Signifor (pasireotide diaspartate)

The following drug information is obtained from various newswires, published medical journal articles, and medical conference presentations.

Company:

Approval Status:

Approved December of 2012

Specific Treatments:

Cushing's disease

Therapeutic Areas

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General Information

Signifor (pasireotide diaspartate) is a somatostatin analog. Pasireotide exerts its pharmacological activity via binding to somatostatin receptor subtypes (ssts) 1, 2, 3, 4, and 5. These receptor subtypes are expressed in different tissues under normal physiological conditions. Corticotroph tumor cells from Cushing’s disease patients frequently over-express ssts5 whereas the other receptor subtypes are often not expressed or are expressed at lower levels. Pasireotide binds and activates the hsst receptors resulting in inhibition of Adrenocorticotropic hormone secretion, which leads to decreased cortisol secretion.

Signifor is specifically indicated for the treatment of adults with Cushing’s disease for whom pituitary surgery is not an option or has not been curative.

Signifor is supplied as a solution for subcutaneous injection. The recommended initial dose is either 0.6 mg or 0.9 mg by subcutaneous injection twice a day. The recommended dosage range is 0.3 to 0.9 mg. Patients should be evaluated for a treatment response [clinically meaningful reduction in 24-hour urinary free cortisol levels and/or improvement in signs or symptoms of the disease] and should continue receiving therapy with Signifor as long as benefit is derived. See prescription label for any dose modifications.

Clinical Results

FDA Approval
The FDA approval of Signifor was based on a phase III, multicenter, randomized study. The trial enrolled 162 subjects with Cushing’s disease with persistent or recurrent disease despite pituitary surgery or de novo patients for whom surgery was not indicated or who had refused surgery. Subjects with a baseline 24-hour urine free cortisol (UFC) >1.5 x upper limit of normal (ULN) were randomized to receive a Signifor dosage of either 0.6 mg subcutaneous b.i.d. or 0.9 mg subcutaneous b.i.d.. After three months of treatment, patients with a mean 24-hour UFC = 2.0 x ULN and below or equal to their baseline values continued blinded treatment at the randomized dose until Month 6. Patients who did not meet these criteria were unblinded and the dose was increased by 0.3 mg b.i.d. After the initial six months in the study, patients entered an additional 6-month open-label treatment period. The dosage could be reduced by 0.3 mg b.i.d. at any time during the study for intolerability. The primary efficacy endpoint was the proportion of patients who achieved normalization of mean 24hour UFC levels after six months of treatment and did not dose increase during this period. At Month 6, the percentages of responders for the primary endpoint were 15% and 26% in the 0.6 mg b.i.d. and 0.9 mg b.i.d. groups, respectively. Signifor resulted in a decrease in the mean 24-hour UFC after 1 month of treatment. For subjects (n=78) who stayed in the trial, similar UFC lowering was observed at Month 12.

Side Effects

Adverse events associated with the use of Signifor may include, but are not limited to, the following:

  • diarrhea
  • nausea
  • hyperglycemia
  • cholelithiasis
  • headache
  • abdominal pain
  • fatigue
  • diabetes mellitus

Mechanism of Action

Signifor (pasireotide diaspartate) is a somatostatin-based cyclohexapeptide somatostatin receptor -1, -2, -3 and -5 agonist. Pasireotide exerts its pharmacological activity via binding to these somatostatin receptors (ssts). These receptor subtypes are expressed in different tissues under normal physiological conditions. Corticotroph tumor cells from Cushing’s disease patients frequently over-express hsst5 whereas the other receptor subtypes are often not expressed or are expressed at lower levels. Pasireotide binds and activates the hsst receptors resulting in inhibition of ACTH secretion, which leads to decreased cortisol secretion.

Literature References

Colao A, Petersenn S, Newell-Price J, Findling JW, Gu F, Maldonado M, Schoenherr U, Mills D, Salgado LR, Biller BM; Pasireotide B2305 Study Group A 12-month phase 3 study of pasireotide in Cushing's disease. The New England Journal of Medicine. 2012 Mar 8;366(10):914-24

Additional Information

For additional information regarding Signifor or Cushing's disease, please visit the Signifor web page.