Feng Gu

A 12-Month Phase 3 Study of Pasireotide in Cushing's Disease

BACKGROUND Cushings 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. METHODS In this double-blind, phase 3 study, we randomly assigned 162 adults with Cushings 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. RESULTS 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 Cushings 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. CONCLUSIONS The significant decrease in cortisol levels in patients with Cushings 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.).

High variability in baseline urinary free cortisol values in patients with Cushing's disease

Twenty‐four‐hour urinary free cortisol (UFC) sampling is commonly used to evaluate Cushings syndrome. Because there are few data on UFC variability in patients with active Cushings disease, we analysed baseline UFC in a large patient cohort with moderate‐to‐severe Cushings disease and assessed whether variability correlates with hypercortisolism severity. These data will help clinicians establish the minimum number of UFC samples required to obtain reliable data.

Pasireotide treatment significantly improves clinical signs and symptoms in patients with Cushing's disease: results from a Phase III study

Signs and symptoms of Cushings disease are associated with high burden of illness. In this analysis, we evaluated the effect of pasireotide treatment on signs and symptoms in patients with Cushings disease.

Efficacy and safety of once-monthly pasireotide in Cushing's disease: a 12 month clinical trial

BACKGROUND Cushings disease is a rare debilitating endocrine disorder for which few prospective interventional studies have been done. We report results of the first phase 3 trial assessing long-acting intramuscular pasireotide in patients with Cushings disease. METHODS In this phase 3 clinical trial we recruited patients aged 18 years or older with persistent, recurrent, or de-novo (non-surgical candidates) Cushings disease who had a mean urinary free cortisol (mUFC) concentration (from three 24 h samples) of 1·5-5·0 times the upper limit of normal (ULN), a normal or greater than normal morning plasma adrenocorticotropic hormone concentration, and a pituitary source of Cushings syndrome, from 57 sites across 19 countries. Exclusion criteria included previous pasireotide treatment, mitotane therapy within 6 months, and pituitary irradiation within 10 years. We randomly allocated patients 1:1 (block size of four) using an interactive-response-technology system to intramuscular pasireotide 10 mg or 30 mg every 4 weeks for 12 months (in the core phase). We stratified randomisation by screening mUFC concentration (1·5 to <2·0 × ULN and 2·0-5·0 × ULN). The dose could be uptitrated (from 10 mg to 30 mg or from 30 mg to 40 mg) at month 4 if the mUFC concentration was greater than 1·5 × ULN, and at month 7, month 9, or month 12 if the mUFC concentration was greater than 1·0 × ULN. Investigators, patients, site personnel, and those assessing outcomes were masked to dose group allocation. The primary endpoint was the proportion of patients in each group with an mUFC concentration of less than or equal to the ULN at month 7. Efficacy analyses were based on intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01374906. FINDINGS Between Dec 28, 2011, and Dec 9, 2014, we randomly allocated 150 patients to receive pasireotide 10 mg (74 [49%] patients) or 30 mg (76 [51%] patients). The primary efficacy endpoint was met by 31 (41·9% [95% CI 30·5-53·9]) of 74 patients in the 10 mg group and 31 (40·8% [29·7-52·7]) of 76 in the 30 mg group. The most common adverse events were hyperglycaemia (36 [49%] in the 10 mg group and 36 [47%] in the 30 mg group), diarrhoea (26 [35%] and 33 [43%]), cholelithiasis (15 [20%] and 34 [45%]), diabetes mellitus (14 [19%] and 18 [24%]), and nausea (15 [20%] and 16 [21%]). Serious adverse events suspected to be study drug related were reported in eight (11%) patients in the 10 mg group and four (5%) in the 30 mg group. Two (3%) patients in the 30 mg group died during the study (pulmonary artery thrombosis and cardiorespiratory failure); neither death was judged to be related to the study drug. INTERPRETATION Long-acting pasireotide normalised mUFC concentration in about 40% of patients with Cushings disease at month 7 and had a similar safety profile to that of twice-daily subcutaneous pasireotide. Long-acting pasireotide is an efficacious treatment option for some patients with Cushings disease who have persistent or recurrent disease after initial surgery or are not surgical candidates, and provides a convenient monthly administration schedule. FUNDING Novartis Pharma AG.

The benefits of pasireotide in patients with Cushing's disease are not restricted to patients with normalisation of UFC; results from a large, 12-month study

Are Not Restricted to Patients with Normalization of UFC: Results from a Large 12-Month Study R Pivonello,1 S Petersenn,2 F Gu,3 A Trovato,4 G Hughes,5 M Ligueros-Saylan,5 LR Salgado,6 A Lacroix,7 J Schopohl8 and BMK Biller9 1Dipartimento di Medicina Clinica e Chirurgia, Endocrinologia e Metabolismo, Università Federico II di Napoli, Naples, Italy; 2ENDOC Center for Endocrine Tumors, Hamburg, Germany; 3Department of Endocrinology, Key Laboratory of Endocrinology, Ministry of Health, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, China; 4Clinical Development, Oncology Business Unit, Novartis Pharma AG, Basel, Switzerland; 5Novartis Pharmaceuticals Corporation, East Hanover, New Jersey, USA; 6Division of General Internal Medicine, Hospital das Clínicas, University of São Paulo Medical School, São Paulo, Brazil; 7Division of Endocrinology, Department of Medicine, Centre hospitalier de l’Université de Montréal, Montreal, Quebec, Canada; 8Medizinische Klinik IV, University of Munich, Munich, Germany; 9Neuroendocrine Clinical Center, Massachusetts General Hospital, Boston, Massachusetts, USA

Treatment with pasireotide LAR normalizes prolactin levels in patients with acromegaly and hyperprolactinemia: randomized, double-blind, 12-month, phase III study

A Colao,1 P Freda,2 F Gu,3 K Hermosillo Resendiz,4 M Ruffin,5 Y Chen,4 M Bronstein6 1Dipartimento di Medicina Clinica e Chirurgia, Universita Federico II di Napoli, Naples, Italy; 2Department of Medicine, Columbia University College of Physicians & Surgeons, New York, New York, USA; 3Department of Endocrinology, Key Laboratory of Endocrinology, Ministry of Health, Peking Union Medical College Hospital, Beijing, China; 4Novartis Pharmaceuticals Corporation, Florham Park, New Jersey, USA; 5Clinical Development, Oncology Business Unit, Novartis Pharma AG, Basel, Switzerland; 6Neuroendocrine Unit, Division of Endocrinology and Metabolism, University of Sao Paulo Medical School, Sao Paulo, Brazil