Pegvisomant is a new growth hormone receptor antagonist that improves symptoms and normalises insulin-like growth factor-1 (IGF-1) in a high proportion of patients with acromegaly treated for up to ...12 weeks. We assessed the effects of pegvisomant in 160 patients with acromegaly treated for an average of 425 days.
Treatment efficacy was assessed by measuring changes in tumour volume by magnetic resonance imaging, and serum growth hormone and IGF-1 concentrations in 152 patients who received pegvisomant by daily subcutaneous injection for up to 18 months. The safety analysis included 160 patients some of whom received weekly injections and are excluded from the efficacy analysis.
Mean serum IGF-1 concentrations fell by at least 50%: 467 μg/L (SE 24), 526 μg/L (29), and 523 μg/L (40) in patients treated for 6, 12 and 18 months, respectively (p<0·001), whereas growth hormone increased by 12·5 μg/L (2·1), 12·5 μg/L (3·0), and 14·2 μg/L (5·7) (p<0·001). Of the patients treated for 12 months or more, 87 of 90 (97%) achieved a normal serum IGF-1 concentration. In patients withdrawn from pegvisomant (n=45), serum growth hormone concentrations were 8·0 μg/L (2·5) at baseline, rose to 15·2 μg/L (2·4) on drug, and fell back within 30 days of withdrawal to 8·3 μg/L (2·7). Antibodies to growth hormone were detected in 27 (16·9%) of patients, but no tachyphylaxis was seen. Serum insulin and glucose concentrations were significantly decreased (p<0·05). Two patients experienced progressive growth of their pituitary tumours, and two other patients had increased alanine and asparate aminotransferase concentrations requiring withdrawal from treatment. Mean pituitary tumour volume in 131 patients followed for a mean of 11·46 months (0·70) decreased by 0·033 cm
3(0·057; p=0·353).
Pegvisomant is an effective medical treatment for acromegaly.
We describe the case of an acromegalic subject, who was the first patient ever treated with the GH receptor antagonist pegvisomant. Furthermore, in this particular patient, progression in tumor size ...was encountered during treatment with pegvisomant. The patient described did benefit from cotreatment with pegvisomant and octreotide, including decreased GH levels, normalization of serum insulin-like growth factor I concentrations, and improvement of visual field defects.
We describe the case of an acromegalic subject, who was the first
patient ever treated with the GH receptor antagonist pegvisomant.
Furthermore, in this particular patient, progression in tumor size ...was
encountered during treatment with pegvisomant. The patient described
did benefit from cotreatment with pegvisomant and octreotide, including
decreased GH levels, normalization of serum insulin-like growth factor
I concentrations, and improvement of visual field defects.
Patients with acromegaly are currently treated with surgery, radiation therapy, and drugs to reduce hypersecretion of growth hormone, but the treatments may be ineffective and have adverse effects. ...Pegvisomant is a genetically engineered growth hormone-receptor antagonist that blocks the action of growth hormone.
We conducted a 12-week, randomized, double-blind study of three daily doses of pegvisomant (10 mg, 15 mg, and 20 mg) and placebo, given subcutaneously, in 112 patients with acromegaly.
The mean (+/-SD) serum concentration of insulin-like growth factor I (IGF-I) decreased from base line by 4.0+/-16.8 percent in the placebo group, 26.7+/-27.9 percent in the group that received 10 mg of pegvisomant per day, 50.1+/-26.7 percent in the group that received 15 mg of pegvisomant per day, and 62.5+/-21.3 percent in the group that received 20 mg of pegvisomant per day (P<0.001 for the comparison of each pegvisomant group with placebo), and the concentrations became normal in 10 percent, 54 percent, 81 percent, and 89 percent of patients, respectively (P<0.001 for each comparison with placebo). Among patients treated with 15 mg or 20 mg of pegvisomant per day, there were significant decreases in ring size, soft-tissue swelling, the degree of excessive perspiration, and fatigue. The score fortotal symptoms and signs of acromegaly decreased significantly in all groups receiving pegvisomant (P< or =0.05). The incidence of adverse effects was similar in all groups.
On the basis of these preliminary results, treatment of patients who have acromegaly with a growth hormone-receptor antagonist results in a reduction in serum IGF-I concentrations and in clinical improvement.
Transsphenoidal surgical resection is the primary therapy for acromegaly caused by GH secreting pituitary adenomas. Medical therapy for patients not controlled by surgery includes primarily ...somatostatin analogs and secondarily dopamine agonists, both of which inhibit pituitary growth hormone secretion. A novel GH receptor antagonist (pegvisomant) binds to hepatic GH receptors and inhibits peripheral insulin-like growth factor-1 generation. Six patients resistant to maximal doses of octreotide therapy received pegvisomant - three received placebo or pegvisomant 30 mg or 80 mg weekly for 6 weeks and three received placebo and pegvisomant 10-20 mg/d for 12 weeks. Thereafter, all patients received daily pegvisomant injections of doses determined by titrating IGF-1 levels. Serum total IGF-1 levels were normalized in all six acromegalic patients previously shown to be resistant to somatostatin analogs via a novel mechanism of peripheral GH receptor antagonism. The GH receptor antagonist is a useful treatment for patients harboring GH-secreting tumors who are resistant to octreotide.
B2036-PEG, a GH receptor (GH-R) antagonist, is an analog of GH that is PEG-modified to prolong its action. Nine mutations alter the binding properties of this molecule, preventing GH-R dimerization ...and GH action. A potential therapeutic role of B2036-PEG is to block GH action, e.g. in refractory acromegaly. A phase I, placebo-controlled, single rising-dose study was performed in 36 normal young men (ages, 18-37 yr; within 15% ideal body weight). Four groups received a single s.c. injection of either placebo (n = 3 in each group, total n = 12) or B2036-PEG (0.03, 0.1, 0.3, or 1.0 mg/kg; n = 6 each dose). B2036-PEG and GH concentrations were measured 0, 0.25, 0.5, 1, 3, 6, 9, 12, 24, 36, 48, 72, 96, 120, and 144 h after dosing. Serum insulin-like growth factor-I was measured before and 1-7 days after dosing. All doses were well tolerated, with no serious or severe adverse reactions. B2036-PEG, at 1.0 mg/kg, reduced insulin-like growth factor-I by 49 +/- 6% on day 5 (P < 0.001 vs. placebo). GH was measured by two independent methods: 1) modified Nichols chemiluminescence assay (empirically corrected for B2036-PEG cross-reactivity); and 2) direct GH two-site immunoassay, using monoclonal antibodies that did not react with B2036-PEG. There was good agreement between the two methods. GH did not change substantially at any B2036-PEG dose, suggesting that B2036-PEG does not interact with hypothalamic GH-Rs to block short-loop feedback. B2036-PEG may thus block peripheral GH action without enhancing its secretion.
Transsphenoidal surgical resection is the primary therapy for
acromegaly caused by GH secreting pituitary adenomas. Medical therapy
for patients not controlled by surgery includes primarily ...somatostatin
analogs and secondarily dopamine agonists, both of which inhibit
pituitary growth hormone secretion. A novel GH receptor antagonist
(pegvisomant) binds to hepatic GH receptors and inhibits peripheral
insulin-like growth factor-1 generation. Six patients resistant to
maximal doses of octreotide therapy received pegvisomant—three
received placebo or pegvisomant 30 mg or 80 mg weekly for 6 weeks and
three received placebo and pegvisomant 10–20 mg/d for 12 weeks.
Thereafter, all patients received daily pegvisomant injections of doses
determined by titrating IGF-1 levels. Serum total IGF-1 levels were
normalized in all six acromegalic patients previously shown to be
resistant to somatostatin analogs via a novel mechanism of peripheral
GH receptor antagonism. The GH receptor antagonist is a useful
treatment for patients harboring GH-secreting tumors who are resistant
to octreotide.
B2036-PEG, a GH receptor (GH-R) antagonist, is an analog of GH that is
PEG-modified to prolong its action. Nine mutations alter the binding
properties of this molecule, preventing GH-R dimerization ...and GH
action. A potential therapeutic role of B2036-PEG is to block GH
action, e.g. in refractory acromegaly. A phase I,
placebo-controlled, single rising-dose study was performed in 36 normal
young men (ages, 18–37 yr; within 15% ideal body weight). Four groups
received a single sc injection of either placebo (n = 3 in each
group, total n = 12) or B2036-PEG (0.03, 0.1, 0.3, or 1.0 mg/kg;
n = 6 each dose). B2036-PEG and GH concentrations were measured 0,
0.25, 0.5, 1, 3, 6, 9, 12, 24, 36, 48, 72, 96, 120, and 144 h
after dosing. Serum insulin-like growth factor-I was measured
before and 1–7 days after dosing. All doses were well tolerated, with
no serious or severe adverse reactions. B2036-PEG, at 1.0 mg/kg,
reduced insulin-like growth factor-I by 49 ± 6% on day 5
(P < 0.001 vs. placebo). GH was
measured by two independent methods: 1) modified Nichols
chemiluminescence assay (empirically corrected for B2036-PEG
cross-reactivity); and 2) direct GH two-site immunoassay, using
monoclonal antibodies that did not react with B2036-PEG. There was good
agreement between the two methods. GH did not change substantially at
any B2036-PEG dose, suggesting that B2036-PEG does not interact with
hypothalamic GH-Rs to block short-loop feedback. B2036-PEG may thus
block peripheral GH action without enhancing its secretion.
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