Pasireotide

What is Pasireotide?

Pasireotide (brand names SIGNIFOR twice-daily SC and SIGNIFOR LAR once-monthly IM; development code SOM230) is a synthetic cyclohexapeptide somatostatin analogue with a distinctive multi-receptor binding profile that distinguishes it from older somatostatin analogues like octreotide and lanreotide. It was approved by the FDA on December 14, 2012 for Cushing's disease and on December 15, 2014 as a long-acting release (LAR) formulation for acromegaly.

Pasireotide is the only somatostatin analogue approved for Cushing's disease, where its strong SSTR5 affinity is mechanistically critical.

Structure

Pasireotide is a cyclic hexapeptide built on a rigid 6-residue scaffold designed to mimic the biologically active β-turn region of native somatostatin-14. Synthetic D-amino acids and unnatural amino acid building blocks confer:

• Resistance to enzymatic degradation
• Defined three-dimensional structure
• Distinctive multi-receptor binding profile spanning SSTR1, SSTR2, SSTR3, and SSTR5

This contrasts with the SSTR2-selective binding of octreotide and lanreotide.

Mechanism of Action

Five somatostatin receptor subtypes (SSTR1-5) are differentially expressed across tumor types:

Pasireotide's relative receptor binding (SSTR5 > SSTR2 > SSTR3 > SSTR1) makes it uniquely effective for ACTH-secreting pituitary adenomas, which express predominantly SSTR5 — a receptor that octreotide and lanreotide bind only weakly.

In Cushing's disease, pasireotide-mediated SSTR5 activation suppresses ACTH secretion from the corticotroph adenoma, restoring normal cortisol levels and reversing Cushing's syndrome.

Clinical Evidence

Phase 3 in Cushing's disease (NEJM 2012):

• 162 patients with persistent or recurrent Cushing's disease, randomized to pasireotide 600 µg or 900 µg twice daily for 12 months
• Urinary free cortisol normalization at 6 months: 14.6% (600 µg) and 26.3% (900 µg) — vs 0% baseline; statistically significant
• Significant reductions in body weight, blood pressure, LDL, and clinical signs of Cushing's syndrome

Phase 3 in acromegaly (Lancet D&E 2014):

• 358 inadequately controlled acromegaly patients on octreotide LAR or lanreotide, switched to pasireotide LAR
• Biochemical control (GH<2.5 µg/L AND IGF-1 normalization): superior to staying on octreotide LAR

Approval History

• December 14, 2012 — FDA approval for Cushing's disease (Signifor SC, twice daily)
• December 15, 2014 — FDA approval for acromegaly (Signifor LAR, monthly IM)
• April 2012 — EMA approval (Cushing's first)

Place in Therapy

In Cushing's disease, pasireotide is the only somatostatin analogue with proven efficacy and is positioned as a medical option after surgical failure or in non-surgical candidates. Alternatives include adrenal-targeted drugs (ketoconazole, metyrapone, mitotane, osilodrostat), pituitary-targeted cabergoline, or repeat surgery/radiation.

In acromegaly, pasireotide LAR is reserved for patients inadequately controlled on octreotide LAR or lanreotide, given its higher cost and worse glycemic side-effect profile.

Safety Profile

The major safety concern unique to pasireotide is hyperglycemia — both worsening of pre-existing diabetes and new-onset diabetes:

• SSTR5 activation suppresses insulin secretion (in addition to suppressing GH/ACTH/IGF-1)
• Up to 40-50% of pasireotide-treated patients experience clinically significant hyperglycemia
• Most can be managed with metformin, GLP-1 analogues, or insulin
• This is a class effect distinct from the milder hyperglycemia seen with octreotide/lanreotide

Other adverse events: cholelithiasis (class effect), bradycardia, GI upset, fatigue.

Distinction from Octreotide and Lanreotide