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 μg 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 μg b.i.d. and 900 μg 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.