Discovery and mechanism of action of pegvisomant

Kopchick, John J.

doi:10.1530/eje.0.148s021

Cited by 43 publications

(29 citation statements)

References 25 publications

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“…Pegvisomant is a GH analogue that binds to GH receptors on the cell surface, and blocks GH-receptor dimerisation. Thereby it inhibits GH activation of the cell, including IGF-I production (6,7). The target of pegvisomant therapy is peripheral GH effects, and the efficacy of treatment is independent of tumour characteristics, such as the density and subtype of somatostatin and dopamine receptors.…”

Section: Discussionmentioning

confidence: 99%

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Pegvisomant therapy in pituitary gigantism: successful treatment in a 12-year-old girl

Rix¹,

Laurberg²,

Hoejberg³

et al. 2005

eur j endocrinol

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Objective: The use of a growth hormone (GH) receptor antagonist, pegvisomant has shown great promise in adults with acromegaly, but experience in paediatric patients is lacking. We aimed to describe the results of pegvisomant therapy in a 12-year-old girl with an aggressive GH-secreting pituitary tumour. Design: To evaluate the ability of pegvisomant therapy to control the effects of peripheral GH excess in a case of pituitary gigantism. Methods: Pegvisomant was introduced at 10 mg/day, given subcutaneously, and gradually increased to 20 mg/day until serum IGF-I was normal for age. Results: A large pituitary adenoma with suprasellar extension was diagnosed in a 12-year-old girl with progressive tall stature (178 cm), GH hypersecretion without suppression during oral glucose loading (nadir serum GH, 90 mU/l), high serum IGF-I and serum prolactin levels. Surgical extirpation was not possible because tumour tissue was fibrous and adherent to the optical nerves. Histological examination showed a mixed GH-and prolactin-secreting adenoma with lymphocytic infiltration of B and T cells. Treatment with a dopamine agonist, cabergoline, normalized serum prolactin, but GH secretion was resistant to both somatostatin analogue, octreotide and cabergoline. Radiation followed by pegvisomant therapy titrated up in dose to 20 mg/day led to a marked reduction in GH secretion and normalization of IGF-I, and to growth arrest and improvement of well-being. Conclusions: We suggest that treatment in pituitary gigantism with pegvisomant is safe and may normalize IGF-I levels and effectively stop growing.

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Section: Discussionmentioning

confidence: 99%

“…Medical therapy has taken on a more important role in the management of patients with GH excess with development of somatostatin analogues and dopamine agonists. Recently a novel GH receptor antagonist, pegvisomant (6,7) has shown great promise in adults with acromegaly (8,9), but experience in paediatric patients is lacking.…”

Section: Introductionmentioning

confidence: 99%

Pegvisomant therapy in pituitary gigantism: successful treatment in a 12-year-old girl

Rix¹,

Laurberg²,

Hoejberg³

et al. 2005

eur j endocrinol

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“…Pegvisomant is the only drug in the GHR antagonist class and acts by binding to the GHR without triggering its intracellular pathways (19). It can be used in monotherapy or in combination therapy with SA, in this case with greater efficacy.…”

Section: Introductionmentioning

confidence: 99%

Experience with pegvisomant treatment in acromegaly in a single Brazilian tertiary reference center: efficacy, safety and predictors of response

Kasuki

Machado

Ogino

et al. 2016

Arch. Endocrinol. Metab.

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Objective: To describe the safety and efficacy of pegvisomant therapy and the predictors of treatment response in acromegaly patients at a single tertiary reference center in Brazil. Materials and methods: We retrospectively reviewed the clinical, hormonal and radiological data of acromegaly patients treated with pegvisomant in our center. We also evaluated the presence of the d3 isoform of the growth hormone receptor (d3GHR). Results: Twenty-seven patients were included (17 women). Pegvisomant was used in combination with octreotide LAR in 20 patients (74%), in combination with cabergoline in one (4%) and as monotherapy in six (22%). IGF-I normalization was achieved in 23 patients (85%). Mild and transitory elevation of liver enzymes was observed in two patients (7.4%), tumor growth in one (3.4%) and lipodystrophy in two (7.4%). One patient stopped the drug due to headaches. The GHR isoforms were evaluated in 14 patients, and the presence of at least one d3GHR allele was observed in 43% of them, but it was not a predictor of treatment response. Only pretreatment IGF-I level was a predictor of treatment response. Conclusion: Pegvisomant treatment was highly effective and safe in our series of Brazilian patients. A better chance of disease control can be expected in those with lower pre-pegvisomant IGF-I levels. Arch Endocrinol Metab. 2016;60(5):479-85

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“…1). In contrast, only 10% of patients receiving placebo achieved normal IGF-I concentrations (21). All three pegvisomant treatment groups demonstrated statistically significant decreases in serum IGF-I concentrations compared with placebo, with the greatest mean decrease from baseline (60%) seen in the 20-mg pegvisomant group (Fig.…”

Section: Clinical Efficacy Of Pegvisomantmentioning

confidence: 91%

Pegvisomant: an advance in clinical efficacy in acromegaly

Stewart

2003

European Journal of Endocrinology

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Acromegaly is a chronic disorder invariably caused by a growth hormone (GH)-secreting pituitary tumour and is characterised by disabling symptoms (sweating, arthralgia, headache, paraesthesiae, fatigue), significant comorbidities (diabetes mellitus, hypertension, sleep apnoea), and premature mortality. Symptomatic control can be achieved by lowering insulin-like growth factor-I (IGF-I) concentrations to within the age-adjusted normal range, and survival can be improved to match that of the general population. However, even with optimal surgery and current medical therapies (dopamine agonists, somatostatin analogues), 30% to 50% of patients do not achieve target concentrations of IGF-I and GH.Pegvisomant is a new GH-receptor antagonist that blocks GH activity by inhibiting functional dimerisation of GH-receptors. Given as subcutaneous injections at dosages of 10 mg, 15 mg, or 20 mg/day for 3 months, pegvisomant normalised serum IGF-I concentrations in, respectively, 54%, 81%, and 89% of acromegalic patients. Moreover, long-term pegvisomant therapy normalised IGF-I concentrations in 97% of patients treated for 12 months or longer, with no evidence of tachyphylaxis. Pegvisomant is the most effective medical therapy, reported to date, in terms of normalisation of circulating IGF-I concentrations. In addition, pegvisomant appears to be safe and well tolerated. Although additional long-term studies are required to further assess safety, the introduction of this innovative treatment should allow for optimal disease control in patients with acromegaly.

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Discovery and mechanism of action of pegvisomant

Cited by 43 publications

References 25 publications

Pegvisomant therapy in pituitary gigantism: successful treatment in a 12-year-old girl

Pegvisomant therapy in pituitary gigantism: successful treatment in a 12-year-old girl

Experience with pegvisomant treatment in acromegaly in a single Brazilian tertiary reference center: efficacy, safety and predictors of response

Pegvisomant: an advance in clinical efficacy in acromegaly

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