Medical Treatment of Cushing's 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-, 30- and 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 mu 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 mu g b.i.d. and 900 mu 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 treatment. Finally, preliminary results from a study on 17 patients with Cushing's disease suggest that the combined use of pasireotide, cabergoline and low-dose ketoconazole may have additive beneficial effects in the medical treatment of Cushing's disease. Copyright (C) 2010 S. Karger AG, Basel