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Pegvisomant

Also known as B2036-PEG, Somavert, pegylated B2036

Growth hormone receptor antagonist for acromegaly: it blocks GH action rather than GH secretion.

clinically proven Growth hormone approved drug

At a glance

Category
Growth hormone
Status
approved drug
Made from
recombinant A mutated growth hormone molecule produced in Escherichia coli by recombinant DNA technology, then covalently coupled to polyethylene glycol chains.
Route
subcutaneous injection into the upper arm, upper thigh, abdomen or buttocks, rotating sites daily
Half-life
mean elimination half-life of approximately 74 to 172 hours (roughly 3 to 7 days) after single or multiple doses; peak serum concentrations are not generally reached until 33 to 77 hours after a subcutaneous dose 2
Onset
IGF-1 falls over the first weeks; the label directs assessing serum IGF-1 and adjusting the dose every 4 to 6 weeks, so titration steps are deliberately slow 2
Molecular weight
approximately 42,000-48,000 g/mol depending on the degree of pegylation; the protein backbone alone is approximately 22 kDa
Sequence
A 191-amino-acid analogue of human growth hormone (B2036) carrying nine amino acid substitutions: eight in binding site 1 that increase affinity, and the critical G120K substitution in binding site 2 that abolishes functional receptor dimerisation. Four to six polyethylene glycol chains of approximately 5 kDa each are covalently attached, predominantly to lysine residues

Prescription medicine. Authorised in the European Union on 12 November 2002 (Somavert, Pfizer) for adults with acromegaly who have had an inadequate response to surgery and/or radiotherapy and in whom a somatostatin analogue did not normalise IGF-1 or was not tolerated 7; approved in the US in 2003 for acromegaly in patients with an inadequate response to surgery or radiation therapy, or for whom these are not appropriate 2. It is a biological product administered by daily subcutaneous injection and is not available in any other form 2.

Doping status: Not listed by WADA

Checked against the WADA 2026 Prohibited List. For a specific product and country, Global DRO is the lookup athletes are expected to use — the List names substances, not brand names.

Mechanism of action

Pegvisomant is the only growth hormone receptor antagonist in clinical use, and it works by exploiting the geometry of GH receptor activation. A single growth hormone molecule must bind two receptor molecules sequentially, using two structurally distinct surfaces — binding site 1 and binding site 2 — to form the 1:2 complex that activates JAK2 and phosphorylates STAT5b. Pegvisomant binds site 1 with enhanced affinity thanks to eight engineered substitutions, but the G120K substitution destroys site 2. The result is a molecule that occupies the receptor, cannot recruit the second receptor, and therefore blocks signalling.

Because signalling is blocked at the receptor, hepatic IGF-1 production falls. IGF-1, not GH, is the parameter that correlates with the clinical manifestations of acromegaly, so IGF-1 is the treatment target. This is a fundamentally different approach from every other drug in this category: octreotide, lanreotide and pasireotide reduce GH secretion from the tumour, dopamine agonists reduce it partially, and surgery removes the source — pegvisomant leaves GH secretion entirely alone and blocks its effect downstream.

That has an important practical consequence. Serum GH rises during pegvisomant treatment, both because IGF-1 negative feedback on the pituitary is removed and because the assay may cross-react with the drug itself. GH is therefore useless as a monitoring parameter on pegvisomant; only IGF-1 is meaningful. Clinicians unfamiliar with the drug sometimes misinterpret a rising GH as treatment failure when the patient is in fact biochemically controlled.

The pegylation is what makes daily dosing feasible. Unmodified B2036 has high receptor affinity but is cleared within hours; attaching PEG chains reduces renal clearance and immunogenicity at the cost of some receptor affinity, and shifts the half-life to about six days. The long half-life is why dose changes are assessed at 4-6 week intervals rather than weekly.

Because it does not act on the pituitary adenoma, pegvisomant has no antitumour effect. The tumour continues to grow at whatever rate it was growing, which is why periodic MRI surveillance is part of the treatment protocol rather than an optional extra.

What the research shows

The efficacy evidence is unusually clean: a dose-ranging placebo-controlled trial followed by a large long-term open-label study, both showing IGF-1 normalisation rates higher than any other medical therapy for acromegaly. What is less well characterised is very long-term safety, particularly liver injury and tumour growth, which is why registry surveillance (ACROSTUDY) was mandated.

Research in humans

Trainer et al. (New England Journal of Medicine, 2000) randomised 112 patients with acromegaly to placebo or pegvisomant 10, 15 or 20 mg daily for 12 weeks: IGF-1 normalised in 10, 54, 81 and 89 per cent of the placebo, 10 mg, 15 mg and 20 mg groups respectively, with significant improvement in ring size, soft tissue swelling, perspiration and fatigue 3. Van der Lely et al. (Lancet, 2001) followed 160 patients for an average of 425 days: of those treated for 12 months or more, 97 per cent achieved a normal serum IGF-1 4. Later Japanese and European studies reproduced these results. No other medical therapy for acromegaly reaches comparable IGF-1 normalisation rates.

Animal and lab research

The design rests on structural biology rather than animal pharmacology: crystallographic and mutational work by Cunningham, Wells and colleagues mapped the two binding sites on growth hormone and showed that a site-2 mutation converts an agonist into an antagonist. Transgenic mice expressing the G120K analogue are dwarfed, which confirmed the mechanism in vivo before the human programme.

Caveats. Transaminase elevations occur in a meaningful minority of patients and occasionally require discontinuation; the mechanism is not fully understood and appears more common in patients also receiving a somatostatin analogue and in those with Gilbert's syndrome. Because pegvisomant does not act on the adenoma, tumour growth continues and MRI surveillance is required. Lipohypertrophy at injection sites occurs and is thought to reflect local GH receptor blockade. Long-term data come mainly from ACROSTUDY, a manufacturer-run observational registry rather than a controlled trial, which limits what can be concluded about rare harms. Cost is a substantial practical barrier and is the usual reason it is positioned after somatostatin analogues rather than first.

What it is used for

  • Approved: acromegaly in patients who have had an inadequate response to surgery or radiation therapy, or for whom these therapies are not appropriate — the label states the goal of treatment is to normalise serum IGF-1 2
  • Used in combination with a somatostatin analogue in patients partially controlled on the analogue alone, allowing lower pegvisomant doses; this combination increases the rate of transaminase elevation and requires closer liver monitoring
  • Studied off-label in acromegaly-associated diabetes and in a small number of other conditions of GH excess

Dosing

Dose
A 40 mg loading dose subcutaneously, administered under physician supervision, followed from the next day by 10 mg once daily. The daily dose is then titrated in 5 mg increments or decrements based on serum IGF-1 measured every 4-6 weeks, to a maximum of 30 mg per day.
Frequency
once daily
Route
subcutaneous, into thigh, abdomen, buttock or upper arm, rotating sites to reduce lipohypertrophy
Duration
long-term and continuous; the effect is entirely dependent on ongoing administration and IGF-1 rises again after stopping
  • These figures are taken directly from the FDA-approved Somavert prescribing information 2. This is a specialist-prescribed medicine requiring biochemical and imaging surveillance.
  • Titrate on IGF-1 only. Pegvisomant is structurally similar enough to growth hormone to cross-react in commercial GH assays, and because therapeutic serum concentrations are 100 to 1000 times higher than actual GH levels in acromegaly, measured serum GH appears falsely elevated 2. GH also genuinely rises within two weeks of starting, as IGF-1 feedback on the pituitary is removed 2.
  • Do not adjust the dose more often than every 4-6 weeks; the label specifies serum IGF-1 measured and the dose adjusted at 4- to 6-week intervals, in 5 mg steps, to a maximum of 30 mg daily 2. The half-life of roughly 3 to 7 days means earlier IGF-1 measurements do not reflect the new steady state 2.
  • Baseline ALT, AST, total bilirubin and alkaline phosphatase must be obtained before starting, and the label carries a table governing both whether to start and how to monitor thereafter 2.
  • Pituitary MRI is performed at baseline and periodically thereafter, because pegvisomant does not restrain adenoma growth. In the ACROSTUDY registry, of 747 patients with a baseline and follow-up MRI, 51 (7 per cent) had an increase reported locally, of which 16 (2 per cent) were confirmed centrally 2.
  • Patients with diabetes frequently need reductions in insulin or oral antidiabetic doses: GH opposes the effect of insulin, so glucose tolerance may improve once GH action is blocked 2.
  • The reconstituted solution must be administered within 6 hours 2.

These figures describe what the literature and published protocols report. They are not advice and not a dosing instruction.

Protocols

Somavert, acromegaly

approved product information

Source: FDA prescribing information, SOMAVERT, 2013

Day 140 mg loading dose subcutaneously, under physician supervision
From the following day10 mg subcutaneously once daily
Every 4-6 weeks, IGF-1 still elevatedincrease by 5 mg per day
Every 4-6 weeks, IGF-1 below the normal rangedecrease by 5 mg per day
Recommended range10 mg to 30 mg once daily; maximum 30 mg per day

Titration is on serum IGF-1 and on nothing else. Pegvisomant blocks the GH receptor rather than GH secretion, so serum GH rises during treatment - using GH as the monitoring parameter produces exactly the wrong dose decision. The 4-6 week interval is not caution for its own sake either: with a half-life of about six days, an IGF-1 measured sooner does not reflect the new steady state.

Schedules are reproduced as their source states them. Units, IU and milligrams explains why the figures are not interchangeable between products.

Reconstitution

Vial sizes
10 mg, 15 mg, 20 mg, 25 mg and 30 mg single-dose vials of lyophilised powder
Solvent
Sterile Water for Injection, supplied with the kit — 1 ml per vial. Bacteriostatic water is not used with this product.
Storage
Unreconstituted vials 2-8 °C, protected from light, do not freeze. After reconstitution the solution is used within 6 hours; it is not a multi-dose preparation and is not stored for later.

Worked example

One 20 mg vial reconstituted with the supplied 1 ml of sterile water gives 20 mg/ml; the entire volume is drawn up and injected. The 40 mg loading dose is prepared from two vials.

Direct the water down the side of the vial and swirl gently — do not shake. Pegvisomant is a pegylated protein and shaking causes denaturation and foaming; a foamed or cloudy solution is discarded. Do not use if particulate matter is visible. Each vial is a single dose.

Work it out for Pegvisomant

Safety

Side effects

  • Elevation of hepatic transaminases (ALT and AST). Asymptomatic, transient elevations up to 15 times the upper limit of normal were seen in under 2 per cent of subjects across two open-label trials of 147 patients, and elevations above ten times ULN in two patients (0.8 per cent) in pre-approval studies — one rechallenge recurrence suggested a probable causal relationship, and one liver biopsy was consistent with chronic hepatitis. Elevations generally occurred within 4 to 12 weeks of starting and normalised after discontinuation 2
  • Lipohypertrophy at injection sites — one case (1.3 per cent) in the 12-week placebo-controlled study and two among 147 patients in open-label trials, one of which led to discontinuation; the label directs rotating injection sites daily to help prevent it 2
  • Injection site pain, erythema, bruising, and systemic hypersensitivity reactions requiring caution if treatment is restarted 2
  • Headache, fatigue 2
  • Nausea, diarrhoea, abdominal pain
  • Flu-like symptoms, sweating
  • Growth of the underlying pituitary adenoma. This is not caused by the drug, but the drug does not restrain it, and removal of IGF-1 feedback is a theoretical additional driver — periodic MRI is mandated for this reason 2
  • Hypoglycaemia in patients with diabetes: GH decreases insulin sensitivity, so glucose tolerance may improve on treatment and antidiabetic doses need reducing to avoid hypoglycaemia 2
  • About 17 per cent of treated patients in pre-marketing studies developed low-titre, non-neutralising anti-GH antibodies; these did not appear to affect efficacy, though their long-term significance is unknown and no anti-pegvisomant antibody assay is commercially available 2
  • Reduction of IGF-1 below the reference range with overdosing, producing symptoms resembling growth hormone deficiency

Do not use if

  • The FDA label lists no contraindications at all 2; what follows are its warnings and precautions plus general clinical caution. Note also that the vial stoppers are not made with natural rubber latex, so latex allergy is not a barrier 2.
  • Systemic hypersensitivity: caution and close monitoring are advised when restarting treatment in patients who have had a systemic hypersensitivity reaction 2
  • Abnormal baseline liver tests — the label carries a table governing whether treatment may be started, and directs a comprehensive hepatic workup for transaminases at least 5 times ULN, or at least 3 times ULN with any rise in bilirubin, discontinuing if liver injury is confirmed 2
  • Caution and close surveillance in patients with a pituitary adenoma at risk of compressing the optic chiasm, since pegvisomant does not shrink the tumour 2
  • Caution in diabetes mellitus: glucose tolerance may improve on treatment and doses of antidiabetic drugs should be reduced as necessary to avoid hypoglycaemia 2
  • Pregnancy: no adequate and well-controlled studies in pregnant women, and the label directs use during pregnancy only if clearly needed. It is not known whether pegvisomant is excreted in human milk, and caution is advised in nursing women 2
  • Not studied adequately in children

Interactions

In clinical studies, patients taking opioids often needed higher pegvisomant doses to normalise IGF-1 than patients not on opioids; the mechanism of this interaction is not known 2. Patients with acromegaly and diabetes may require careful monitoring and dose reductions of insulin or oral hypoglycaemic agents, because blocking GH action improves insulin sensitivity 2. Combination with a somatostatin analogue is used deliberately and works well, but raises the incidence of transaminase elevation and needs closer liver monitoring. Pegvisomant cross-reacts in commercially available GH assays and produces falsely elevated GH readings, because therapeutic serum concentrations are 100 to 1000 times higher than the actual GH concentrations in acromegaly; GH assays must therefore not be used for monitoring 2. Pegvisomant binds selectively to the GH receptor and does not cross-react with 19 other cytokine receptors tested, prolactin among them 2. Pegvisomant is a pharmacological antagonist of somatropin and of every GH secretagogue and GHRH analogue in this category, acting at the receptor rather than at the pituitary.

Sources