Long-term efficacy and safety of once-monthly pasireotide in Cushing's disease: A Phase III extension study

Abstract

Objectives: Many patients with Cushing's disease (CD) require chronic pharmacotherapy to control their hypercortisolism. We evaluated the efficacy and safety of long-acting pasireotide during a long-term extension study in patients with CD.

Design: Open-label extension to a 12-month Phase III study of long-acting pasireotide in CD (N = 150; NCT01374906).

Patients: Patients with mean urinary free cortisol (mUFC) ≤ upper limit of normal (ULN) or receiving clinical benefit at core study end could continue long-acting pasireotide during the extension.

Results: Eighty-one of 150 (54.0%) enrolled patients entered the extension. Median overall exposure to pasireotide at study end was 23.9 months; 39/81 (48.1%) patients completed the extension (received ≥ 12 months' treatment during the extension and could transit to a separate pasireotide safety study). mUFC was ≤ULN in 42/81 (51.9%), 13/81 (16.0%) and 43/81 (53.1%) patients at extension baseline, month (M) 36 and last assessment. Median mUFC remained within normal limits. Median late-night salivary cortisol was 2.6 × ULN at core baseline and 1.3 × ULN at M36. Clinical improvements were sustained over time. Forty-two (51.9%) patients discontinued during the extension: 25 (30.9%) before M24 and 17 (21.0%) after M24. Hyperglycaemia-related AEs occurred in 39.5% of patients. Mean fasting glucose (FPG) and glycated haemoglobin (HbA1c ) were stable during the extension, with antidiabetic medication initiated/escalated in some patients. Sixty-six (81.5%) and 71 (88.9%) patients were classified as having diabetes (HbA1c ≥ 6.5%, FPG ≥ 7.0 mmol/L, antidiabetic medication use, or history of diabetes) at extension baseline and last assessment.

Conclusions: Long-acting pasireotide provided sustained biochemical and clinical improvements, with no new safety signals emerging, supporting its use as an effective long-term therapy for CD.

Keywords: Cushing syndrome; Cushing's disease; Phase III; extension; hypercortisolism; pasireotide; pituitary.

Conflict of interest statement

Maria Fleseriu has received research support (paid to Oregon Health & Science University) from Novartis, Millendo Therapeutics and Strongbridge Biopharma, and scientific consultancy fees from Novartis and Strongbridge Biopharma. Stephan Petersenn had served as lecturer for Ipsen, Novartis and Pfizer, and as an advisory board member for Ipsen and Novartis. Beverly MK Biller has been the PI of research grants (paid to Massachusetts General Hospital) from Novartis, Millendo and Strongbridge Biopharma, and has received occasional consulting honoraria from Novartis and Strongbridge Biopharma. Pinar Kadioglu has no conflicts of interest to disclose. Christophe De Block has served as a lecturer and as an advisory board member for Ipsen and Novartis. Guy T'Sjoen has received scientific grants as principal investigator for Ipsen, Bayer Schering and Sandoz; consulting fees as an advisory board member for Ipsen and Novartis; and lecture fees as a speaker for Ferring and Novartis. Marie‐Christine Vantyghem has received funding as an investigator (paid to Lille University Hospital) from Novartis and Ipsen. Libuse Tauchmanova, Judi Wojna and Michael Roughton are employees of Novartis. John Newell‐Price has received research and consultancy fees (paid to the University of Sheffield) from Novartis, Diurnal, Ipsen, HRA Pharma and ONO Pharma. André Lacroix has received funding as an investigator or consultant from Novartis, Cortendo, Strongbridge Biopharma and GLWL Research, Inc.

© 2019 The Authors. Clinical Endocrinology published by John Wiley & Sons Ltd.

Figures

Figure 1

Patient disposition. *Reasons for not entering the extension were not recorded; †The death occurred 16 d after the 16th injection and was not suspected by the treating physician to be related to pasireotide11; ‡Patients were considered to have completed the extension if both of the following criteria were met: they had received an additional ≥12 mo of treatment during the extension; and the core study had been unblinded, which occurred once all 150 patients who were enrolled in the core study had reached month 12 or discontinued treatment. The AEs leading to discontinuation in 8 patients during the extension phase were as follows: diabetes mellitus, n = 2; hyperglycaemia, n = 3 (one of these patients also had increased gamma‐glutamyltransferase); hyperkalaemia, n = 1; endometrial cancer, n = 1; and acute cholecystitis, cholelithiasis, elevated liver enzymes, bilirubin increased, oedematous pancreatitis and ascites, n = 1 [Colour figure can be viewed at http://wileyonlinelibrary.com]

Figure 2

Median mUFC, ACTH, serum cortisol and LNSC over time, by duration of pasireotide treatment. Continuous lines represent data collected during the extension; dashed lines represent data collected during the core study for patients who were later enrolled in the extension. Horizontal reference lines represent the ULN range for mUFC (166.5 nmol/24 h), morning plasma ACTH (45.4 ng/L), morning serum cortisol (532.2 nmol/L) and LNSC (3.2 nmol/L). The number of patients contributing to the median is displayed under the X axis

Figure 3

Median SBP, DBP, waist circumference and BMI, by duration of pasireotide treatment. Continuous lines represent data collected during the extension; dashed lines represent data collected during the core study for patients who were later enrolled in the extension

Figure 4

Mean (SD) FPG and HbA1c levels during the extension phase. Continuous lines represent data collected during the extension; dashed lines represent data collected during the core study for patients who were later enrolled in the extension