Clinical Endocrinology (2014) 81, 408–417
doi: 10.1111/cen.12431
ORIGINAL ARTICLE
Pasireotide treatment significantly improves clinical signs and symptoms in patients with Cushing’s disease: results from a Phase III study Rosario Pivonello*, Stephan Petersenn†, John Newell-Price‡, James W. Findling§, Feng Gu¶, Lacroix§§, Mario Maldonado**, Andrew Trovato**, Gareth Hughes††, Luiz R. Salgado‡‡, Andre Jochen Schopohl¶¶ and Beverly M.K. Biller*** on behalf of the Pasireotide B2305 Study Group1 *Dipartimento di Medicina Clinica e Chirurgia, Sezione di Endocrinologia, Universita Federico II di Napoli, Naples, Italy, †ENDOC Center for Endocrine Tumors, Hamburg, Germany, ‡The Medical School, University of Sheffield, Sheffield, UK, §Division of Endocrinology, Metabolism, and Clinical Nutrition, Medical College of Wisconsin, Milwaukee, WI, USA, ¶Department of Endocrinology, Key Laboratory of Endocrinology, Ministry of Health, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, China, **Clinical Development, Oncology Business Unit, Novartis Pharma AG, Basel, Switzerland, ††Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA, ‡‡Division of General Internal Medicine, Hospital das Clınicas, University of S~ao Paulo Medical School, S~ao Paulo, Brazil, §§Division of Endocrinology, Department of Medicine, Centre hospitalier de l’Universite de Montreal, Montreal, QC, Canada, ¶¶Medizinische Klinik IV, University of Munich, Munich, Germany and ***Neuroendocrine Clinical Center, Massachusetts General Hospital, Boston, MA, USA
Summary Objective Signs and symptoms of Cushing’s 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 Cushing’s disease. Design Phase III study with double-blind randomization of two pasireotide doses. Methods Patients (n = 162) with persistent/recurrent or de novo Cushing’s disease and urinary free cortisol (UFC) levels ≥159 upper limit of normal (ULN) were randomized to receive subcutaneous pasireotide (600/900 lg bid). At month 3, patients with UFC ≤2 9 ULN and not exceeding the baseline value continued their randomized dose; all others received 300 lg bid uptitration. At month 6, patients could enter an open-label phase until month 12 with a maximal dose of 1200 lg bid. Changes in signs and symptoms of hypercortisolism over 12 months’ treatment in patients still enroled in the study and with evaluable measurements were assessed in relation to degree of UFC control. Results Reductions in blood pressure were observed even without full UFC control and were greatest in patients who did not receive antihypertensive medications during the study. Significant reductions in total cholesterol and low-density lipoprotein
Correspondence: Rosario Pivonello, Dipartimento di Medicina Clinica e Chirurgia, Sezione di Endocrinologia, Universita Federico II di Napoli, IT–80131 Naples, Italy. Tel.: +39 081 746 4737; Fax: +39 081 546 5443; E-mail: [email protected] 1
See Appendix for Pasireotide B2305 Study Group.
408
(LDL)-cholesterol were observed in patients who achieved UFC control. Reductions in BMI, weight and waist circumference occurred during the study even without full UFC control. Adverse effects were typical of somatostatin analogues except for hyperglycaemia-related events, which were experienced by 728% of patients. Conclusions In the largest Phase III study of medical therapy in Cushing’s disease, significant improvements in signs and symptoms were seen during 12 months of pasireotide treatment, as UFC levels decreased. (Received 27 September 2013; returned for revision 28 January 2014; finally revised 10 February 2014; accepted 11 February 2014)
Introduction Cushing’s disease is usually caused by an adrenocorticotropic hormone (ACTH)-secreting pituitary tumour, leading to overproduction of cortisol by the adrenal glands and to the signs and symptoms of hypercortisolism.1–3 These signs and symptoms are associated with a high burden of illness, impaired health-related quality of life (HRQoL) and elevated mortality.4–7 The aims of treatment for Cushing’s disease are to normalize cortisol levels and to reverse the signs and symptoms of hypercortisolism. First-line treatment for the majority of patients with Cushing’s disease is surgical removal of the corticotroph tumour3; however, this is not always successful, so other treatment options such as medical therapy, radiotherapy and bilateral adrenalectomy may be required.3 © 2014 John Wiley & Sons Ltd
Pasireotide in Cushing’s disease 409
Changes in signs and symptoms of hypercortisolism at months 6 and 12 were assessed in relation to the degree of UFC response at month 6.
after 5 min of rest) at baseline, days 1, 15, 30, 45, 60, 75 and 90, and then monthly to month 12. The study allowed the initiation of antihypertensive medication and dose increases in patients already receiving such medications. However, information regarding the individual contribution of pasireotide on antihypertensive medication adjustments cannot be clearly established. Body weight was measured monthly using a calibrated balance, and height was recorded at screening; these measurements were used to calculate the body mass index (BMI). Waist circumference was measured midway between the palpated iliac crest and lowest rib margin in the left and right mid-axillary line at months 3, 6 and 12. Facial rubor, hirsutism (females only), cutaneous striae, bruising, and supraclavicular and dorsal fat pads were evaluated at baseline and months 3, 6 and 12. These features were assessed by a blinded reviewer at each site who was familiar with Cushing’s disease but not involved in other aspects of the study.13 Two photographs (one frontal and one dorsal from the shoulders up) were used to assess facial plethora and supraclavicular and dorsal fat pads. Two other photographs (one frontal and one dorsal of the trunk with the patient in a standing position) were used to assess striae, bruising and hirsutism. The severity of rubor, striae, bruising and fat pads was scored on a scale of 0–3 (0 = no signs, 1 = mild, 2 = moderate and 3 = severe). Hirsutism was measured using the Ferriman–Gallwey score: the extent of hair growth in nine locations was rated 0–4, resulting in a score of 0–36.14 Proximal muscle strength was assessed at baseline and months 3, 6 and 12 by placing patients in a low seated position, then having them extend their arms in front of them and stand up. Patients were evaluated using the following scale: 3 = completely unable to stand; 2 = able to stand using arms as assistance; 1 = able to stand after several efforts without using arms as assistance; and 0 = able to stand easily with arms extended. Bone mineral density (BMD) of the lumbar vertebrae (L1–L4 together) and left proximal femur (total hip and neck), as well as body composition (full body scan), was measured at baseline, months 6 and 12, using Lunar or Hologic dual-energy X-ray absorptiometry (DXA) instruments. Patients were scanned on the same DXA instrument throughout the study. Blood chemistry assessments [including triglyceride, total cholesterol and low-density lipoprotein (LDL)-cholesterol levels] were performed monthly from baseline to month 12. All samples were analysed by central laboratories [Eurofins Medinet BV, Breda, The Netherlands; CRL Medinet Inc, Lenexa, KS, USA; and Eurofins Technology Services (Suzhou) Co Ltd, Suzhou, China]. Health-related quality of life was measured using the CushingQoL questionnaire4 at baseline and months 3, 6 and 12, as previously reported.13 Depression status was assessed using the Beck Depression Inventory II (BDI-II), a 21-item instrument that measures each item on a four-point scale.15 BDI-II scores range from 0 to 63, with a total score of 0–13 indicating minimal, 14–19 mild, 20–28 moderate and 29–63 severe depression.
Assessment of signs and symptoms
Safety
Systolic (SBP) and diastolic blood pressure (DBP) were recorded (mean of three values at 1- to 2-min intervals in sitting posture
As reported previously,13 safety was assessed throughout the study.
A large proportion of corticotroph tumours predominantly express somatostatin receptor subtype 5 (sst5).8 Activation of sst5 inhibits ACTH secretion in vitro9–11 and is a potential therapeutic target for Cushing’s disease. Pasireotide is a multireceptor-targeted somatostatin analogue with high affinity for sst5.12 A 12-month, randomized, Phase III study (the largest prospective trial of a medical therapy in Cushing’s disease) showed that pasireotide treatment resulted in rapid and sustained decreases in urinary free cortisol (UFC) levels.13 The current study expands on the effect of pasireotide on the clinical signs and symptoms of hypercortisolism in patients with Cushing’s disease by describing changes on treatment in relation to UFC response.
Methods Patients and study design Patients (aged ≥18 years) with a confirmed diagnosis of persistent/recurrent or de novo (if not surgical candidates) Cushing’s disease [defined as mean 24-h UFC ≥15 9 the upper limit of normal (ULN), from four 24-h urine samples collected within 2 weeks; morning plasma ACTH ≥5 ng/l (≥11 nmol/l); and pituitary source of Cushing’s syndrome confirmed by at least one of the following: pituitary macroadenoma on magnetic resonance imaging (MRI), bilateral inferior petrosal sinus sampling central-to-peripheral ACTH gradient >2 basally, or >3 after corticotrophin-releasing hormone stimulation in patients with a microadenoma, or histopathology confirming an ACTH-staining adenoma] were enroled into this international, double-blind, multicentre study. Eligible patients were randomized to receive subcutaneous (sc) pasireotide 600 or 900 lg bid. Patients with UFC ≤2 9 ULN and not exceeding the baseline value at month 3 continued on their randomized dose, double-blind, until month 6. All other patients were unblinded, and their dose increased by 300 lg bid until month 6. Dose reductions of 300 lg bid were permitted throughout the study. At month 6, patients could enter an open-label phase to month 12, during which dose titration (to a maximum of 1200 lg bid) could occur at any time. Full details of the inclusion and exclusion criteria and study design have been reported previously.13 The study was approved by the independent ethics committee, research ethics board or institutional review board at each centre and complied with the ICH Harmonized Tripartite Guidelines for Good Clinical Practice, the Declaration of Helsinki and local laws. All patients provided written informed consent. Study end-points
© 2014 John Wiley & Sons Ltd Clinical Endocrinology (2014), 81, 408–417
410 R. Pivonello et al. Analysis The primary end-point of the Phase III trial was the proportion of patients who achieved UFC ≤ ULN at month 6 without prior dose uptitration.13 In accordance with the prespecified analysis plan, secondary end-points are summarized descriptively, with associated 95% two-sided confidence intervals (CIs). For the analyses of signs and symptoms, only patients still enroled in the study and who had an evaluable measurement at each time point were included. Exploratory analysis to investigate the correlation between baseline blood pressure and changes in blood pressure during the study was performed using Pearson’s correlation. Changes in signs and symptoms were assessed at month 6 in patients whose UFC levels were controlled (UFC ≤ ULN), partially controlled (UFC > ULN but with ≥50% reduction from baseline) or uncontrolled (UFC > ULN and without a 50% reduction from baseline) at month 6. Changes in signs and symptoms at month 12 were also assessed in patients whose UFC levels were controlled, partially controlled or uncontrolled at (i) month 6 and (ii) month 12. Use of antihypertensive agents [those starting with Anatomical Therapeutic Chemical (ATC) codes C02, C03, C07, C08 or C09] and lipid-modifying agents (those starting with ATC code C10) was also evaluated during the study. The effect of pasireotide on blood pressure and blood lipid levels with and without concomitant medications was investigated. For these analyses, hypertension was defined at baseline as at least one of the following: a history of antihypertensive medications, medical history of hypertension, baseline SBP >130 mmHg or baseline DBP >90 mmHg, and dyslipidaemia was defined at baseline as patients with at least one of the following: a history of lipid-lowering medications, a medical history of dyslipidaemia, baseline total cholesterol ≥200 mg/dl (52 mmol/l), triglyceride >150 mg/dl (17 mmol/l), high-density lipoprotein (HDL)-cholesterol ULN and with 30%) than in the general population, with reported prevalence estimates of 2–13% [diabetes mellitus defined as FPG ≥70 mmol/l (126 mg/dl) and/ or 2-h plasma glucose during oral glucose tolerance test ≥111 mmol/l (200 mg/dl)].23–25 Mean baseline HRQoL scores in the current study are worse than those previously reported in patients with Cushing’s syndrome,4 further confirming the high level of comorbidity in patients enroled in the current study. During the study, pasireotide treatment was associated with significant improvements in SBP, DBP, total cholesterol, LDL-cholesterol, weight, BMI, waist circumference and HRQoL. Significant reductions in blood pressure were of a smaller magnitude than those reported in patients in remission following
414 R. Pivonello et al. Table 4. Percentage changes from baseline to months 6 and 12 in total, LDL- and HDL-cholesterol levels and in triglycerides in patients with baseline dyslipidaemia by lipid-modifying medication status* Percentage change in total cholesterol [mean (95% CI)] Month 6 Dyslipidaemia at baseline, no lipid-lowering medication during study, n = 110 Dyslipidaemia at baseline, lipid-lowering medication during study, n = 39 Month 12 Dyslipidaemia at baseline, no lipid-lowering medication during study, n = 110 Dyslipidaemia at baseline, lipid-lowering medication during study, n = 39
Percentage change in LDL-cholesterol [mean (95% CI)]
31 ( 69, 06) n = 74 135 ( 206, n = 30
49 ( 94, n = 74 63)
194 ( 292, n = 30
04)
97)
Percentage change in HDL-cholesterol [mean (95% CI)]
Percentage change in triglycerides [mean (95% CI)]
23 ( 46, 92) n = 74
72 ( 34, 179) n = 74
35 ( 139, 68) n = 29
48 ( 118, 213) n = 30
48 ( 104, 09) n = 46
65 ( 134, 05) n = 46
57 ( 47, 162) n = 46
52 ( 179, 74) n = 46
179 ( 251, n = 26
260 ( 353, n = 26
32 ( 103, 167) n = 26
68 ( 202, 65) n = 26
107)
167)
*Total patient numbers at baseline are given in the left-hand column; patients with evaluable measurements at each time point for each parameter are given for individual changes. CI, confidence interval; LDL, low-density lipoprotein; and HDL, high-density lipoprotein.
transsphenoidal surgery (12–17%).26–28 Hypertension has been reported in 55–85% of patients with Cushing’s disease,18 contributing to an increased cardiovascular risk compared with the general population.29 Following treatment with pasireotide, reductions in SBP and DBP were observed in patients with controlled, partially controlled and uncontrolled UFC, although they were greatest in those with UFC control at month 6. Similar reductions were seen when stratified by UFC response at month 12. Pasireotide treatment was also accompanied by reductions in blood pressure in patients with baseline hypertension, irrespective of any antihypertensive medication. Taken together, these results suggest that pasireotide treatment may confer an additional benefit in managing hypertension in patients with Cushing’s disease, independent of its effects on UFC secretion. The significant improvements in BMI during this study are comparable to those seen postsurgery (6–8% improvement 12 months after surgery).27,28,30 The significant reduction in total cholesterol levels also approaches that seen after successful surgery (109%).28 However, the effects of pasireotide treatment on cholesterol and triglyceride levels were inconclusive when stratified by UFC control and lipid-lowering medication status and require further investigation. Patients in all three UFC response subgroups had a decrease in total body fat mass and lean body mass. No changes in BMD were observed during 12 months’ treatment with pasireotide. Clinical improvements in rubor, striae and fat pads were greatest in controlled and partially controlled patients, indicating that a reduction in UFC levels may be important if these features of hypercortisolism are to be effectively managed. In this study, a hyperglycaemia-related event occurred in 728% of patients and mean FPG and HbA1c increased from baseline
irrespective of decreases in UFC. Recent studies of pasireotide in healthy volunteers have shown that pasireotide-associated hyperglycaemia is a result of decreases in insulin secretion and incretin hormone response.31 During treatment with pasireotide, blood glucose levels should be monitored and appropriate intervention initiated promptly if blood glucose levels increase. Greater attention should be given to patients with impaired glucose tolerance or diabetes mellitus prior to treatment.32 In this analysis of signs and symptoms from the largest prospective, multicentre study of a medical therapy in Cushing’s disease to date, only patients enroled in the study and who had evaluable measurements at each time point were included. There are limitations of this study: several of the subgroups analysed contained relatively small numbers of patients, reducing the extent to which the results can be interpreted and reflecting only the experience of patients who continued treatment rather than the overall experience with the medication; histology was not performed at baseline owing to a lack of consistent pathological specimen availability; the relative impact of concomitant medications on signs and symptoms could not be evaluated; while photographs depicting changes in clinical signs and symptoms were analysed by a blinded assessor at each centre, a central, blinded review would have been more robust. These subanalyses show that the reduction in UFC levels observed during treatment with pasireotide was accompanied by corresponding improvements in the signs and symptoms of hypercortisolism and, in some cases, these improvements occurred in patients who did not achieve normal UFC levels. These results suggest that while normalization of UFC should be a clear goal of treatment for Cushing’s disease, a partial response to medical therapy may be beneficial to some patients, for example, those await-
© 2014 John Wiley & Sons Ltd Clinical Endocrinology (2014), 81, 408–417
Pasireotide in Cushing’s disease 415 (a)
(a)
(b) (b)
Fig. 3 Mean (SE) (a) fasting plasma glucose and (b) HbA1c levels up to month 12 by urinary free cortisol response status at month 6. Fig. 2 Proportion of patients with a shift in signs of Cushing’s disease by urinary free cortisol response status at month 6, from baseline to (a) month 6 {number of patients in the full analysis set with measurements at both month 6 and baseline were as follows: facial rubor, 96 [25 controlled (C), 18 partially controlled (PC), 53 uncontrolled (UC)]; striae, 94 (24 C, 18 PC, 52 UC); bruising, 92 (24 C, 18 PC, 50 UC); supraclavicular fat pads, 93 (24 C, 18 PC, 51 UC); dorsal fat pads, 93 (24 C, 18 PC, 51 UC); and muscle strength, 110 (30 C, 22 PC, 58 UC)} and (b) month 12 [number of patients in the full analysis set with measurements at both month 12 and baseline were as follows: facial rubor, 69 (23 C, 15 PC, 31 UC); striae, 68 (23 C, 15 PC, 30 UC); bruising, 66 (22 C, 15 PC, 29 UC); supraclavicular fat pads, 68 (23 C, 14 PC, 31 UC); dorsal fat pads, 67 (23 C, 14 PC, 30 UC); and muscle strength, 75 (27 C, 17 PC, 31 UC)]. Note: UFC control was defined as UFC ≤ upper limit of normal (ULN), partial control was defined as UFC > ULN but with ≥50% reduction from baseline, and uncontrolled UFC was defined as UFC > ULN and without ≥50% reduction from baseline.
ing the effects of radiotherapy or to undergo pituitary surgery. Patients with a partial response to monotherapy with pasireotide may be good candidates for combination therapy with cabergoline or ketoconazole,33 but this would have to be assessed in further larger studies.
Acknowledgements This study was funded by Novartis Pharma AG. Financial support for medical editorial assistance was provided by Novartis Pharmaceuticals Corporation. We thank Daniel Webber PhD, Mudskipper Business Ltd, for medical editorial assistance with this manuscript. We thank all investigators who contributed to
© 2014 John Wiley & Sons Ltd Clinical Endocrinology (2014), 81, 408–417
the CSOM230B2305 study, as well as the numerous nurses, study co-ordinators and patients.
Conflicts of interest AT and GH are employees of Novartis. MM was an employee of Novartis during this study and is now employed by Boehringer Ingelheim. RP has served as principal investigator on research grants from Novartis and has received research grants from Novartis, Viropharma, Pfizer and IBSA, has been an occasional consultant for Novartis, Ipsen, Italfarmaco, Pfizer, Ferring and Viropharma, and has received lecture fees from Novartis and Pfizer. AL has received research support and served as a consultant for Novartis and Viropharma. SP and JS have received consulting fees from Novartis, Pfizer and Ipsen. JWF served as a consultant for Novartis and Corcept Therapeutics. JNP has received research income and consultancy fees from Novartis. FG and LRS have no conflict of interest. BMKB has served as the principal investigator on research grants from Novartis and Corcept Therapeutics to Massachusetts General Hospital and as a consultant to Novartis and HRA Pharma.
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20 Clayton, R.N., Raskauskiene, D., Reulen, R.C. et al. (2011) Mortality and morbidity in Cushing’s disease over 50 years in Stokeon-Trent, UK: audit and meta-analysis of literature. Journal of Clinical Endocrinology & Metabolism, 96, 632–642. 21 Cutler, J.A., Sorlie, P.D., Wolz, M. et al. (2008) Trends in hypertension prevalence, awareness, treatment, and control rates in United States adults between 1988-1994 and 1999-2004. Hypertension, 52, 818–827. 22 Kearney, P.M., Whelton, M., Reynolds, K. et al. (2005) Global burden of hypertension: analysis of worldwide data. The Lancet, 365, 217–223. 23 Rathmann, W., Haastert, B., Icks, A. et al. (2003) High prevalence of undiagnosed diabetes mellitus in Southern Germany: target populations for efficient screening. The KORA survey 2000. Diabetologia, 46, 182–189. 24 Shaw, J.E., Sicree, R.A. & Zimmet, P.Z. (2010) Global estimates of the prevalence of diabetes for 2010 and 2030. Diabetes Research & Clinical Practice, 87, 4–14. 25 Cowie, C.C., Rust, K.F., Ford, E.S. et al. (2009) Full accounting of diabetes and pre-diabetes in the U.S. population in 1988-1994 and 2005-2006. Diabetes Care, 32, 287–294. 26 De Leo, M., Pivonello, R., Auriemma, R.S. et al. (2010) Cardiovascular disease in Cushing’s syndrome: heart versus vasculature. Neuroendocrinology, 92(Suppl 1), 50–54. 27 Faggiano, A., Pivonello, R., Spiezia, S. et al. (2003) Cardiovascular risk factors and common carotid artery caliber and stiffness in patients with Cushing’s disease during active disease and 1 year after disease remission. Journal of Clinical Endocrinology & Metabolism, 88, 2527–2533. 28 Libe, R., Morpurgo, P.S., Cappiello, V. et al. (2005) Ghrelin and adiponectin in patients with Cushing’s disease before and after successful transsphenoidal surgery. Clinical Endocrinology, 62, 30–36. 29 Colao, A., Pivonello, R., Spiezia, S. et al. (1999) Persistence of increased cardiovascular risk in patients with Cushing’s disease after five years of successful cure. Journal of Clinical Endocrinology & Metabolism, 84, 2664–2672. 30 Pivonello, R., Faggiano, A., Lombardi, G. et al. (2005) The metabolic syndrome and cardiovascular risk in Cushing’s syndrome. Endocrinology & Metabolism Clinics of North America, 34, 327–339. 31 Henry, R.R., Ciaraldi, T.P., Armstrong, D. et al. (2013) Hyperglycemia associated with pasireotide: results from a mechanistic study in healthy volunteers. Journal of Clinical Endocrinology & Metabolism, 98, 3446–3453. 32 Colao, A., De Block, C., Gaztambide, M.S. et al. (2013) Managing hyperglycemia in patients with Cushing’s disease treated with pasireotide: medical expert recommendations. Pituitary, doi: 10. 1007/s11102-013-0483-3. [Epub ahead of print]. 33 Feelders, R.A., de Bruin, C., Pereira, A.M. et al. (2010) Pasireotide alone or with cabergoline and ketoconazole in Cushing’s disease. The New England Journal of Medicine, 362, 1846–1848.
Appendix The Pasireotide B2305 Study Group consisted of R. Abs, B. Allolio, R. Auchus, J. Bertherat, B.M.K. Biller, C. Boguszewski, M. Boscaro, T. Brue, O. Bruno, P. Caron, F. Cavagnini, D. Carv€mlekcßi, C. alho, O. Chabre, A. Chervin, C. Chik, A. Colao, A. C ßo Cortet, M. Czepielewski, E. Degli Uberti, A. Estour, U. Feldt© 2014 John Wiley & Sons Ltd Clinical Endocrinology (2014), 81, 408–417
Pasireotide in Cushing’s disease 417 Rasmussen, M. Fleseriu, P. Freda, M. Gadelha, M. Gershinsky, E. Ghigo, B. Glaser, F. Gu, M. Guitelman, S. Guler, A. Hamrahian, S.A. Imran, Z. Jin, J.O. Jorgensen, P. Kadioglu, L. Katznelson, A. Lacroix, A. Leal Cerro, P. Loli, L. Lu, W. Ludlam, F. Mantero, E. Martino, M. Mercado, A. Moreira, K. Nogueira, G.
© 2014 John Wiley & Sons Ltd Clinical Endocrinology (2014), 81, 408–417
Ning, L. Østergaard Kristensen, S. Petersenn, G. Piaditis, L. Portocarrero, V. Rohmer, R. Rubens, L. Salgado, S. Samson, J. Schopohl, I. Shimon, C. Strasburger, A. Tabarin, M. Terzolo, S. Tsagarakis, N. Unger, Z. Valkusz, L. Van Gaal, M. V€alim€aki, E. Vidal, S. Webb, R. Weiss and W. Zgliczy nski.
doi: 10.1111/cen.12431
ORIGINAL ARTICLE
Pasireotide treatment significantly improves clinical signs and symptoms in patients with Cushing’s disease: results from a Phase III study Rosario Pivonello*, Stephan Petersenn†, John Newell-Price‡, James W. Findling§, Feng Gu¶, Lacroix§§, Mario Maldonado**, Andrew Trovato**, Gareth Hughes††, Luiz R. Salgado‡‡, Andre Jochen Schopohl¶¶ and Beverly M.K. Biller*** on behalf of the Pasireotide B2305 Study Group1 *Dipartimento di Medicina Clinica e Chirurgia, Sezione di Endocrinologia, Universita Federico II di Napoli, Naples, Italy, †ENDOC Center for Endocrine Tumors, Hamburg, Germany, ‡The Medical School, University of Sheffield, Sheffield, UK, §Division of Endocrinology, Metabolism, and Clinical Nutrition, Medical College of Wisconsin, Milwaukee, WI, USA, ¶Department of Endocrinology, Key Laboratory of Endocrinology, Ministry of Health, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, China, **Clinical Development, Oncology Business Unit, Novartis Pharma AG, Basel, Switzerland, ††Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA, ‡‡Division of General Internal Medicine, Hospital das Clınicas, University of S~ao Paulo Medical School, S~ao Paulo, Brazil, §§Division of Endocrinology, Department of Medicine, Centre hospitalier de l’Universite de Montreal, Montreal, QC, Canada, ¶¶Medizinische Klinik IV, University of Munich, Munich, Germany and ***Neuroendocrine Clinical Center, Massachusetts General Hospital, Boston, MA, USA
Summary Objective Signs and symptoms of Cushing’s 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 Cushing’s disease. Design Phase III study with double-blind randomization of two pasireotide doses. Methods Patients (n = 162) with persistent/recurrent or de novo Cushing’s disease and urinary free cortisol (UFC) levels ≥159 upper limit of normal (ULN) were randomized to receive subcutaneous pasireotide (600/900 lg bid). At month 3, patients with UFC ≤2 9 ULN and not exceeding the baseline value continued their randomized dose; all others received 300 lg bid uptitration. At month 6, patients could enter an open-label phase until month 12 with a maximal dose of 1200 lg bid. Changes in signs and symptoms of hypercortisolism over 12 months’ treatment in patients still enroled in the study and with evaluable measurements were assessed in relation to degree of UFC control. Results Reductions in blood pressure were observed even without full UFC control and were greatest in patients who did not receive antihypertensive medications during the study. Significant reductions in total cholesterol and low-density lipoprotein
Correspondence: Rosario Pivonello, Dipartimento di Medicina Clinica e Chirurgia, Sezione di Endocrinologia, Universita Federico II di Napoli, IT–80131 Naples, Italy. Tel.: +39 081 746 4737; Fax: +39 081 546 5443; E-mail: [email protected] 1
See Appendix for Pasireotide B2305 Study Group.
408
(LDL)-cholesterol were observed in patients who achieved UFC control. Reductions in BMI, weight and waist circumference occurred during the study even without full UFC control. Adverse effects were typical of somatostatin analogues except for hyperglycaemia-related events, which were experienced by 728% of patients. Conclusions In the largest Phase III study of medical therapy in Cushing’s disease, significant improvements in signs and symptoms were seen during 12 months of pasireotide treatment, as UFC levels decreased. (Received 27 September 2013; returned for revision 28 January 2014; finally revised 10 February 2014; accepted 11 February 2014)
Introduction Cushing’s disease is usually caused by an adrenocorticotropic hormone (ACTH)-secreting pituitary tumour, leading to overproduction of cortisol by the adrenal glands and to the signs and symptoms of hypercortisolism.1–3 These signs and symptoms are associated with a high burden of illness, impaired health-related quality of life (HRQoL) and elevated mortality.4–7 The aims of treatment for Cushing’s disease are to normalize cortisol levels and to reverse the signs and symptoms of hypercortisolism. First-line treatment for the majority of patients with Cushing’s disease is surgical removal of the corticotroph tumour3; however, this is not always successful, so other treatment options such as medical therapy, radiotherapy and bilateral adrenalectomy may be required.3 © 2014 John Wiley & Sons Ltd
Pasireotide in Cushing’s disease 409
Changes in signs and symptoms of hypercortisolism at months 6 and 12 were assessed in relation to the degree of UFC response at month 6.
after 5 min of rest) at baseline, days 1, 15, 30, 45, 60, 75 and 90, and then monthly to month 12. The study allowed the initiation of antihypertensive medication and dose increases in patients already receiving such medications. However, information regarding the individual contribution of pasireotide on antihypertensive medication adjustments cannot be clearly established. Body weight was measured monthly using a calibrated balance, and height was recorded at screening; these measurements were used to calculate the body mass index (BMI). Waist circumference was measured midway between the palpated iliac crest and lowest rib margin in the left and right mid-axillary line at months 3, 6 and 12. Facial rubor, hirsutism (females only), cutaneous striae, bruising, and supraclavicular and dorsal fat pads were evaluated at baseline and months 3, 6 and 12. These features were assessed by a blinded reviewer at each site who was familiar with Cushing’s disease but not involved in other aspects of the study.13 Two photographs (one frontal and one dorsal from the shoulders up) were used to assess facial plethora and supraclavicular and dorsal fat pads. Two other photographs (one frontal and one dorsal of the trunk with the patient in a standing position) were used to assess striae, bruising and hirsutism. The severity of rubor, striae, bruising and fat pads was scored on a scale of 0–3 (0 = no signs, 1 = mild, 2 = moderate and 3 = severe). Hirsutism was measured using the Ferriman–Gallwey score: the extent of hair growth in nine locations was rated 0–4, resulting in a score of 0–36.14 Proximal muscle strength was assessed at baseline and months 3, 6 and 12 by placing patients in a low seated position, then having them extend their arms in front of them and stand up. Patients were evaluated using the following scale: 3 = completely unable to stand; 2 = able to stand using arms as assistance; 1 = able to stand after several efforts without using arms as assistance; and 0 = able to stand easily with arms extended. Bone mineral density (BMD) of the lumbar vertebrae (L1–L4 together) and left proximal femur (total hip and neck), as well as body composition (full body scan), was measured at baseline, months 6 and 12, using Lunar or Hologic dual-energy X-ray absorptiometry (DXA) instruments. Patients were scanned on the same DXA instrument throughout the study. Blood chemistry assessments [including triglyceride, total cholesterol and low-density lipoprotein (LDL)-cholesterol levels] were performed monthly from baseline to month 12. All samples were analysed by central laboratories [Eurofins Medinet BV, Breda, The Netherlands; CRL Medinet Inc, Lenexa, KS, USA; and Eurofins Technology Services (Suzhou) Co Ltd, Suzhou, China]. Health-related quality of life was measured using the CushingQoL questionnaire4 at baseline and months 3, 6 and 12, as previously reported.13 Depression status was assessed using the Beck Depression Inventory II (BDI-II), a 21-item instrument that measures each item on a four-point scale.15 BDI-II scores range from 0 to 63, with a total score of 0–13 indicating minimal, 14–19 mild, 20–28 moderate and 29–63 severe depression.
Assessment of signs and symptoms
Safety
Systolic (SBP) and diastolic blood pressure (DBP) were recorded (mean of three values at 1- to 2-min intervals in sitting posture
As reported previously,13 safety was assessed throughout the study.
A large proportion of corticotroph tumours predominantly express somatostatin receptor subtype 5 (sst5).8 Activation of sst5 inhibits ACTH secretion in vitro9–11 and is a potential therapeutic target for Cushing’s disease. Pasireotide is a multireceptor-targeted somatostatin analogue with high affinity for sst5.12 A 12-month, randomized, Phase III study (the largest prospective trial of a medical therapy in Cushing’s disease) showed that pasireotide treatment resulted in rapid and sustained decreases in urinary free cortisol (UFC) levels.13 The current study expands on the effect of pasireotide on the clinical signs and symptoms of hypercortisolism in patients with Cushing’s disease by describing changes on treatment in relation to UFC response.
Methods Patients and study design Patients (aged ≥18 years) with a confirmed diagnosis of persistent/recurrent or de novo (if not surgical candidates) Cushing’s disease [defined as mean 24-h UFC ≥15 9 the upper limit of normal (ULN), from four 24-h urine samples collected within 2 weeks; morning plasma ACTH ≥5 ng/l (≥11 nmol/l); and pituitary source of Cushing’s syndrome confirmed by at least one of the following: pituitary macroadenoma on magnetic resonance imaging (MRI), bilateral inferior petrosal sinus sampling central-to-peripheral ACTH gradient >2 basally, or >3 after corticotrophin-releasing hormone stimulation in patients with a microadenoma, or histopathology confirming an ACTH-staining adenoma] were enroled into this international, double-blind, multicentre study. Eligible patients were randomized to receive subcutaneous (sc) pasireotide 600 or 900 lg bid. Patients with UFC ≤2 9 ULN and not exceeding the baseline value at month 3 continued on their randomized dose, double-blind, until month 6. All other patients were unblinded, and their dose increased by 300 lg bid until month 6. Dose reductions of 300 lg bid were permitted throughout the study. At month 6, patients could enter an open-label phase to month 12, during which dose titration (to a maximum of 1200 lg bid) could occur at any time. Full details of the inclusion and exclusion criteria and study design have been reported previously.13 The study was approved by the independent ethics committee, research ethics board or institutional review board at each centre and complied with the ICH Harmonized Tripartite Guidelines for Good Clinical Practice, the Declaration of Helsinki and local laws. All patients provided written informed consent. Study end-points
© 2014 John Wiley & Sons Ltd Clinical Endocrinology (2014), 81, 408–417
410 R. Pivonello et al. Analysis The primary end-point of the Phase III trial was the proportion of patients who achieved UFC ≤ ULN at month 6 without prior dose uptitration.13 In accordance with the prespecified analysis plan, secondary end-points are summarized descriptively, with associated 95% two-sided confidence intervals (CIs). For the analyses of signs and symptoms, only patients still enroled in the study and who had an evaluable measurement at each time point were included. Exploratory analysis to investigate the correlation between baseline blood pressure and changes in blood pressure during the study was performed using Pearson’s correlation. Changes in signs and symptoms were assessed at month 6 in patients whose UFC levels were controlled (UFC ≤ ULN), partially controlled (UFC > ULN but with ≥50% reduction from baseline) or uncontrolled (UFC > ULN and without a 50% reduction from baseline) at month 6. Changes in signs and symptoms at month 12 were also assessed in patients whose UFC levels were controlled, partially controlled or uncontrolled at (i) month 6 and (ii) month 12. Use of antihypertensive agents [those starting with Anatomical Therapeutic Chemical (ATC) codes C02, C03, C07, C08 or C09] and lipid-modifying agents (those starting with ATC code C10) was also evaluated during the study. The effect of pasireotide on blood pressure and blood lipid levels with and without concomitant medications was investigated. For these analyses, hypertension was defined at baseline as at least one of the following: a history of antihypertensive medications, medical history of hypertension, baseline SBP >130 mmHg or baseline DBP >90 mmHg, and dyslipidaemia was defined at baseline as patients with at least one of the following: a history of lipid-lowering medications, a medical history of dyslipidaemia, baseline total cholesterol ≥200 mg/dl (52 mmol/l), triglyceride >150 mg/dl (17 mmol/l), high-density lipoprotein (HDL)-cholesterol ULN and with 30%) than in the general population, with reported prevalence estimates of 2–13% [diabetes mellitus defined as FPG ≥70 mmol/l (126 mg/dl) and/ or 2-h plasma glucose during oral glucose tolerance test ≥111 mmol/l (200 mg/dl)].23–25 Mean baseline HRQoL scores in the current study are worse than those previously reported in patients with Cushing’s syndrome,4 further confirming the high level of comorbidity in patients enroled in the current study. During the study, pasireotide treatment was associated with significant improvements in SBP, DBP, total cholesterol, LDL-cholesterol, weight, BMI, waist circumference and HRQoL. Significant reductions in blood pressure were of a smaller magnitude than those reported in patients in remission following
414 R. Pivonello et al. Table 4. Percentage changes from baseline to months 6 and 12 in total, LDL- and HDL-cholesterol levels and in triglycerides in patients with baseline dyslipidaemia by lipid-modifying medication status* Percentage change in total cholesterol [mean (95% CI)] Month 6 Dyslipidaemia at baseline, no lipid-lowering medication during study, n = 110 Dyslipidaemia at baseline, lipid-lowering medication during study, n = 39 Month 12 Dyslipidaemia at baseline, no lipid-lowering medication during study, n = 110 Dyslipidaemia at baseline, lipid-lowering medication during study, n = 39
Percentage change in LDL-cholesterol [mean (95% CI)]
31 ( 69, 06) n = 74 135 ( 206, n = 30
49 ( 94, n = 74 63)
194 ( 292, n = 30
04)
97)
Percentage change in HDL-cholesterol [mean (95% CI)]
Percentage change in triglycerides [mean (95% CI)]
23 ( 46, 92) n = 74
72 ( 34, 179) n = 74
35 ( 139, 68) n = 29
48 ( 118, 213) n = 30
48 ( 104, 09) n = 46
65 ( 134, 05) n = 46
57 ( 47, 162) n = 46
52 ( 179, 74) n = 46
179 ( 251, n = 26
260 ( 353, n = 26
32 ( 103, 167) n = 26
68 ( 202, 65) n = 26
107)
167)
*Total patient numbers at baseline are given in the left-hand column; patients with evaluable measurements at each time point for each parameter are given for individual changes. CI, confidence interval; LDL, low-density lipoprotein; and HDL, high-density lipoprotein.
transsphenoidal surgery (12–17%).26–28 Hypertension has been reported in 55–85% of patients with Cushing’s disease,18 contributing to an increased cardiovascular risk compared with the general population.29 Following treatment with pasireotide, reductions in SBP and DBP were observed in patients with controlled, partially controlled and uncontrolled UFC, although they were greatest in those with UFC control at month 6. Similar reductions were seen when stratified by UFC response at month 12. Pasireotide treatment was also accompanied by reductions in blood pressure in patients with baseline hypertension, irrespective of any antihypertensive medication. Taken together, these results suggest that pasireotide treatment may confer an additional benefit in managing hypertension in patients with Cushing’s disease, independent of its effects on UFC secretion. The significant improvements in BMI during this study are comparable to those seen postsurgery (6–8% improvement 12 months after surgery).27,28,30 The significant reduction in total cholesterol levels also approaches that seen after successful surgery (109%).28 However, the effects of pasireotide treatment on cholesterol and triglyceride levels were inconclusive when stratified by UFC control and lipid-lowering medication status and require further investigation. Patients in all three UFC response subgroups had a decrease in total body fat mass and lean body mass. No changes in BMD were observed during 12 months’ treatment with pasireotide. Clinical improvements in rubor, striae and fat pads were greatest in controlled and partially controlled patients, indicating that a reduction in UFC levels may be important if these features of hypercortisolism are to be effectively managed. In this study, a hyperglycaemia-related event occurred in 728% of patients and mean FPG and HbA1c increased from baseline
irrespective of decreases in UFC. Recent studies of pasireotide in healthy volunteers have shown that pasireotide-associated hyperglycaemia is a result of decreases in insulin secretion and incretin hormone response.31 During treatment with pasireotide, blood glucose levels should be monitored and appropriate intervention initiated promptly if blood glucose levels increase. Greater attention should be given to patients with impaired glucose tolerance or diabetes mellitus prior to treatment.32 In this analysis of signs and symptoms from the largest prospective, multicentre study of a medical therapy in Cushing’s disease to date, only patients enroled in the study and who had evaluable measurements at each time point were included. There are limitations of this study: several of the subgroups analysed contained relatively small numbers of patients, reducing the extent to which the results can be interpreted and reflecting only the experience of patients who continued treatment rather than the overall experience with the medication; histology was not performed at baseline owing to a lack of consistent pathological specimen availability; the relative impact of concomitant medications on signs and symptoms could not be evaluated; while photographs depicting changes in clinical signs and symptoms were analysed by a blinded assessor at each centre, a central, blinded review would have been more robust. These subanalyses show that the reduction in UFC levels observed during treatment with pasireotide was accompanied by corresponding improvements in the signs and symptoms of hypercortisolism and, in some cases, these improvements occurred in patients who did not achieve normal UFC levels. These results suggest that while normalization of UFC should be a clear goal of treatment for Cushing’s disease, a partial response to medical therapy may be beneficial to some patients, for example, those await-
© 2014 John Wiley & Sons Ltd Clinical Endocrinology (2014), 81, 408–417
Pasireotide in Cushing’s disease 415 (a)
(a)
(b) (b)
Fig. 3 Mean (SE) (a) fasting plasma glucose and (b) HbA1c levels up to month 12 by urinary free cortisol response status at month 6. Fig. 2 Proportion of patients with a shift in signs of Cushing’s disease by urinary free cortisol response status at month 6, from baseline to (a) month 6 {number of patients in the full analysis set with measurements at both month 6 and baseline were as follows: facial rubor, 96 [25 controlled (C), 18 partially controlled (PC), 53 uncontrolled (UC)]; striae, 94 (24 C, 18 PC, 52 UC); bruising, 92 (24 C, 18 PC, 50 UC); supraclavicular fat pads, 93 (24 C, 18 PC, 51 UC); dorsal fat pads, 93 (24 C, 18 PC, 51 UC); and muscle strength, 110 (30 C, 22 PC, 58 UC)} and (b) month 12 [number of patients in the full analysis set with measurements at both month 12 and baseline were as follows: facial rubor, 69 (23 C, 15 PC, 31 UC); striae, 68 (23 C, 15 PC, 30 UC); bruising, 66 (22 C, 15 PC, 29 UC); supraclavicular fat pads, 68 (23 C, 14 PC, 31 UC); dorsal fat pads, 67 (23 C, 14 PC, 30 UC); and muscle strength, 75 (27 C, 17 PC, 31 UC)]. Note: UFC control was defined as UFC ≤ upper limit of normal (ULN), partial control was defined as UFC > ULN but with ≥50% reduction from baseline, and uncontrolled UFC was defined as UFC > ULN and without ≥50% reduction from baseline.
ing the effects of radiotherapy or to undergo pituitary surgery. Patients with a partial response to monotherapy with pasireotide may be good candidates for combination therapy with cabergoline or ketoconazole,33 but this would have to be assessed in further larger studies.
Acknowledgements This study was funded by Novartis Pharma AG. Financial support for medical editorial assistance was provided by Novartis Pharmaceuticals Corporation. We thank Daniel Webber PhD, Mudskipper Business Ltd, for medical editorial assistance with this manuscript. We thank all investigators who contributed to
© 2014 John Wiley & Sons Ltd Clinical Endocrinology (2014), 81, 408–417
the CSOM230B2305 study, as well as the numerous nurses, study co-ordinators and patients.
Conflicts of interest AT and GH are employees of Novartis. MM was an employee of Novartis during this study and is now employed by Boehringer Ingelheim. RP has served as principal investigator on research grants from Novartis and has received research grants from Novartis, Viropharma, Pfizer and IBSA, has been an occasional consultant for Novartis, Ipsen, Italfarmaco, Pfizer, Ferring and Viropharma, and has received lecture fees from Novartis and Pfizer. AL has received research support and served as a consultant for Novartis and Viropharma. SP and JS have received consulting fees from Novartis, Pfizer and Ipsen. JWF served as a consultant for Novartis and Corcept Therapeutics. JNP has received research income and consultancy fees from Novartis. FG and LRS have no conflict of interest. BMKB has served as the principal investigator on research grants from Novartis and Corcept Therapeutics to Massachusetts General Hospital and as a consultant to Novartis and HRA Pharma.
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Appendix The Pasireotide B2305 Study Group consisted of R. Abs, B. Allolio, R. Auchus, J. Bertherat, B.M.K. Biller, C. Boguszewski, M. Boscaro, T. Brue, O. Bruno, P. Caron, F. Cavagnini, D. Carv€mlekcßi, C. alho, O. Chabre, A. Chervin, C. Chik, A. Colao, A. C ßo Cortet, M. Czepielewski, E. Degli Uberti, A. Estour, U. Feldt© 2014 John Wiley & Sons Ltd Clinical Endocrinology (2014), 81, 408–417
Pasireotide in Cushing’s disease 417 Rasmussen, M. Fleseriu, P. Freda, M. Gadelha, M. Gershinsky, E. Ghigo, B. Glaser, F. Gu, M. Guitelman, S. Guler, A. Hamrahian, S.A. Imran, Z. Jin, J.O. Jorgensen, P. Kadioglu, L. Katznelson, A. Lacroix, A. Leal Cerro, P. Loli, L. Lu, W. Ludlam, F. Mantero, E. Martino, M. Mercado, A. Moreira, K. Nogueira, G.
© 2014 John Wiley & Sons Ltd Clinical Endocrinology (2014), 81, 408–417
Ning, L. Østergaard Kristensen, S. Petersenn, G. Piaditis, L. Portocarrero, V. Rohmer, R. Rubens, L. Salgado, S. Samson, J. Schopohl, I. Shimon, C. Strasburger, A. Tabarin, M. Terzolo, S. Tsagarakis, N. Unger, Z. Valkusz, L. Van Gaal, M. V€alim€aki, E. Vidal, S. Webb, R. Weiss and W. Zgliczy nski.
