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FDA Panel Recommends Approval of Cushing's Drug

Treatment reduces urinary-free cortisol levels (Nov. 7)

The FDA’s Endocrinologic and Metabolic Drugs Advisory Committee (EMDAC) has voted unanimously in support of the use of pasireotide (Signifor, Novartis) for the treatment of patients with Cushing's disease who require medical therapeutic intervention.

The recommendation was based on data from clinical studies of pasireotide, including the PASPORT–CUSHINGS (PASireotide clinical trial PORTfolio – CUSHING'S disease) trial — the largest randomized phase III study of medical therapy in patients with Cushing's disease.

Although the FDA is not obliged to follow the recommendation, the agency can seek the advice of its advisory committees as it reviews and decides whether to approve treatments.

The PASPORT–CUSHINGS study found that mean urinary-free cortisol (UFC), the key measure of biochemical control of Cushing’s disease, was rapidly decreased and sustained in a majority of patients, with a subset of patients reaching normal levels. The study also showed that, as UFC levels were reduced, clinical manifestations of Cushing's disease improved.

The adverse events (AEs) most commonly associated with pasireotide were diarrhea, nausea, hyperglycemia, cholelithiasis, abdominal pain, diabetes mellitus, injection-site reactions, fatigue, and increased glycosylated hemoglobin (HbA1c). Most events were grade 1–2 in severity. The safety profile of pasireotide was similar to that of other somatostatin analogs, with the exception of the greater degree of hyperglycemia.

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.

Cushing's disease most commonly occurs in adults aged 20 to 50 years, and it affects women three times more often than men. The disorder may present with weight gain, central obesity, a round, red full face, severe fatigue and weakness, striae (purple stretch marks), high blood pressure, depression, and anxiety. The first-line and most common treatment approach for Cushing's disease is surgical removal of the tumor.

Pasireotide is a multireceptor-targeting somatostatin analog that binds with high affinity to four of the five somatostatin receptor subtypes (sst 1, 2, 3, and 5). The drug has been approved in Europe for the treatment of adult patients with Cushing's disease for whom surgery is not an option or for whom surgery has failed.

Pasireotide has been studied as a twice-daily subcutaneous injection in patients with Cushing's disease, and it is currently being evaluated as a long-acting release (LAR), once-monthly intramuscular injection as part of a global phase III program in Cushing's disease and acromegaly.

Source: Novartis; November 7, 2012.

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