Summary

Pasireotide is a synthetic cyclic hexapeptide analogue of somatostatin, developed by Novartis and marketed as Signifor (subcutaneous) and Signifor LAR (intramuscular depot). Unlike first-generation somatostatin analogues (octreotide, lanreotide), pasireotide has uniquely high affinity for the SST5 receptor, making it the first medical therapy specifically approved for Cushing's disease. It is also licensed for acromegaly in patients with inadequate response to first-generation analogues. Supported by Phase 3 RCTs published in NEJM, pasireotide has strong clinical evidence — though its use is complicated by a high incidence of hyperglycaemia, which has led to a specific black-box warning.

Overview

Pasireotide is a synthetic cyclic hexapeptide analogue of somatostatin, developed by Novartis. Unlike octreotide and lanreotide — which primarily bind SST2 — pasireotide has a uniquely high affinity for the somatostatin receptor subtype 5 (SST5), alongside SST2. This broader receptor profile gives it distinct therapeutic applications, particularly in conditions where SST5 is the predominant receptor, such as Cushing's disease.

Marketed under the brand names Signifor (subcutaneous, twice daily) and Signifor LAR (intramuscular depot, monthly), pasireotide is a licensed medicine approved by the MHRA, EMA, and FDA for:

  • Cushing's disease (pituitary ACTH hypersecretion) where surgery has failed or is not an option
  • Acromegaly where first-generation somatostatin analogues (octreotide, lanreotide) are inadequate

Pasireotide represents a second-generation somatostatin analogue and is particularly important as the first medical therapy specifically approved for Cushing's disease — a condition for which treatment options were previously very limited.

Research Summary

Cushing's Disease — Phase 3 RCT

The pivotal evidence comes from the PASSPORT/CSOM230B2309 trial (Colao et al., NEJM, 2012). This Phase 3, double-blind, randomised trial enrolled 162 patients with persistent or recurrent Cushing's disease. Patients received pasireotide 600 µg or 900 µg subcutaneously twice daily.

At 6 months, mean urinary free cortisol (UFC) levels normalised in 15% and 26% of patients in the 600 µg and 900 µg groups, respectively. Among patients with baseline UFC >2× the upper limit of normal, response rates were higher. Clinical benefits included reductions in blood pressure, weight, and LDL cholesterol.

Notably, hyperglycaemia was a significant adverse effect — 73% of patients experienced hyperglycaemia-related adverse events, and 6% developed diabetes. This led to a specific black-box warning for hyperglycaemia.

Acromegaly — Phase 3 RCT

The C2305 trial (Gadelha et al., 2014) randomised 198 patients with inadequately controlled acromegaly (despite first-generation somatostatin analogues) to pasireotide LAR 40 mg or 60 mg monthly, or continued octreotide LAR or lanreotide depot.

At 24 weeks, 15% and 20% of pasireotide LAR patients achieved biochemical control (normal IGF-1 and GH <2.5 µg/L) versus 0% in the active comparator group. This demonstrated that pasireotide can provide benefit in patients resistant to first-generation analogues.

Emerging Research

  • Neuroendocrine tumours: Pasireotide has been investigated in GEP-NETs, particularly in patients refractory to octreotide. The NETTER-1 study evaluated radiolabelled pasireotide derivatives.
  • Cushing's disease paediatric use: Small case series suggest pasireotide is effective in paediatric Cushing's disease, though data are limited.
  • Polycystic ovary syndrome (PCOS): Preclinical and early-phase studies have explored pasireotide's effect on ACTH-mediated androgen excess, though no Phase 3 data exist.

Evidence grade: Strong — supported by Phase 3 RCTs for both Cushing's disease and acromegaly, published in NEJM and peer-reviewed journals.

Commonly Discussed Protocols

All protocols below are documented from clinical trial literature and prescribing information for research reference only. Pasireotide is a licensed POM in the UK and must only be administered under medical supervision.

Cushing's Disease (Subcutaneous)

  • Starting dose: 0.6 mg or 0.9 mg subcutaneously, twice daily
  • Titration: Adjust based on 24-hour urinary free cortisol at 2–3 month intervals (0.3–0.9 mg bid range)
  • Route: Subcutaneous injection
  • Frequency: Twice daily

Cushing's Disease (Intramuscular Depot — investigational)

  • Dose: Signifor LAR 10–30 mg intramuscularly
  • Frequency: Every 4 weeks
  • Note: Signifor LAR is approved for acromegaly, not Cushing's; use in Cushing's is investigational

Acromegaly (Intramuscular Depot)

  • Starting dose: Signifor LAR 40 mg intramuscularly every 4 weeks
  • Titration: Increase to 60 mg after 3 months if inadequate biochemical response
  • Route: Intramuscular injection (gluteal region)
  • Frequency: Every 4 weeks

Stacking

There is no established research literature on combining pasireotide with other peptides. In clinical practice:

  • Pasireotide is used as a second-line agent when first-generation somatostatin analogues (octreotide, lanreotide) have failed — it is not used in combination with them.
  • Combination with cabergoline (dopamine agonist) or pegvisomant (GH receptor antagonist) has been explored in refractory acromegaly, though data are limited.

Storage & Reconstitution

Signifor (subcutaneous)

  • Supplied as single-dose vials of lyophilised powder
  • Storage: Store at 2–8°C (refrigerated). Do not freeze.
  • Reconstitution: Reconstitute with supplied diluent immediately before use. Do not store reconstituted solution.
  • Post-reconstitution: Use immediately; discard unused portion.

Signifor LAR (intramuscular depot)

  • Supplied as a powder and solvent kit for suspension
  • Storage: Store at 2–8°C. Do not freeze.
  • Reconstitution: Reconstitute with supplied diluent immediately before use per manufacturer instructions. The suspension must be homogeneous before administration.
  • Post-reconstitution: Use immediately after reconstitution; do not store.

Blood Work

In clinical practice, the following biomarkers are monitored during pasireotide therapy:

  • 24-hour urinary free cortisol (UFC): Primary efficacy biomarker for Cushing's disease. Measured every 2–3 months during titration.
  • Serum cortisol (morning): Monitored alongside UFC.
  • ACTH: May paradoxically increase during therapy; not used as a sole response marker.
  • Growth Hormone (GH) and IGF-1: Primary biomarkers for acromegaly. Monitored every 3–6 months.
  • Fasting blood glucose / HbA1c / fasting insulin: Critical — pasireotide causes hyperglycaemia in up to 73% of patients. Baseline and ongoing monitoring required; antidiabetic medication is frequently needed.
  • Liver function tests: Monitor periodically for hepatic enzyme elevations.
  • Electrocardiogram (ECG): Monitor for QT prolongation, particularly in patients with risk factors.
  • Gallbladder ultrasound: Annual screening for gallstones (common adverse effect).

UK Legal Status

Pasireotide is a Prescription-Only Medicine (POM) in the UK, licensed by the MHRA for:

  • Cushing's disease (pituitary-dependent) in adults where surgery has failed or is not suitable
  • Acromegaly in adults where response to first-generation somatostatin analogues is inadequate

Supplied as Signifor and Signifor LAR (Novartis). It is available on the NHS for its licensed indications, subject to NICE/SMC approval criteria. Unlicensed supply for human use is illegal. Purchase of non-pharmaceutical-grade pasireotide by research institutions for in vitro or animal studies is legal under research chemical exemptions, but suppliers must not market it for human consumption.

References

References

  1. Colao A, De Block C, Gaztambide MS, et al. Pasireotide for Cushing's disease: 12-month results from PASSPORT/CSOM230B2309. N Engl J Med. 2012;366(10):913-24. doi:10.1056/NEJMoa1105553
  2. Gadelha MR, Kasuki L, Correa LL, et al. Pasireotide LAR vs continued treatment with octreotide LAR or lanreotide depot in acromegaly (C2305). Presented at: Endocrine Society Annual Meeting; 2014. doi:10.1530/endoabs.32.OC1.2
  3. Petersenn S, Fleseriu M, Casanueva FF, et al. Diagnosis and management of Cushing's disease: Pasireotide outcomes. Endocrine. 2016;53(3):655-67. doi:10.1007/s12020-016-0924-6
  4. Schmid HA. Pasireotide: a new somatostatin analogue with broad receptor binding. Mol Cell Endocrinol. 2008;286(1-2):46-53. doi:10.1016/j.mce.2007.09.009
  5. Signifor and Signifor LAR (pasireotide) Summary of Product Characteristics. Novartis. MHRA. Accessed 2025.
  6. Fleseriu M, Biller BM, Findling JW, et al. A phase 3 trial of pasireotide in Cushing's disease. Endocrine Society Abstract OR02-2. 2014.