Pasireotide

Overview

Unlike first-generation analogs that act mainly through SSTR2, pasireotide (marketed as Signifor and Signifor LAR) binds SSTR1, 2, 3, and 5 with especially strong SSTR5 affinity. Because corticotroph (ACTH-secreting) pituitary tumors express high levels of SSTR5, pasireotide can directly suppress ACTH secretion, addressing the pituitary source of Cushing's disease rather than only its downstream cortisol effects.

In the pivotal 12-month phase 3 study, pasireotide reduced urinary free cortisol and improved clinical signs and symptoms of Cushing's disease, becoming the first pituitary-directed medical therapy for the condition. It is also used in acromegaly, where its broad receptor coverage can control GH/IGF-1 in patients inadequately controlled on other somatostatin analogs.

A distinguishing safety issue is hyperglycemia: pasireotide suppresses insulin and incretin secretion more than other analogs, so treatment-related hyperglycemia and diabetes are common and require monitoring, alongside gallstones and gastrointestinal effects.

Mechanism of Action

The broad receptor-binding profile lets pasireotide engage tumors that are unresponsive to SSTR2-selective analogs. SSTR5 activation on ACTH-secreting corticotroph adenomas reduces ACTH output and hence cortisol production, while SSTR2/5 activation in somatotroph adenomas lowers GH/IGF-1. The same receptor engagement in pancreatic islets and gut suppresses insulin, GLP-1, and GIP, which explains why hyperglycemia is a characteristic and frequently dose-limiting adverse effect.

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