The European Commission has approved Novartis' Signifor (pasireotide) for the treatment of adult patients with Cushing's disease for whom surgery is not an option or for whom surgery has failed. Signifor is the first medicine to be approved in the European Union (EU) targeting Cushing's disease.

The approval is based on data from the largest randomized phase III study to evaluate a medical therapy in patients with Cushing's disease, a disorder caused by excess cortisol in the body due to the presence of a non-cancerous pituitary tumour. In the study, mean urinary-free cortisol (UFC) levels were normalized in 26.3 per cent and 14.6 per cent of the 162 patients randomized to receive Signifor 900µg and 600µg subcutaneous (sc) injection twice daily, respectively, at month six. The primary endpoint, the proportion of patients who achieved normalization of UFC after six months without dose up-titration relative to randomized dose, was met in patients treated with 900µg twice daily.

In addition, the study showed the majority of the patients remaining on the study at month six (91 out of 103 patients; 88%) had any reduction in their mean UFC. The median reduction in mean UFC was 47.9 per cent in both dose groups. Reductions in UFC were rapid and sustained through the end of the study, with the majority of patients experiencing a decrease within the first two months.

Overall reductions in the clinical manifestations of Cushing's disease, including blood pressure, total cholesterol, weight and body mass index, were observed at months six and twelve in patients with both full and partial mean UFC control, with the greatest reductions observed in patients with normalized UFC levels.

Signifor (pasireotide) is approved in the European Union (EU) for the treatment of adult patients with Cushing's disease for whom surgery is not an option or for whom surgery has failed. For the treatment of Cushing's disease, Signifor has been studied as a twice-daily subcutaneous (sc) injection and is currently being evaluated as a long-acting release (LAR), once-monthly intramuscular (IM) injection as part of a global Phase III programme. Signifor is a multireceptor targeting somatostatin analog (SSA) that binds with high affinity to four of the five somatostatin receptor subtypes (sst 1, 2, 3 and 5).

“As the first therapeutic option to specifically target Cushing's disease, Signifor has the potential to redefine treatment of this debilitating disease,” said Hervé Hoppenot, president, Novartis Oncology. “By focusing research efforts on our understanding of this rare disease where there is significant unmet need, we have been able to successfully bring a novel treatment option to patients in the European Union.”

Cushing's disease most commonly affects adults as young as 20 to 50 years and affects women three times more often than men. It may present with weight gain, central obesity, a round, red and full face, severe fatigue and weakness, striae (purple stretch marks), high blood pressure, depression and anxiety.

“Patients with Cushing's disease often struggle with a variety of debilitating health issues associated with the overproduction of cortisol and previously were faced with a treatment approach limited to surgery,” said Ellen van Veldhuizen, board member of the Dutch Adrenal Society. “The approval of pasireotide as a new treatment option that may help patients with Cushing's disease is welcome news.”

The decision follows the positive opinion the Committee for Medicinal Products for Human Use (CHMP) adopted for Signifor in January 2012 for the treatment of Cushing's disease and applies to all 27 EU member states, plus Iceland and Norway. Signifor has orphan drug designation for Cushing's disease, a condition which affects no more than five in 10,000 people in the EU, the threshold for orphan designation. Additional regulatory submissions for pasireotide for the treatment of Cushing's disease are under way worldwide.

Cushing's syndrome is an endocrine disorder caused by excessive cortisol, a vital hormone that regulates metabolism, maintains cardiovascular function and helps the body respond to stress. Cushing's disease is a form of Cushing's syndrome, in which excess cortisol production is triggered by an adrenocorticotropic hormone (ACTH)-secreting pituitary adenoma. It is a rare but serious disease that affects approximately one to two patients per million per year. The first line and most common treatment approach for Cushing's disease is surgical removal of the tumour.

PASPORT-CUSHINGS (PASireotide clinical trial PORTfolio - CUSHING'S disease) is a prospective, randomized, double-blind, Phase III study conducted at 68 sites in 18 countries. The study evaluated the efficacy and safety of Signifor in 162 adult patients with persistent or recurrent Cushing's disease and UFC levels greater than 1.5 times the upper limit of normal (ULN), as well as in patients with newly diagnosed Cushing's disease who were not candidates for surgery.

Patients with primarily moderate to severe hypercortisolism were randomized to receive Signifor sc injection in doses of 900µg (n=80) or 600µg (n=82) 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, which was met in patients treated with 900µg twice daily.