Growth Hormone Receptor Antagonists

Müller, Alex F.; Kopchick, John J.; Flyvbjerg, Allan; Lely, Aart Jan van der

doi:10.1210/jc.2002-022049

Cited by 77 publications

(63 citation statements)

References 107 publications

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“…Pegvisomant PEG is a GH receptor antagonist which blocks the peripheral synthesis of IGF1 (Muller et al 2004). Initial trials demonstrated normalization of serum IGF1 concentration in 97% of the cases treated for at least 12 months (van der Lely et al 2001).…”

Section: Medical Treatmentmentioning

confidence: 99%

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60 YEARS OF NEUROENDOCRINOLOGY: Acromegaly

Căpățînă¹,

Wass²

2015

Journal of Endocrinology

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Acromegaly (ACM) is a chronic, progressive disorder caused by the persistent hypersecretion of GH, in the vast majority of cases secreted by a pituitary adenoma. The consequent increase in IGF1 (a GH-induced liver protein) is responsible for most clinical features and for the systemic complications associated with increased mortality. The clinical diagnosis, based on symptoms related to GH excess or the presence of a pituitary mass, is often delayed many years because of the slow progression of the disease. Initial testing relies on measuring the serum IGF1 concentration. The oral glucose tolerance test with concomitant GH measurement is the gold-standard diagnostic test. The therapeutic options for ACM are surgery, medical treatment, and radiotherapy (RT). The outcome of surgery is very good for microadenomas (80-90% cure rate), but at least half of the macroadenomas (most frequently encountered in ACM patients) are not cured surgically. Somatostatin analogs are mainly indicated after surgical failure. Currently their routine use as primary therapy is not recommended. Dopamine agonists are useful in a minority of cases. Pegvisomant is indicated for patients refractory to surgery and other medical treatments. RT is employed sparingly, in cases of persistent disease activity despite other treatments, due to its long-term side effects. With complex, combined treatment, at least three-quarters of the cases are controlled according to current criteria. With proper control of the disease, the specific complications are partially improved and the mortality rate is close to that of the background population.

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Section: Medical Treatmentmentioning

confidence: 99%

“…During treatment with PEG, no direct measure of GH secretion is useful (due to possible increase of secretion as a result of negative feedback, as well as cross-reactivity between the drug and some diagnostic assays; Muller et al 2004). Instead, IGF1 normalization is the only marker of disease control .…”

Section: Follow-up Under Treatmentmentioning

confidence: 99%

60 YEARS OF NEUROENDOCRINOLOGY: Acromegaly

Căpățînă¹,

Wass²

2015

Journal of Endocrinology

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“…Medical therapy with dopamine agonists or somatostatin analogs is an adjunctive treatment option in case of inadequate disease control (1,2). Recently, pegvisomant (Somavert), a pegylated recombinant analog of human growth hormone (GH) which acts functionally as a GH receptor antagonist, received approval for the treatment of acromegaly (3)(4)(5). Data from clinical studies on the treatment of acromegaly have shown that the pegvisomant is a highly effective and well-tolerated therapeutic option for disease control with a normalization rate of IGF-I of up to 97% (6)(7)(8)(9).…”

Section: Introductionmentioning

confidence: 99%

Treatment of acromegaly with the GH receptor antagonist pegvisomant in clinical practice: Safety and efficacy evaluation from the German Pegvisomant Observational Study

et al. 2007

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Objective: The GH receptor antagonist pegvisomant is a highly effective new treatment option in acromegaly. The German Pegvisomant Observational Study (GPOS) was started to monitor long-term safety and efficacy of pegvisomant as prescribed in clinical practice. Design: GPOS is an observational, multi-center, surveillance study, which comprises noninterventional data collection. Methods: Of the 229 patients included in the study, 90.4% had previous pituitary surgery, 43.2% were treated by radiation therapy, and 94.3% had previous medical therapy for acromegaly that had been discontinued mainly due to persistent IGF-I elevation or side effects. The intention-to-treat population included 177 patients with at least one post-baseline efficacy measurement. Results: IGF-I levels decreased from 1.75G0.91-fold the upper limit of normal at baseline to 1.05G 0.62 at the 6-month visit, 0.96G0.60 at the 12-month visit, and to 0.89G0.41-fold after 24 months (P!0.0001). Mean duration of pegvisomant therapy was 51.8G35.8 weeks (medianZ51.9 weeks). IGF-I was normalized in 64.4% at 6 months with a median dose of 15.0 mg/day, in 70.9% at 12 months, and in 76.3% at 24 months. Fasting glucose levels improved from 114.4G45.9 to 101.5G 42.8 mg/dl after 6 months (P!0.01) and to 100.6G33.2 mg/ml after 12 months (P!0.01). General physical condition measured by specific signs and symptoms score improved significantly. Adverse events occurring in O1% were injection site reactions in 7.4%, elevated liver enzymes (O3 times of normal) in 5.2% (3.1% spontaneously normalized during continued treatment), reported increase of pituitary tumor volume in 5.2% (which was verified in 3.1%), and headache in 1.7%. Conclusions: Pegvisomant is generally well tolerated with a safety profile similar to that reported in clinical trials and can effectively reduce IGF-I in patients with acromegaly refractory to conventional therapy. 156 75-82 European Journal of Endocrinology

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“…The final recombinant protein, a drug named pegvisomant (Somavert), consists of G120K with the eight site 1 mutations described above along with 4-5 conjugated PEG-5000 moities. While pegvisomant has a 20-fold reduced affinity for cell-surface GHR due to pegylation [67], it is an effective antagonist due to an increase in serum half life of approximately 100 hours, a characteristic conferred by pegylation [68]. An additional benefit of the site 1 mutations is that they abolish the ability of the molecule to bind to the prolactin receptor [69], thus reducing off-target pharmacologic effects.…”

Section: Development and Design Of Pegvisomantmentioning

confidence: 99%