Pegvisomant

Description

Acromegaly is a rare debilitating endocrine disease caused by the excessive secretion of growth hormone (GH) and increased production of insulin-like growth factor I(IGF-I) in middle-aged adults. In over 90% of acromegaly patients, excess of GH is associated with a benign pituitary adenoma. The clinical manifestations of uncontrolled acromegaly include soft-tissue swelling, joint pain, nerve entrapment, glucose intolerance, hypertension, and cardiac disease. Patients with acromegaly have increased morbidity and mortality relative to the general population. The currently available treatment options for acromegaly are surgical removal of the adenoma, radiation therapy, and drug therapy with dopamine antagonists or somatostatin analogues. Pegvisomant, launched as a new treatment for acromegaly, is a modified form of human GH that acts as a highly selective GH receptor antagonist. It is a PEGylated form of a recombinant human GH antagonist (B2036). Pegvisomant selectively binds to GH receptors on cell surfaces, where it blocks the binding of endogenous GH, and thus interferes with GH signal transduction. This leads to a decrease in serum concentrations of IGF-I. A 12-week randomized, double-blind, placebo-controlled clinical study found that daily treatment of acromegaly patients with 10, 15, and 20 mg of pegvisomant resulted in normalized IGF-I concentrations in 54, 81, and 89% of patients, respectively, compared to 10% in the placebo group. An open-label extension study in which pegvisomant was individually titrated demonstrated that 12-month or longer treatment resulted in normalized IGF-I concentrations in 97% of patients. The recommended dosage regimen of pegvisomant consists of a 40 mg loading dose, followed by 10 mg daily dose, administered subcutaneously. The t_max of pegvisomant following SC administration is 33–77 h, with a bioavailability of 57% and t_1/2 of six days. Pegvisomant is generally well tolerated and the most common side effects include injection-site reactions, diarrhea, nausea, chest pain and flu-like symptoms.

Originator

Sensus (Pfizer) (US)

Uses

Treatment of acromegaly (competitive inhibition of peripheral growth hormone receptors to block IFG-I production).

brand name

Somavert (Pharmacia & Upjohn) [Note—The FDA has designated pegvisomant (B2036-PEG) as an Orphan Drug for the treatment of acromegaly.].

Biological Functions

This product contains 191 amino acid residues (of recombinant origin), the same number as in GH, but there are substitutions at residues 18, 21, 120, 167, 168, 171, 172, 174, and 179. This product is then covalently linked to several polyethylene glycol molecules, and this pegylated protein is a GH-receptor antagonist. Thus, pegvisomant binds to the GH receptor and blocks endogenous GH from binding. The result is a blocking of the GH-stimulated overproduction of IGF-I that contributes to the disabling symptoms and long-term health problems associated with acromegaly.

Raw materials

Preparation Products