Medical Treatment of Cushings Disease: Somatostatin Analogues and Pasireotide

Cushing’s disease is Cushing’s syndrome caused by an adrenocorticotropic hormone-secreting pituitary adenoma and, in the absence of adequate treatment, can be fatal. Cushing’s disease represents an unmet medical need, with no approved medical therapies. Pasireotide is a novel multi-receptor-targeted somatostatin analogue with high affinity for sst 1,2,3 and sst 5 . Compared with octreotide, pasireotide has an in vitro binding affinity 40-, 30and 5-fold higher for sst 5, sst 1 and sst 3 , respectively, and 2-fold lower for sst 2 . Adrenocorticotropic hormone-secreting pituitary adenomas predominantly express sst 5 , followed by sst 2 and sst 1 , suggesting that pasireotide may be effective in the treatment of Cushing’s disease. In a 15-day phase II trial of pasireotide 600 g s.c. b.i.d. in patients with de novo or persistent/recurrent Cushing’s disease, 22 of 29 patients (76%) achieved reduced urinary free cortisol (UFC) levels, 5 of whom (17%) achieved normalized UFC. Patients who achieved normalized UFC had a significantly greater reduction in serum cortisol than those who did not (p = 0.04), and minimum pasireotide plasma concentrations appeared to be higher in responders. Based on these results, a randomized, double-blind phase III study comparing pasireotide 600 g b.i.d. and 900 g b.i.d. was initiated and is ongoing. This is the largest ever phase III study in patients with Cushing’s disease. The primary end point of this study is normalization of UFC after 6 months of Published online: September 10, 2010 A.M. Pedroncelli Novartis Oncology, Forum 1, Novartis Campus CH–4056 Basle (Switzerland) Tel. +41 61 324 0486, Fax +41 61 696 3089, E-Mail alberto.pedroncelli @ novartis.com © 2010 S. Karger AG, Basel 0028–3835/10/0925–0120$26.00/0 Accessible online at: www.karger.com/nen D ow nl oa de d by : 54 .1 91 .4 0. 80 9 /1 6/ 20 17 8 :1 4: 01 P M Pasireotide in Cushing’s Disease Neuroendocrinology 2010;92(suppl 1):120–124 121 ease have a mortality rate four times higher than ageand sex-matched controls [2] . Treatment goals in Cushing’s disease include the reversal of clinical features, the normalization of biochemical changes with minimal morbidity, and long-term control without recurrence [1] . First-line treatment for Cushing’s disease is pituitary surgery. Second-line options include repeat surgery, radiotherapy, bilateral adrenalectomy and medical therapy. Currently, there are no approved medications for the treatment of Cushing’s disease. The most commonly used medical therapies, such as ketoconazole, metyrapone and mitotane, target the adrenal glands and, therefore, do not treat the underlying cause of the disease or restore normal function of the hypothalamo-pituitary-adrenal axis [5] . The commercially available somatostatin analogue octreotide is mostly ineffective in treating Cushing’s disease [6–8] . Pasireotide, a Multi-Receptor Targeted Somatostatin Analogue Pasireotide is a novel multi-receptor-targeted somatostatin analogue with high binding affinity to somatostatin receptor subtypes sst 1,2,3 and sst 5 . Octreotide has high affinity for somatostatin receptor subtype sst 2 and marginal affinity for sst 5 , which accounts for its efficacy in treating patients with acromegaly and symptomatic gastroenteropancreatic neuroendocrine tumors (GEPNETs), and can partly explain its lack of efficacy in Cushing’s disease [9] . Compared with octreotide, pasireotide has an in vitro binding affinity 40-, 30and 5-fold higher for sst 5 , sst 1 and sst 3 , respectively, and 2-fold lower for sst 2 [10] . Because of these differences in binding affinity, it can be speculated that in cells and tissues that express somatostatin receptors other than sst 2 , pasireotide will have a stronger inhibitory effect on hormone secretion than octreotide. ACTH-secreting pituitary adenomas predominantly express sst 5 , followed by sst 2 and sst 1 [11, 12] . Therefore, by targeting multiple somatostatin receptor subtypes, pasireotide may prove to be effective not only in patients with acromegaly or GEP-NETs, but also in patients with Cushing’s disease. Preclinical Evidence In vitro evaluation of a mouse corticotropic adenoma cell line (AtT-20 cells) showed high mRNA expression of sst 5 receptors but few sst 2 receptors, reflecting the expression profile of human corticotropic adenomas [13] . Furthermore, in vitro studies in human ACTH-secreting pituitary adenomas and AtT-20 murine corticotropic tumor cells showed that pasireotide inhibits basal and stimulated ACTH release. A 72-hour incubation with pasireotide 10 n M in human corticotropic adenoma cells resulted in inhibition of ACTH release in three of five cultures (–30% to –40%), whereas octreotide 10 n M inhibited ACTH release in only one culture (–28%) [14] . Importantly, the suppression of CRH-induced ACTH release exhibited by pasireotide in AtT-20 cells was unaffected by a 48-hour pretreatment with dexamethasone. By contrast, the suppressive effects of octreotide were almost completely blocked by dexamethasone [14, 15] , suggesting that sst 2 may be downregulated by glucocorticoid treatment (or by elevated endogenous cortisol levels), and that sst 5 is more resistant to downregulation. This also suggested that by inhibiting ACTH release and subsequent cortisol levels via sst 5 , the expression of sst 2 may be restored, thus further enhancing ACTH inhibition by an sst 2 /sst 5 receptor ligand such as pasireotide.