Pasireotide

In plain language

Pasireotide is an injected drug for two rare hormonal diseases: Cushing's disease (when the body makes too much cortisol) and acromegaly (too much growth hormone). It is sold as Signfora in the U.S. (Somactul in Europe).

It is a cousin of octreotide but built as a ring of six amino acids that binds to four of the five receptor types that somatostatin uses, letting it suppress hormones that octreotide cannot. Its main drawback is that it raises blood sugar and can slow the heart.

For students

Pasireotide is a cyclic hexapeptide somatostatin analogue (about 1,047 Da) that, unlike octreotide (selective for SSTR2 and SSTR5), binds SSTR1, 2, 3 and 5 with useful affinity. In corticotroph pituitary adenomas, SSTR2 is downregulated and SSTR5 is expressed, which is why pasireotide can suppress ACTH where octreotide fails.

The PAOLA extension of the SOM230 (SOM-230-B2205) trial established that twice-daily pasireotide normalizes urine free cortisol in a subset of Cushing's disease patients who cannot have surgery; hyperglycemia is a signature effect (via incretin and glucagon suppression), managed with GLP-1 agonists or DPP-4 inhibitors. Approved in 2012 for Cushing's disease and in 2014 for acromegaly patients who respond inadequately to surgery or another somatostatin analogue, it also carries warnings for bradycardia and QT prolongation, cholelithiasis, and injection-site reactions.

For researchers and instructors

Biochemistry. Receptor-subtype selectivity engineering within the somatostatin pharmacophore is the lesson: the Phe-Trp-Lys-Thr core is conserved while flanking residues tune SSTR1/3/5 engagement; this is the counterpoint to octreotide's SSTR2/5 profile.

Pharmacology. Twice-daily 0.6 or 0.9 mg subcutaneous injection or monthly intramuscular depot for acromegaly; hyperglycemia management is a labeled consideration with GLP-1 receptor agonists recommended first-line.

Human evidence. SOM230-B2205 (n=162) and PAOLA (n=58) showed UFC normalization in 15-26% at 6-12 months; PAOLA showed 5-year safety; acromegaly approval rested on head-to-head data versus lanreotide with pasireotide superior on GH and IGF-1 control.

Teaching point. Teaches how receptor subtype expression in a disease (SSTR5 in corticotrophs) can be exploited by redesigning a known pharmacophore.