Pasireotide in Acromegaly: An Overview of Current Mechanistic and Clinical Data

Abstract

Background: Acromegaly is an insidious neuroendocrine disorder caused by hypersecretion of growth hormone (GH) by a somatotroph adenoma. Somatostatin receptor ligands (SRLs) are recommended as first-line medical therapy in patients for whom surgery has failed or is contraindicated. There are 5 known somatostatin receptor subtypes (SSTRs), 2 of which, i.e. SSTR2 and SSTR5, are expressed by a majority of somatotroph adenomas. The currently available SRLs, i.e. octreotide and lanreotide, primarily bind to SSTR2. Pasireotide (SOM230) is a new multireceptor-targeted SRL which has a broader binding profile and an increased affinity for SSTR1, 2, 3, and 5. Methods: PubMed searches were performed to identify all of the available published English language data on pasireotide with regard to the mechanism of action, in vitro effects, and clinical data. Results: Preclinical studies have demonstrated that pasireotide has a broader range of functional activity than octreotide. Recently, the efficacy of pasireotide in attenuating GH and insulin-like growth factor 1 (IGF-1) levels in patients with acromegaly has been evaluated in phase III clinical trials. Pasireotide demonstrated superiority over octreotide in achieving biochemical control (i.e. GH ≤2.5 µg/l and age- and sex-matched IGF-1 normalization) in patients with acromegaly, as well as significant efficacy in treating patients who were previously inadequately controlled on the maximum allowed doses of octreotide and lanreotide. Pasireotide-induced hyperglycemia was the most concerning adverse event but was reversible upon discontinuation of pasireotide. Conclusion: The clinical data support pasireotide as a promising new therapy for the treatment of acromegaly, and the long-acting formulation was recently approved in the US and Europe for the treatment of acromegaly.

Pasireotide in an insulin-requiring diabetic acromegalic patient without worsening of hyperglycemia

“…Although pasireotide, octreotide and lanreotide are all SSAs with a similar mechanism of action, their affinities for different somatostatin receptors vary. Notably, compared with other approved SSAs, pasireotide binds with greatest affinity to sst 5 , which is expressed in 86% of the tumors (4). …”

“…Medical treatment options are available for patients with recurrent disease after surgery, who are poor candidates for surgery, or who refuse surgery, including somatostatin analogs (SSAs) that exert pharmacological activity via binding to somatostatin receptors (2, 3). There are 5 subclasses of somatostatin receptors (sst 1–5 ) that, when activated, inhibit the release of a variety of hormones, including GH and insulin (4). …”

“…After beginning pasireotide treatment, mean fasting plasma glucose (FPG) and glycated hemoglobin (HbA 1c ) levels initially increased and then quickly stabilized for up to 26 months (7). Pasireotide has a higher affinity for sst 5 (4), a key regulator of insulin secretion in the pancreas (3), than other SSAs. A randomized, open-label study in healthy volunteers demonstrated that pasireotide-associated hyperglycemia was caused by a decrease in insulin secretion, not by a decrease in insulin sensitivity (8).…”

Acromegalia

“…Uno de ellos es dirigido a disminuir y/o bloquear los efectos de la hormona de crecimiento a nivel periférico (el antagonista del receptor de hormona de crecimiento llamado Pegvisomant). 19,20,21…”

“…Han surgido datos de resultados de los ensayos clínicos que respaldan la eficacia y seguridad de pasireótido en pacientes con acromegalia. 21 Los estudios enfocados en la eficacia y seguridad a largo plazo (más de 3 años) de los análogos de somatostatina han tenido resultados reconfortantes. Se puede considerar disminuir la dosis o reducir la frecuencia de administración en pacientes que los necesitan durante un periodo prolongado para el control de la acromegalia; sin embargo se deben evaluar a intervalos regulares para asegurar el mantenimiento del efecto terapéutico.…”