Mechanism
Pasireotide is a synthetic cyclohexapeptide analog of somatostatin. The structural design produces a distinct receptor-binding profile from first-generation analogs:
| Receptor | Native somatostatin | Octreotide | Pasireotide |
|---|---|---|---|
| SSTR1 | High | Negligible | High |
| SSTR2 | High | High | Moderate |
| SSTR3 | High | Low | High |
| SSTR4 | High | Negligible | Low |
| SSTR5 | High | Moderate | Very high |
The high SSTR5 affinity is the clinically distinctive feature. Corticotroph adenomas (Cushing’s disease) preferentially express SSTR5 and SSTR2; the broader binding allows pasireotide to suppress ACTH secretion in these tumors when SSTR2-only agents fail.
The trade-off: SSTR5 activation in pancreatic beta cells suppresses insulin secretion more than SSTR2-only activation does. Combined with retained SSTR2-mediated suppression of incretin signaling, this drives the characteristic hyperglycemia adverse-event signal.
Half-life: ~12 hours subcutaneous (Signifor IR), ~28 days for LAR depot.
What the evidence shows
Phase 3 in Cushing’s disease (Colao et al, NEJM 2012): 162 patients with persistent or recurrent Cushing’s disease randomized to pasireotide 600 mcg or 900 mcg subcutaneous twice daily. At 6 months, urinary free cortisol normalization in ~26% (900 mcg) vs ~15% (600 mcg). Modest but meaningful — for patients with no good alternatives, this is the option that works when others don’t.
Phase 3 in acromegaly (PAOLA, Gadelha et al, Lancet Diabetes Endocrinol 2014): Pasireotide LAR vs continued octreotide LAR or lanreotide Autogel in patients inadequately controlled on first-line. ~31% achieved biochemical control on pasireotide LAR vs ~19% on continued first-line — meaningful incremental efficacy in the resistant population.
SOM230 trials, multi-year extension data: Long-term efficacy maintained; hyperglycemia adverse-event signal also persists.
The evidence supports a clear positioning: second-line for Cushing’s disease (after surgery/radiation) and acromegaly (after first-gen somatostatin analog failure). Not a first-line drug.
Dosing literature
Approved dosing varies by indication and formulation:
- Cushing’s disease (Signifor IR): 600 mcg or 900 mcg subcutaneous twice daily; titrate to cortisol response
- Cushing’s disease (Signifor LAR): 10 mg, 20 mg, or 30 mg every 4 weeks
- Acromegaly (Signifor LAR): 40 mg or 60 mg every 4 weeks
Glucose monitoring is required at baseline and during therapy — fasting glucose, HbA1c, oral glucose tolerance test as clinically indicated.
Risks and adverse events
Major:
- Hyperglycemia / new-onset diabetes — affects ~70% of patients to some degree; new-onset diabetes ~40% in Cushing’s trials. Often requires concomitant glucose-lowering therapy (metformin, DPP-4 inhibitors, GLP-1 agonists, insulin)
- GI effects — diarrhea, nausea, abdominal pain (class effect, similar to first-gen somatostatin analogs)
- Cholelithiasis — class effect
Less common:
- QT prolongation (modest; ECG monitoring at therapy initiation)
- Hepatic enzyme elevations
- Bradycardia
- Hypothyroidism with chronic use
Practical note: The hyperglycemia is dose- and time-dependent. Patients with pre-existing diabetes or impaired fasting glucose are at higher risk and should be counseled and monitored intensively. The safety profile is what positions pasireotide as second-line — its activity advantage is real but only worth the trade-off when first-line therapy has failed.
Regulatory status
| Region | Status | Notes |
|---|---|---|
| United States | Approved (Signifor, Signifor LAR) | For Cushing’s disease (resistant to surgery) and acromegaly (resistant to first-line) |
| European Union | Approved | Same indications |
| United Kingdom | Approved | NHS access via specialized commissioning |
| Most major markets | Approved |
Manufacturer: Recordati Rare Diseases (acquired from Novartis 2020).
Where to get it
Through specialized endocrinology — typically pituitary or adrenal-disease centers. Specialty pharmacy distribution; cost is significant ($30,000+ per year US list).
We have no fulfillment partner for pasireotide. (See How we make money.)
References (selected)
- Colao A et al. A 12-month phase 3 study of pasireotide in Cushing’s disease. N Engl J Med 2012. PubMed
- Gadelha MR et al. Pasireotide versus continued treatment with octreotide or lanreotide in patients with inadequately controlled acromegaly (PAOLA): a randomised, phase 3 trial. Lancet Diabetes Endocrinol 2014.
- Schmid HA et al. Pasireotide (SOM230): development, mechanism of action and potential applications. Mol Cell Endocrinol 2008.
- Pivonello R et al. The medical treatment of Cushing’s disease: effectiveness of chronic treatment with the dopamine agonist cabergoline in
Quick Facts
| Also Known As | SOM230, Signifor, SOM-230 |
|---|---|
| Sequence | H-D-Phe-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr(ol) (cyclic disulfide bridge between Cys2 and Cys7) |
| Molecular Formula | C58H66N10O9 |
| Molecular Weight | 1047.2 Da |
| PubChem CID | 9941444 |
Research Parameters
| Half-Life | ~12 hours (subcutaneous); ~28 days (long-acting release, LAR, formulation) |
|---|---|
| Stability | Lyophilized powder is stable when stored as directed. After reconstitution of the immediate-release formulation, chemical and physical stability has been demonstrated for 24 hours at 25°C or 28 days at 2-8°C. The LAR formulation is a suspension for intramuscular injection. |
| Solubility | Sterile Water for Injection (for immediate-release subcutaneous formulation). The powder is reconstituted per manufacturer instructions. |
| Storage (Lyophilized) | Store unopened vials at 2-8°C. Protect from light. |
| Storage (Reconstituted) | For the immediate-release solution: Store at 2-8°C and use within 28 days. Do not freeze. For the LAR suspension: Use immediately after preparation. |
| Typical Research Dose | 600-900 mcg (0.6-0.9 mg) subcutaneously twice daily (clinical research doses for Cushing's disease). |
| Cycle Parameters | Chronic, continuous administration in clinical studies for management of Cushing's disease and acromegaly, often with dose titration based on biomarker response. |
| Amino Acid Count | 11 |
Mechanism of Action
Pasireotide exerts its effects by mimicking the endogenous hormone somatostatin, binding with high affinity to somatostatin receptors (SSTRs) and inhibiting excessive hormone secretion and cell proliferation.
Binding Profile: Pasireotide binds with high affinity to four of the five known somatostatin receptor subtypes (SSTR1, 2, 3, and 5). Its particularly strong binding to SSTR5 is a key differentiator from older analogues.
Inhibition of Hormone Secretion: Upon binding to SSTRs, primarily on pituitary and neuroendocrine cells, it activates inhibitory G-proteins (Gi/Go). This leads to inhibition of adenylate cyclase, reduced intracellular cAMP levels, and decreased calcium influx, ultimately suppressing the secretion of hormones like growth hormone, insulin, glucagon, IGF-1, and ACTH.
Antiproliferative Effects: Through SSTR-mediated activation of protein tyrosine phosphatases (PTPs), pasireotide can inhibit mitogenic signaling and induce cell cycle arrest and apoptosis in certain tumor cell types.
Secondary Effects: It also reduces blood flow to tumors by inhibiting the release of vasoactive peptides and can modulate immune cell function via SSTRs expressed on lymphocytes.
Research Applications
Cushing's Disease: Pasireotide is a first-line medical therapy for Cushing's disease, where it directly targets the pituitary adenoma to suppress pathological ACTH secretion, leading to reduced cortisol levels and clinical improvement.
Acromegaly: Research demonstrates its efficacy in patients with acromegaly who are inadequately controlled by first-generation somatostatin analogues, often due to its broader receptor binding profile, including SSTR5.
Neuroendocrine Tumors (NETs): Studies investigate its use in various NETs (e.g., pancreatic, carcinoid) for symptom control and antiproliferative effects, leveraging its affinity for multiple SSTR subtypes commonly expressed in these tumors.
Polycystic Liver Disease (PLD): Clinical research has shown pasireotide can reduce liver volume and cyst growth in PLD associated with autosomal dominant polycystic kidney disease, likely by inhibiting cAMP-driven fluid secretion in cholangiocytes.
Safety & Side Effects
The safety profile is well-characterized from clinical trials. Common side effects are related to its antisecretory effects and include hyperglycemia/diabetes mellitus (due to inhibition of insulin secretion), diarrhea, nausea, abdominal pain, cholelithiasis, and injection site reactions. Hypoglycemia is less common. Bradycardia and QT interval prolongation have been reported. The hyperglycemia is a significant and frequent adverse event requiring monitoring and management. Theoretical concerns include the potential for pituitary hormone deficiencies with long-term use due to broad SSTR inhibition.
Dosage Information
This information is derived from published clinical research and is for educational purposes only. In clinical studies for Cushing's disease, the typical starting dose is 0.6 mg or 0.9 mg administered subcutaneously twice daily. Dose titration is based on urinary free cortisol response. For acromegaly, doses of 0.4 mg or 0.6 mg administered subcutaneously twice daily have been used. A long-acting release (LAR) intramuscular formulation (Signifor LAR) is administered at doses of 20 mg, 40 mg, or 60 mg every 28 days. Treatment duration in studies often extends for several months to years for chronic management.
References
Colao, A., et al. 'A 12-month phase 3 study of pasireotide in Cushing's disease.' The New England Journal of Medicine, vol. 366, pp. 914-924, 2012.
Petersenn, S., et al. 'Pasireotide (SOM230) demonstrates efficacy and safety in patients with acromegaly: a randomized, multicenter, phase II trial.' The Journal of Clinical Endocrinology & Metabolism, vol. 95, no. 6, pp. 2781-2789, 2010.
Schmid, H.A., 'Pasireotide (SOM230): development, mechanism of action and potential applications.' Molecular and Cellular Endocrinology, vol. 286, no. 1-2, pp. 69-74, 2008.
Boscaro, M., et al. 'Extended treatment of Cushing's disease with pasireotide: results from a 2-year, phase II study.' Pituitary, vol. 17, no. 4, pp. 320-326, 2014.
Gadelha, M.R., et al. 'Pasireotide versus continued treatment with octreotide or lanreotide in patients with inadequately controlled acromegaly (PAOLA): a randomised, phase 3 trial.' The Lancet Diabetes & Endocrinology, vol. 2, no. 11, pp. 875-884, 2014.
van Aerts, R.M.M., et al. 'Lanreotide reduces liver growth in patients with autosomal dominant polycystic liver and kidney disease.' Gastroenterology, vol. 157, no. 2, pp. 481-491, 2019.