Signifor/Signifor LAR (pasireotide diaspartate) - 2 indications

Scroll down for information on each indication:

• for the treatment of Cushing's disease; approved December of 2012; Signifor LAR approved June 2018
• for the treatment of acromegaly; approved December 2014 (Signifor LAR)

General Information

Signifor (pasireotide diaspartate) is a somatostatin analog. Signifor LAR is a long acting release formulation.

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

Signifor LAR is specifically indicated for the following:

• for patients with acromegaly who have had an inadequate response to surgery and/or for whom surgery is not an option
• for patients 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. Signifor LAR is supplied as an injectable suspension for intramuscular injection.

Scroll down to see dosing/administration recommendations for each indication.

Mechanism of Action

Signifor is an injectable cyclohexapeptide somatostatin analogue. Pasireotide exerts its pharmacological activity via binding to somatostatin receptors (SSTRs). Five human somatostatin receptor subtypes are known: SSTR 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 SSTR5 whereas the other receptor subtypes are often not expressed or are expressed at lower levels. Pasireotide binds and activates the SSTRs resulting in inhibition of ACTH secretion, which leads to decreased cortisol secretion. 

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

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

• diarrhea
• cholelithiasis
• hyperglycemia
• diabetes mellitus

Indication 1 - Cushing's disease

approved December of 2012; Signifor LAR approved June 2018

Dosing/Administration

Signifor:

• 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.

Signifor LAR: 

• The recommended initial dosage of Signifor LAR for Cushing’s disease is 10 mg by intramuscular (IM) injection once every four weeks.

Clinical Trial Results

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.

The safety and efficacy of Signifor LAR for Cushing’s disease was studied in 150 patients who received two different dosages (10 mg and 30 mg) of Signifor LAR for 12 months. The primary endpoint was the proportion of patients in each arm who were mean urinary free cortisol (mUFC) responders (mUFC ≤ upper limit of normal) after 7 months of treatment. — The proportion of patients with mUFC response at month 7 was 39.2% in the 10 mg arm and 40.8% in the 30 mg arm. Both groups achieved the primary endpoint. — In addition, the responder rates at month 12 were 35.1% and 25.0% in the 10 mg and 30 mg starting dose groups, respectively. 

Indication 2 - acromegaly

approved December 2014 (Signifor LAR)

Dosing/Administration

The recommended initial dose is 40 mg administered by intramuscular injection once every 4 weeks.

Clinical Trial Results

The FDA approval of Signifor LAR for acromegaly was based on two studies in two populations.

Treatment naive population:

• A multicenter, randomized, double-blind study was conducted to assess the safety and efficacy of Signifor LAR in subjects with active acromegaly. A total of 358 subjects naïve to drugs used to treat acromegaly were randomized to Signifor LAR or another somatostatin analog active comparator. Randomization was stratified based on previous pituitary surgical status. The starting dose of Signifor LAR was 40 mg. Dose increase was allowed in both arms, at the discretion of investigators, after three and six months of treatment if mean GH was greater than or equal to 2.5 mcg/L and/or IGF-1 was greater than the ULN for age and sex. The maximum allowed dose for Signifor LAR was 60 mg. The maximum dose of the active comparator was not used in this trial because the trial was multi-national and the maximum dose approved in the US was not approved in all participating countries. The efficacy endpoint was the proportion of patients with a mean GH level less than 2.5mcg/L and a normal IGF-1 levels at month 12 (age and sex adjusted). The proportion of patients achieving this level of control was 31.3% and 19.2% for Signifor LAR and active comparator, respectively.

Population Inadequately Controlled on other Somatostatin Analog

• A multicenter, randomized, 3-arm trial was conducted in subjects with acromegaly inadequately controlled on somatostatin analogs. Subjects were randomized to double-blind Signifor LAR 40 mg (n=65) or Signifor LAR 60 mg (n=65) or to continued open-label pre-trial somatostatin analog therapies at maximal or near maximal doses (n=68). A total of 181 subjects completed the 6 month trial. The efficacy endpoint was the proportion of subjects with a mean GH level less than 2.5 mcg/L and normal IGF-1 levels at week 24. The primary analysis compared Signifor LAR 60 mg and 40 mg to continued pretrial therapy (i.e., no change in treatment). The proportion of subjects achieving biochemical control was 15.4% and 20.0% for Signifor LAR 40 mg and 60 mg, respectively, at 6 months. Biochemical control was achieved by Month 3 in 15.4% and 18.5% of subjects in the Signifor LAR 40 mg and 60 mg arms, respectively.