Novartis announced that the results of a phase III study of SOM230 (pasireotide) showed a reduction in cortisol levels in patients with Cushing's disease, a condition in which a benign (non-cancerous) pituitary tumour causes the adrenal glands to produce excess cortisol and can be fatal. Results will be presented at the 14th Congress of the European Neuroendocrine Association (ENEA).

At six months, the majority of evaluable patients (91/103) experienced a reduction from baseline in urinary free cortisol (UFC) levels, the main measure of biochemical control of the disease. UFC levels were normalized in 26 per cent of patients randomized to SOM230 900µg twice daily, meeting the primary endpoint of the study. Additionally, median UFC was reduced by 48 per cent in both the 900µg and 600µg dose groups. After 12 months of treatment, results confirmed the durability of the effect.

On average, as UFC levels were reduced, clinical symptoms of Cushing's disease improved including reduction of blood pressure, total cholesterol, weight and body mass index (BMI).

Cushing's disease is caused by a benign tumour in the pituitary gland that secretes adrenocorticotropic hormone (ACTH), which triggers the adrenal glands to produce excess cortisol. Cortisol is a powerful steroid hormone that regulates a broad range of physiologic functions, including metabolism and immunity. Cushing's disease can cause severe cardiovascular and metabolic-related illnesses or death. There are currently no approved medicines to treat Cushing's disease.

"Up to half of patients with Cushing's disease cannot be cured with currently available options, which include surgery or radiotherapy of the tumour, leaving a critical need for medical treatments," said Annamaria Colao, MD, Professor of Endocrinology and Chief of the Neuroendocrine Unit at the Department of Molecular and Clinical Endocrinology and Oncology, Federico II University of Naples and one of the study investigators. "The study findings show that SOM230 has the potential to directly target the underlying pituitary tumour and suppress cortisol production, thereby helping patients achieve biochemical control of their Cushing's disease and the associated debilitating symptoms."

PASPORT-CUSHINGS (PASireotide clinical trial PORTfolio - Cushing's disease) is the largest randomized study to evaluate a medical therapy in patients with Cushing's disease. The trial is part of a large-scale global clinical development programme to assess the efficacy and safety of SOM230 in a range of pituitary and neuroendocrine tumors.

"Positive results from this trial bring us one step closer to providing physicians with a new treatment option to offer people living with the physically and emotionally debilitating symptoms associated with Cushing's disease," said Hervé Hoppenot, president, Novartis Oncology.

These data will form the basis for the first regulatory filing of SOM230 planned this year. SOM230 has orphan drug designation for Cushing's disease in the US and Europe. In the US, orphan drugs are those developed to treat diseases affecting fewer than 200,000 people. In Europe, orphan drugs are those developed to treat conditions affecting fewer than five in 10,000 people.

PASPORT-CUSHINGS is a prospective phase III study of 162 patients conducted at 68 sites in 18 countries. The study evaluated the efficacy and safety of SOM230 in patients with persistent or recurrent Cushing's disease, as well as in patients with newly diagnosed Cushing's disease who are not candidates for surgery.

Patients with primarily moderate to severe hypercortisolism were randomized to receive SOM230 subcutaneous (sc) injection in doses of 600µg (n=82) or 900µg (n=80) twice daily. The primary endpoint was the proportion of patients who achieved normalization of UFC after six months without dose up-titration relative to randomized dose. UFC is typically used to diagnose and monitor Cushing's disease. In this test, urine is collected over 24 hours to assess average cortisol secretion. The primary endpoint was met for the higher dose tested (900µg sc twice daily). Secondary endpoints included safety, time to response, response duration and changes from baseline in clinical signs, symptoms, tumour volume and health-related quality of life.

After six months, the primary efficacy responder rate was 26.3% (95% CI, 16.6 to 35.9) and 14.6% (95% confidence interval [CI], 7.0 to 22.3), respectively, for the 900µg and 600µg groups. Based on pre-specified criteria (lower bound of 95% CI >15%), the 900µg group met the primary endpoint and the 600ug group did not meet the primary endpoint. After 12 months, the proportion of responders regardless of dose up-titration was 13.4% and 25.0%, respectively, for the 600µg and 900µg groups. The median reduction in UFC after six months was 47.9% for both groups. The median reduction in UFC after 12 months was 67.6% (600µg) and 62.4% (900µg). Patients who showed little to no improvement in UFC levels (<50% reduction from baseline) by month two were unlikely to show improvement by month six or 12. The most frequently reported adverse events suspected by the investigators to be related to the study drug were diarrhoea (58%), nausea (46.9%), hyperglycaemia (38.9%), cholelithiasis (29.6%), abdominal pain (20.4%), diabetes mellitus (17.9%), fatigue (11.7%) and increased glycosylated haemoglobin (10.5%), with most events being Grade 1-2. Overall, the tolerability profile of SOM230 is similar to other somatostatin analogs with the exception of the greater degree of hyperglycaemia, which appears manageable with early detection and appropriate intervention following established treatment guidelines. As may be expected with a treatment that lowers cortisol levels in Cushing's disease, 13 (8.0%) patients experienced adverse events associated with cortisol levels below the normal range. This was managed by dose reduction without loss of efficacy.

Cushing's disease is a rare but serious disease that affects approximately 10 to 15 patients per million per year. It most commonly affects adults who are as young as 20 to 50 years and affects women three times more often than men. Cushing's disease presents with weight gain, central obesity, moon face, severe fatigue and weakness, striae (purple stretch marks), depression and anxiety. To date, no known causes or risk factors have been identified for the development of the benign tumours in the pituitary gland that cause Cushing's disease.

SOM230 is an investigational pituitary-directed therapy that targets the cause of Cushing's disease, with the aim to control excess cortisol secretion and its debilitating complications. SOM230 targets multiple subtypes of the receptor for somatostatin (sst), a hormone that controls the pituitary gland. Its highest affinity is to sst5, a receptor subtype frequently expressed by the pituitary tumours associated with Cushing's disease. Currently approved somatostatin analogs preferentially bind to sst2 and are not effective in Cushing's disease.

SOM230 is currently being studied as a twice-daily sc injection, as well as a long-acting release (LAR) once-monthly intramuscular injection for the treatment of multiple disease types, including Cushing's disease, carcinoid syndrome and acromegaly.