Controlling Oversecretion and the Disease

Pituitary tumors are the most commonly occurring intracranial neoplasm.1
Acromegaly is characterized by:2,3

    * Chronic hypersecretion of growth factor (GH)
    * Excessive synthesis of insulin-like growth factor 1 (IGF-1)
    * Significant morbidities
    * Increased mortality


Although surgery is first-line therapy in acromegaly, individuals who have had an unsuccessful prior surgery, are unsuitable surgical candidates, or have had a recurrence require medical management.

Current somatostatin analogs are widely used to treat patients with acromegaly, but they have therapeutic limitations:

    * Efficacy is limited in some patients; approximately 30% to 40% of patients fail to achieve biochemical control, ie normalization of GH and IGF-1 levels4
    * Antitumor activity is limited in some patients; approximately 37% achieve a significant reduction in tumor volume5,6
    * Resistance to somatostatin-analog therapy may rarely occur due to the selective loss of the SST2 receptor which is the primary target of current anlaogs7

    [Acromegaly: Controlling Oversecretion and the Disease]

Somatostatin Receptor Expression and Targeting
Analysis of somatostatin-receptor expression in cells from GH-secreting adenomas has shown that:8,9

    * 96% express SST2
    * 86% express SST5
    * 44% express SST1 and SST3
    * Antisecretory effects for GH are regulated by SST1, SST2, and SST5

Current somatostatin analogs bind with high affinity to only 1 of the 5 somatostatin receptors.10 Tumor-specific receptor expression profiles and the multiple signaling pathways regulating secretory function may explain why current somatostatin analogs sometimes fail to induce biochemical control in acromegaly. This is supported by data from a study of patients with acromegaly.7 Analysis of tumor tissue from patients who demonstrated a <50% reduction in GH level when treated with octreotide had no detectable SST2.7
Because of its rational design, pasireotide:10

    * Binds to 4 of the 5 somatostatin receptors
    * Does not bind significantly to other receptor families
    * Potentially activates more receptor-regulated pathways than current analogs
    * May provide improved biochemical and disease control in acromegaly

Pasireotide in Acromegaly: A Phase II Study
In a phase II study of patients with de novo or persistent active acromegaly, after 3 months of therapy with pasireotide:11

    * 56% achieved GH levels of < 2.5 µg/L
    * 49% had normalized sex- and age adjusted IGF-1 levels
    * 39% achieved GH levels of = 2.5 µg/L and normalized sex- and age adjusted IGF-1 levels
    * 39% achieved a > 20% reduction in tumor volume by serial MRI

[Pasireotide in Acromegaly: A Phase II Study]
From Glusman JE, et al.11

PASPORT Acromegaly

PASPORT Acromegaly, part of the PASPORT clinical trial research program, is evaluating the safety and efficacy of pasireotide in patients with active acromegaly. This study is designed as a registration trial for pasireotide in acromegaly.