General Information

Signifor LAR (pasireotide) is a somatostatin analog.

Signifor LAR is specifically indicated for the treatment of patients with acromegaly who have had an inadequate response to surgery and/or for whom surgery is not an option.

Signifor LAR is supplied as an injectable suspension for intramuscular injection. The recommended initial dose is 40 mg administered by intramuscular injection once every 4 weeks (every 28 days). For dose modifications please see drug label.

Clinical Results

FDA Approval

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.

Mechanism of Action

Signifor LAR is an injectable cyclohexapeptide somatostatin analog. Pasireotide exerts its pharmacological activity via binding to somatostatin receptors (SSTR). There are five known human somatostatin receptor subtypes: SSTR 1, 2, 3, 4, and 5. These receptor subtypes are expressed in different tissues under normal physiological conditions. Somatostatin analogs bind to SSTRs with different potencies. Pasireotide binds with high affinity to four of the five SSTRs. Somatostatin receptors are expressed in many tissues including neuroendocrine tumors (e.g., growth hormone secreting pituitary adenomas). Pasireotide binds to SSTR2 and SSTR5 subtype receptors which may be relevant for inhibition of GH secretion. In vivo studies show that Signifor LAR lowers GH and IGF-1 levels in patients with acromegaly.