Beverly Biller, Massachusetts General Hospital, USA

The successful management of Cushing's disease remains an unmet clinical need, with no licensed treatments available. Medical therapy is largely provided in the form of agents that inhibit steroidogenesis or the dopamine agonist bromocriptine.

There is renewed interest in somatostatin analogues in Cushing’s disease because of encouraging data emerging from early studies with pasireotide. In 2006, an open label, single arm Phase II study of fourteen patients with persistent or recurrent Cushing’s disease treated with pasireotide 600 μg subcutaneously twice daily for 15 days reported normalisation of urinary free cortisol less (UFC) in 3 patients (21%) and in a further 7 patients there was at least 40% reduction in UFC compared to baseline.

At the ENEA 2010, the Phase III efficacy and safety results from the PASPORT-CUSHINGS (PASireotide clinical trial PORTfolio - CUSHING'S disease) study were presented. This prospective Phase III, 12-month, randomised, double-blind study included 162 patients from 62 sites across 18 countries with persistent or recurrent, or newly diagnosed Cushing's disease who were not candidates for surgery.

Significant clinical benefit was reported, with reduced hypercortisolism and improved associated signs and symptoms.

Patients were treated with 600µg or 900µg pasireotide twice daily for 3 months. In those inadequately controlled, the dose was increased by 300µg in an unblinded fashion. This cohort was excluded from the primary endpoint analysis. The remainder continued on the same dose for a further 3 months. At the end of the 6-month double-blind phase, patients were entered into a 6-month open-label  phase and were offered the opportunity to continue with treatment after this point in an open label fashion. The primary endpoint (mean UFC than or equal to the upper limit of normal [mUFC≤ULN] at 6 months) was reached by 15% and 26% of patients treated with 600µg and 900µg pasireotide, respectively. This was maintained (13% and 25%) at 12 months. This response was associated with a 50% decrease in cortisol levels at 6 months and 70% reduction at 12 months. When patients were analysed according to their baseline mUFC levels, it was found that  there was a higher rate of normalisation for patients with lower baseline mUFC. In addition, 90% patients who were unresponsive in the first 1-2 months, remained so throughout the study, providing a potentially useful guide to appropriate patients for longer term treatment.  As mUFC decreased, clinical signs and symptoms including lower blood pressure, total cholesterol and weight loss improved. Patient quality of life was also improved. The treatment was generally well tolerated and had a similar adverse event profile to other somatostatin analogues, with the exception of an increased incidence of hyperglycaemia in patients treated with pasireotide. Further studies are ongoing in healthy controls to establish the mechanism of this hyperglycaemia and potential treatment options.

Pasireotide is a new somatostatin analogue with affinity to all the somatostatin receptor subtypes. Compared to octreotide, it has a 40-fold higher affinity for somatostatin receptor subtype 5 and is more potent at suppressing ACTH release and at inhibiting CRH-induced ACTH release in corticotroph tumour cells.

This pivotal trial is the largest study of a medical therapy in Cushing's disease and represents the first specific treatment for corticotroph adenomas and shows promise as a treatment for Cushing's disease.