Beverly Biller, Massachusetts General Hospital, USA

The goal of treatment of Cushing's disease is to normalise cortisol levels. However, current treatment options are limited and are associated with a variety of drug related adverse events and relapse. There are no approved medical therapies for Cushing's disease, and the efficacy of medical treatments that are used is limited, highlighting the unmet need in these patients.

Of great benefit would be a pituitary-directed medical treatment which targets the underlying cause of ACTH hypersecretion. There are a number of agents under investigation for the treatment of Cushing's disease, including pituitary targeted drugs and drugs targeting blockade of the glucocorticoid receptor.

Pasireotide, a new investigational drug with multi-serotonin subtype receptor affinity, is a pituitary targeted medical therapy that has been associated with rapid normalisation of UFC levels in a small number of patients in a Phase II study of patients with Cushing's disease. This has led to a

Phase III, randomised, double-blind, multicentre study, the initial results of which were presented at ENEA 2010. This ongoing clinical trial is the largest study to evaluate a medical therapy in this patient population. After 6 months of treatment with pasireotide 600 or 900 µg sc bid, 14.6% and 26.3% of patients with moderate to severe hypercortisolism achieved UFC ≤ULN. At 12 months, 13.4% and 25.0% patients achieved UFC ≤ULN. Overall, there was a rapid and sustained improvement in clinical signs and symptoms from baseline, as well as improvements in patient health related quality of life. Around 50% of patients at ≥1.5 to <2 ULN achieved UFC ≤ULN with 900 at 6 months. In addition, systolic and diastolic blood pressure and weight improved in line with the decline in cortisol levels. Non-responding patients, based on UFC levels, were identified early after treatment initiation, which may be clinically useful for identifying patients inappropriate for this therapy.

With the exception of hyperglycaemia, the safety profile of pasireotide was similar to that of other somatostatin analogues. As expected with an active agent in Cushing's disease, some patients experienced symptoms of hypocortisolism, which was adequately managed in patients by decreasing the dose of pasireotide.