–73.9; n = 52) and 62.1 % (50.8–73.5; n = 33) after 12 and 24 months’ treatment, respectively. Improvements in clinical signs of Cushing’s disease were sustained up to month 24. The most frequent drug-related adverse events in patients who received ≥1 dose of pasireotide (n = 162) from core baseline until the 24-month cut-off were diarrhea (55.6 %), nausea (48.1 %), hyperglycemia (38.9 %), and cholelithiasis (31.5 %). No new safety issues were identified during the extension.

Conclusions

Reductions in mean UFC and improvements in clinical signs of Cushing’s disease were maintained over 24 months of pasireotide treatment. The safety profile of pasireotide is typical for a somatostatin analogue, except for the frequency and degree of hyperglycemia; patients should be monitored for changes in glucose homeostasis. Pasireotide represents the first approved pituitary-targeted treatment for patients with Cushing’s disease.

Electronic supplementary material

The online version of this article (doi:10.1007/s11102-014-0618-1) contains supplementary material, which is available to authorized users.

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Most cited references 12

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Cushing's syndrome.

John Newell-Price, Xavier Bertagna, Ashley B. Grossman … (2006)

Cushing's syndrome results from lengthy and inappropriate exposure to excessive glucocorticoids. Untreated, it has significant morbidity and mortality. The syndrome remains a challenge to diagnose and manage. Here, we review the current understanding of pathogenesis, clinical features, diagnostic, and differential diagnostic approaches. We provide diagnostic algorithms and recommendations for management.

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A 12-month phase 3 study of pasireotide in Cushing's disease.

Mario Maldonado, John Newell, B. Biller … (2012)

Cushing's disease is associated with high morbidity and mortality. Pasireotide, a potential therapy, has a unique, broad somatostatin-receptor-binding profile, with high binding affinity for somatostatin-receptor subtype 5. In this double-blind, phase 3 study, we randomly assigned 162 adults with Cushing's disease and a urinary free cortisol level of at least 1.5 times the upper limit of the normal range to receive subcutaneous pasireotide at a dose of 600 μg (82 patients) or 900 μg (80 patients) twice daily. Patients with urinary free cortisol not exceeding 2 times the upper limit of the normal range and not exceeding the baseline level at month 3 continued to receive their randomly assigned dose; all others received an additional 300 μg twice daily. The primary end point was a urinary free cortisol level at or below the upper limit of the normal range at month 6 without an increased dose. Open-label treatment continued through month 12. Twelve of the 82 patients in the 600-μg group and 21 of the 80 patients in the 900-μg group met the primary end point. The median urinary free cortisol level decreased by approximately 50% by month 2 and remained stable in both groups. A normal urinary free cortisol level was achieved more frequently in patients with baseline levels not exceeding 5 times the upper limit of the normal range than in patients with higher baseline levels. Serum and salivary cortisol and plasma corticotropin levels decreased, and clinical signs and symptoms of Cushing's disease diminished. Pasireotide was associated with hyperglycemia-related adverse events in 118 of 162 patients; other adverse events were similar to those associated with other somatostatin analogues. Despite declines in cortisol levels, blood glucose and glycated hemoglobin levels increased soon after treatment initiation and then stabilized; treatment with a glucose-lowering medication was initiated in 74 of 162 patients. The significant decrease in cortisol levels in patients with Cushing's disease who received pasireotide supports its potential use as a targeted treatment for corticotropin-secreting pituitary adenomas. (Funded by Novartis Pharma; ClinicalTrials.gov number, NCT00434148.).

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SOM230: a novel somatostatin peptidomimetic with broad somatotropin release inhibiting factor (SRIF) receptor binding and a unique antisecretory profile.

C Bruns, Fraser I Lewis, G. Weckbecker … (2002)

The aim of the present study was to identify a small, metabolically stable somatotropin release inhibiting factor (SRIF) analog with a more universal binding profile similar to that of natural somatostatin, resulting in improved pharmacological properties and hence new therapeutic uses. A rational drug design approach was followed by synthesizing alanine-substituted SRIF-14 analogs to determine the importance of single amino acids in SRIF-14 for SRIF receptor subtype binding. The incorporation of structural elements of SRIF-14 in a stable cyclohexapeptide template in the form of modified unnatural amino acids resulted in the identification of the novel cyclohexapeptide SOM230. SOM230 binds with high affinity to SRIF receptor subtypes sst1, sst2, sst3 and sst5 and displays a 30- to 40-fold higher affinity for sst1 and sst5 than Sandostatin (octreotide; SMS 201-995) or Somatuline (BIM 23014). In vitro, SOM230 effectively inhibited the growth hormone releasing hormone (GHRH)-induced growth hormone (GH) release in primary cultures of rat pituitary cells with an IC(50) of 0.4+/-0.1 nmol/l (n=5). In vivo, SOM230 also potently suppressed GH secretion in rats. The ED(50) values determined at 1 h and 6 h post injection of SOM230 indicated its very long duration of action in vivo. This property was also reflected in pharmacokinetic studies comparing plasma levels of SMS 201-995 and SOM230 after subcutaneous application. Whereas SMS 201-995 had a terminal elimination half life of 2 h, this was markedly prolonged in SOM230-treated animals (t(1/2)=23 h). Furthermore, in rats SOM230 demonstrated a much higher efficacy in lowering plasma insulin-like growth factor-I (IGF-I) levels compared with SMS 201-995. The infusion of 10 microg/kg/h of SOM230 using subcutaneously implanted minipumps decreased plasma IGF-I levels far more effectively than SMS 201-995. After 126 days of continuous infusion of SOM230 plasma IGF-I levels were decreased by 75% of placebo-treated control animals. For comparison SMS 201-995, when used under the same experimental conditions, resulted in only a 28% reduction of plasma IGF-I levels, indicating a much higher efficacy for SOM230 in this animal model. It is important to note that the inhibitory effect of SOM230 was relatively selective for GH and IGF-I in that insulin and glucagon secretion was inhibited only at higher doses of SOM230. This lack of potent inhibition of insulin and glucagon release was also reflected in the lack of effect on plasma glucose levels. Even after high dose treatment over 126 days no obvious adverse side effects were noticed, including changes in plasma glucose levels. We have identified a novel short synthetic SRIF peptidomimetic, which exhibits high affinity binding to four of the five human SRIF receptor subtypes and has potent, long lasting inhibitory effects on GH and IGF-I release. Therefore SOM230 is a promising development candidate for effective GH and IGF-I inhibition and is currently under evaluation in phase 1 clinical trials.

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Author and article information

Contributors

Rosario Pivonello: +39 081 372 2074 , rosario.pivonello@unina.it

Journal

Journal ID (nlm-ta): Pituitary

Journal ID (iso-abbrev): Pituitary

Title: Pituitary

Publisher: Springer US (New York )

ISSN (Print): 1386-341X

ISSN (Electronic): 1573-7403

Publication date (Electronic): 24 December 2014

Publication date PMC-release: 24 December 2014

Publication date (Print): 2015

Volume: 18

Issue: 5

Pages: 604-612

Affiliations

[ ]Medizinische Klinik IV, University of Munich, Munich, Germany

[ ]Department of Endocrinology, Key Laboratory of Endocrinology, Ministry of Health, Peking Union Medical College Hospital, Beijing, China

[ ]Department of Endocrinology and Metabolism, University Hospital Ghent, Ghent, Belgium

[ ]Department of Endocrinology, Diabetology and Metabolism, Antwerp University Hospital, Edegem (Antwerp), Belgium

[ ]INSERM U1016, Institut Cochin, Paris, France

[ ]Reference Centre for Rare Adrenal Diseases, Department of Endocrinology, Assistance Publique Hôpitaux de Paris, Hôpital Cochin, Paris, France

[ ]University Paris Descartes, Paris, France

[ ]Novartis Pharmaceuticals Corporation, East Hanover, NJ USA

[ ]Novartis Pharma AG, Basel, Switzerland

[ ]Division of General Internal Medicine, Hospital das Clínicas, University of São Paulo Medical School, São Paulo, Brazil

[ ]Endocrinology Unit, Department of Medicine (DIMED), University of Padova, Padua, Italy

[ ]Dipartimento di Medicina Clinica e Chirurgia, Università Federico II di Napoli, Via Sergio Pansini 5, 80131 Naples, Italy

Article

Publisher ID: 618

DOI: 10.1007/s11102-014-0618-1

PMC ID: 4560758

PubMed ID: 25537481

SO-VID: bd90c73f-317f-43b4-b485-4fc3ceaca860

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Open AccessThis article is distributed under the terms of the Creative Commons Attribution License which permits any use, distribution, and reproduction in any medium, provided the original author(s) and the source are credited.

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ScienceOpen disciplines: Medicine

Keywords: pasireotide,cushing’s disease,somatostatin analogue,corticotroph tumor,urinary free cortisol

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ScienceOpen disciplines: Medicine

Keywords: pasireotide, cushing’s disease, somatostatin analogue, corticotroph tumor, urinary free cortisol

Pasireotide can induce sustained decreases in urinary cortisol and provide clinical benefit in patients with Cushing’s disease: results from an open-ended, open-label extension trial

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Most cited references 12

Cushing's syndrome.

A 12-month phase 3 study of pasireotide in Cushing's disease.

SOM230: a novel somatostatin peptidomimetic with broad somatotropin release inhibiting factor (SRIF) receptor binding and a unique antisecretory profile.

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