Profile of pegvisomant in the management of acromegaly: an evidence based review of its place in therapy

Abstract

Pegvisomant (PEG) is a genetically engineered growth hormone (GH) analog able to bind and block the GH receptor. PEG blocks all metabolic effects of GH hypersecretion, normalizes insulin-like growth factor I (IGF-I) level and paradoxically produces an increase in GH secretion. When PEG was commercialized, there were some concerns regarding whether the increased GH secretion could cause growth of the residual tumor or cause the overcoming of receptor blockade with loss of efficacy. PEG commercialization was followed by the onset of two main prospective observational studies aiming to evaluate the safety and outcome of PEG long-term treatment: the German Pegvisomant Observational Study and ACROSTUDY. These observational studies, along with several independent studies have provided comprehensive information regarding the actual use, efficacy and safety of long-term treatment with PEG. The efficacy of PEG in clinical setting is somewhat lower than that reported in the pivotal studies, nevertheless PEG normalizes IGF-I levels ranging between 65% and 97% of cases. Side effects in observational studies were uncommon and rarely caused discontinuation of treatment. Liver dysfunction developed in 2.5% of cases, was usually transient and no permanent liver damage was reported. Increased tumor size was developed by about 2.2%-3.2% of acromegalic patients treated with PEG, without differences to that described for other modalities of treatment. Only one third of cases corresponded with true growth after initiation of PEG treatment. Involved mechanism is currently unknown. New modalities of treatments by the combined use of PEG with somatostatin analog or cabergoline have been developed with promising results. Recently, two clinical guidelines written to optimize the use of these treatment modalities and to monitor possible adverse events have been published. Keywords: acromegaly, pegvisomant, pituitary tumor, somatostatin analogs, cabergoline, IGF-I Profile of pegvisomant (PEG) in the management of acromegaly: an evidence based review of its place in therapy Acromegaly is a rare and chronic disease, which in more than 95% of cases is caused by a benign growth hormone (GH)-producing pituitary adenoma, determining an increased production of IGF-I. The clinical picture includes typical somatic changes, multiple general and local comorbidities (metabolic, endocrine, vascular, oncologic, neurologic, ophthalmologic, etc) and an increased mortality that can be corrected by optimal treatment.

Long‐term treatment with pegvisomant for acromegaly: a 10‐year experience

“…Escape to PEG has been previously reported, but, to our knowledge, there is no precise and specific definition for this phenomenon in the literature, and it has not been fully characterized. Several factors recently reviewed may influence the required PEG dose and could be related to the development of escapes to PEG, including sex, weight, baseline GH and IGF‐I levels, previous radiotherapy, diabetes mellitus, GH‐receptor (GHR) genotype and/or IGF‐I and IGFBP3 polymorphisms. Additionally, the progressive clearance of previous SSA treatments, long‐term changes in GH and GHBP levels or modifications in GHR expression induced by treatments could also promote the need for increasing doses of PEG.…”

“…Several reasons for this lower than expected efficacy of PEG in observational studies have been recently outlined . For instance, problems with dose titration or compliance, change in the IGF‐I measuring method, temporary loss of IGF‐I control requiring dose adjustments or the use of different criteria to assess IGF‐I normalization in preclinical versus observational and clinical studies (IGF‐I normalization at any time versus IGF‐I normalization at last evaluation) have been identified.…”

“…14 Several reasons for this lower than expected efficacy of PEG in observational studies have been recently outlined. 15 For instance, problems with dose titration or compliance, change in the IGF-I measuring method, temporary loss of IGF-I control requiring dose adjustments or the use of different criteria to assess IGF-I normalization in preclinical versus observational and clinical studies (IGF-I normalization at any time versus IGF-I normalization at last evaluation) have been identified. The loss of PEG effect during long-term treatment, which has been reported as 'escape to PEG', [9][10][11]13 has been found to be more frequent in patients who did not undergo radiotherapy, 10 and in patients who developed lipohypertrophy at the injection site.…”

Pegvisomant: uso clínico en pacientes con acromegalia

“…El GHR está conformado por un dominio N-terminal que contiene la región extracelular donde se une la hormona, un dominio transmembrana hidrófobo y un dominio C-terminal que contiene estructuras importantes en la señalización intercelular (19,21). El receptor se elimina mediante su degradación proteolítica y un proceso continuo de internalización dependiente de ubiquitina y degradación endolisosómica (29). La escisión proteolítica del dominio extracelular genera GHBP (19,23) y aunque su función no es clara, se considera que funciona como un reservorio de GH, modula su actividad al competir con el GHR (19), reduce la tasa de eliminación (17) y sirve como marcador de la renovación de GHR (20).…”

“…El GHR carece de actividad quinasa intrínseca, por lo cual induce al reclutamiento y la activación de tirosinas-quinasas citoplasmáticas para la señalización, como Janus quinasa 2 (JAK2) (17,19), constituyendo así la más utilizada por el GHR (19). Esta unión desencadena la fosforilación de la quinasa 2 de Janus (JAK2) que induce al reclutamiento y la posterior fosforilación de STATs -1, -3, -5a y -5b (transductores de señal y activadores de la transcripción) (21,29,31). Posteriormente, las STAT fosforiladas se disocian del receptor y se translocan al núcleo, donde se unen a una secuencias de ADN específicas y activan la transcripción de genes sensibles a GH (figura 1) (19,29).…”