Novartis drug SOM230 is first medical therapy to show efficacy in a Phase III trial in Cushing's disease

Novartis drug SOM230 is first medical therapy to show efficacy in a Phase III trial in Cushing's disease, a debilitating hormonal disorder
SOM230 reduced urinary free cortisol (UFC) levels in majority of patients; 26% of patients randomized to SOM230 900µg achieved normal UFC levels

With reduced UFC levels, clinical symptoms improved including lower blood pressure, total cholesterol and weight loss

Cushing's disease is caused by a pituitary tumor that triggers excess cortisol; can lead to severe cardiovascular, metabolic problems and death

This pivotal trial is the largest study of a medical therapy in Cushing's disease and will be basis for first regulatory filing planned by year end

Basel, September 22, 2010 - Novartis announced today 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 tumor causes the adrenal glands to produce excess cortisol and can be fatal[1]. 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% of patients randomized to SOM230 900µg twice daily, meeting the primary endpoint of the study. Additionally, median UFC was reduced by 48% in both the 900µg and 600µg dose groups. After 12 months of treatment, results confirmed the durability of the effect[1].

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)[1].

Cushing's disease is caused by a benign tumor 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[2]. Cushing's disease can cause severe cardiovascular and metabolic-related illnesses or death[3,4]. There are currently no approved medicines to treat Cushing's disease[1].

"Up to half of patients with Cushing's disease cannot be cured with currently available options, which include surgery or radiotherapy of the tumor, 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 tumor 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[1]. The trial is part of a large-scale global clinical development program to assess the efficacy and safety of SOM230 in a range of pituitary and neuroendocrine tumors[6].

"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[7,8]. In the US, orphan drugs are those developed to treat diseases affecting fewer than 200,000 people[9]. In Europe, orphan drugs are those developed to treat conditions affecting fewer than five in 10,000 people[8].

Study details
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[1,10].

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[1]. 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[2]. The primary endpoint was met for the higher dose tested (900µg sc twice daily)[1]. Secondary endpoints included safety, time to response, response duration and changes from baseline in clinical signs, symptoms, tumor volume and health-related quality of life[10].

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 diarrhea (58%), nausea (46.9%), hyperglycemia (38.9%), cholelithiasis (29.6%), abdominal pain (20.4%), diabetes mellitus (17.9%), fatigue (11.7%) and increased glycosylated hemoglobin (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 hyperglycemia, 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[1].

About Cushing's disease
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[2,5]. To date, no known causes or risk factors have been identified for the development of the benign tumors in the pituitary gland that cause Cushing's disease.

Complications of Cushing's disease can include osteoporosis and subsequently fractures, insulin resistance with higher prevalence of impaired glucose tolerance and diabetes mellitus, high blood pressure, lipid disorders, infections, kidney stones and mental illnesses, including depression and psychosis[1,3,4]. Cardiovascular complications resulting from untreated Cushing's disease, including coronary artery disease, congestive heart failure and stroke, contribute to a mortality rate up to four times higher than the healthy population[4].

The most common treatment approach for Cushing's disease is surgical removal of the tumor. Persistent disease and/or relapse can occur in up to 50% of surgery patients[2,5]. If surgery is not appropriate or effective, other treatment options include radiation to the pituitary gland, stereotactic radiosurgery or gamma knife radiation, removal of the adrenal glands and inhibition of cortisol production[2].

About SOM230 (pasireotide)
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[1,2]. 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 tumors associated with Cushing's disease. Currently approved somatostatin analogs preferentially bind to sst2 and are not effective in Cushing's disease[6].

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[10].

Because it is an investigational compound, the safety and efficacy profile of SOM230 has not yet been established. Access to this investigational compound is available only through carefully controlled and monitored clinical trials. These trials are designed to better understand the potential benefits and risks of the compound. There is no guarantee that SOM230 will become commercially available[6].

Information about Novartis clinical trials for SOM230 can be obtained by healthcare professionals at www.pasporttrials.com.

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