Pasireotide (Signifor)

Benefits

About Pasireotide (Signifor)

Pasireotide is a second-generation cyclohexapeptide somatostatin analog approved by the FDA in December 2012 for the treatment of Cushing's disease in adults who cannot undergo pituitary surgery or for whom surgery has failed, and subsequently in 2014 as a long-acting release (LAR) formulation for acromegaly in patients who have had an inadequate response to first-generation somatostatin analogs like octreotide and lanreotide. What distinguishes pasireotide from earlier somatostatin analogs is its unique receptor binding profile. While octreotide and lanreotide bind primarily to SSTR2, pasireotide has 30- to 40-fold higher affinity for SSTR5, 5-fold higher affinity for SSTR1, and 2-fold higher affinity for SSTR3, in addition to comparable SSTR2 binding. This broad-spectrum receptor engagement is clinically significant because corticotroph adenomas in Cushing's disease predominantly express SSTR5, making pasireotide the first medical therapy to directly target the pituitary tumor and normalize urinary free cortisol levels. In the pivotal Phase III trial for Cushing's disease, pasireotide 600-900 mcg SC twice daily normalized urinary free cortisol (UFC) in approximately 26% of patients at 6 months, with meaningful UFC reductions in over 50% of participants. For acromegaly, the PAOLA study demonstrated that Signifor LAR 40-60 mg monthly achieved biochemical control (GH < 2.5 mcg/L and normal IGF-1) in 31.3% of patients who had failed first-generation somatostatin analogs. The primary clinical limitation is hyperglycemia, which occurs in approximately 73% of patients and is related to pasireotide's suppression of insulin and incretin secretion through SSTR5. This often necessitates initiation or intensification of antidiabetic therapy.

Who Should Consider Pasireotide (Signifor)

• Adults with Cushing's disease for whom pituitary surgery is not an option or has not been curative
• Patients with acromegaly who have had inadequate response to first-generation somatostatin analogs
• Individuals with persistent or recurrent Cushing's disease after transsphenoidal surgery
• Acromegaly patients with tumors expressing predominantly SSTR5 rather than SSTR2
• Patients requiring bridging therapy before or after pituitary radiation therapy

How Pasireotide (Signifor) Works

Pasireotide is a cyclohexapeptide somatostatin analog that binds to all five somatostatin receptor subtypes (SSTR1-5), which are G protein-coupled receptors. Its binding profile differs markedly from first-generation analogs: it has 30- to 40-fold higher affinity for SSTR5 (IC50 ~0.16 nM), 5-fold higher affinity for SSTR1 (IC50 ~9.3 nM), 2-fold higher affinity for SSTR3 (IC50 ~1.5 nM), and comparable affinity for SSTR2 (IC50 ~1.0 nM) compared to octreotide. In Cushing's disease, the mechanism centers on SSTR5 engagement. Corticotroph adenomas predominantly express SSTR5, and pasireotide binding activates Gi/Go-coupled inhibitory signaling, reducing cAMP accumulation and suppressing POMC gene transcription and ACTH secretion. This directly lowers adrenal cortisol production. The drug also has antiproliferative effects on corticotroph tumor cells through activation of phosphotyrosine phosphatases (SHP-1, SHP-2) and downstream inhibition of the MAPK/ERK proliferative pathway. In acromegaly, pasireotide suppresses GH secretion via SSTR2 and SSTR5 on somatotroph adenomas. The dual-receptor engagement provides an advantage in tumors with reduced SSTR2 expression that are resistant to octreotide or lanreotide. The hyperglycemic effect is mechanistically linked to SSTR5 suppression of insulin secretion from pancreatic beta cells and inhibition of incretin hormones (GLP-1 and GIP) from enteroendocrine cells, while SSTR2-mediated glucagon suppression is relatively weaker with pasireotide, creating a net diabetogenic effect.

What to Expect

Dosing Protocol

Note: Pasireotide is an FDA-approved somatostatin analog with uniquely broad receptor affinity, binding all five somatostatin receptor subtypes (SSTR1-5) with highest affinity for SSTR5. Available as Signifor (SC injection, 600-900 mcg twice daily) for Cushing's disease and Signifor LAR (IM injection, 10-40 mg every 28 days) for acromegaly. Supplied as a pre-filled solution — no reconstitution with bacteriostatic water is needed. Hyperglycemia is extremely common (up to 73% of patients) and often requires antidiabetic therapy; blood glucose monitoring is mandatory before and during treatment. This is a prescription medication and should only be used under medical supervision.

How to Inject Pasireotide (Signifor)

Signifor SC (Cushing's disease): Starting dose is 600 mcg subcutaneously twice daily, injected in the abdomen or thigh. Rotate injection sites to minimize local reactions. If not tolerated, dose may be reduced to 300 mcg twice daily. If UFC remains above 2x ULN after 2 months, increase to 900 mcg twice daily. Administer doses approximately 12 hours apart. Signifor LAR (acromegaly): Starting dose is 40 mg IM every 28 days, administered as a deep intraglutal injection by a healthcare provider. Blood glucose monitoring is required before starting, weekly for the first 2-3 months, then periodically. ECG at baseline and after 21 days. Gallbladder ultrasound at baseline and every 6-12 months.

Cycling Protocol

Pharmacokinetics

Side Effects

Hyperglycemia is the most prominent side effect, occurring in approximately 73% of patients and frequently requiring antidiabetic therapy (metformin as first-line, DPP-4 inhibitors or GLP-1 receptor agonists preferred). Diarrhea (58%), nausea (52%), abdominal pain (24%), and cholelithiasis/gallstones (30%) are common GI effects. Injection site reactions occur in approximately 17% of patients. QT prolongation has been observed and requires ECG monitoring. Hepatic enzyme elevations (ALT/AST) occur in 5-10% of patients. Bradycardia and adrenal insufficiency (in Cushing's disease patients whose cortisol drops too rapidly) are important to monitor. Fatigue, headache, and decreased appetite are frequently reported.

Contraindications

Drug Interactions

Storage & Stability

Molecular Profile

Related Peptides

Octreotide (Sandostatin)

Metabolic

Lanreotide (Somatuline Depot)

Metabolic

Somatostatin (SST-14 and SST-28)

Metabolic

References

1. Pasireotide treatment significantly reduces tumor volume in Cushing's disease (Phase III)PubMed 22031513
2. A 12-month Phase 3 study of pasireotide in Cushing's diseasePubMed 22455413
3. Pasireotide vs octreotide/lanreotide in acromegaly (PAOLA trial)PubMed 25002177
4. Hyperglycemia associated with pasireotide: management and mechanismPubMed 23471042
5. Pasireotide: a novel somatostatin receptor ligand for acromegaly and Cushing's diseasePubMed 22770986
6. Signifor (pasireotide) FDA Prescribing InformationFDA Label