The place of pegvisomant in the management of acromegaly

The development of a growth hormone (GH) receptor antagonist was driven by the appreciation of the need for additional treatment in the significant minority of patients with acromegaly inadequately controlled by conventional therapies, as well as by the recognition of the therapeutic potential of manipulation of the GH/Insulin-like growth factor I (IGF-1) axis in diseases such as breast cancer and the small vessel complications of diabetes. The design of pegvisomant has exploited the rapid advances in the last decade of our understanding of cytokines and their receptors. GH is a 191 amino acids peptide that contains 2 disulfide bonds and 4 alpha helices, and has a molecular mass of approximately 22,000 d. A glycine at position 120 in the 3rd alpha-helix of human GH (hGH) is crucial to its biologic activity and, if replaced with a variety of amino acids, the GH analog acts not as an agonist, but as a growth suppressor. Pegvisomant (Somavert) is a 191 amino acid GH analog that contains a position 120 amino acid substitution that generates the antagonist, as well as additional amino acid substitutions to optimize site I binding. The antagonist is further modified by addition of polyethylene glycol moieties, which increase its half-life and reduce immunogenicity. In an era when the need for tight control of the GH/IGF-I axis has been convincingly demonstrated, but when pituitary surgery and the combined use of dopamine agonists and somatostatin (SMS) analogs leave significant numbers of patients inadequately controlled, the availability of pegvisomant is a welcome addition to the existing treatment modalities for acromegaly. Early clinical studies indicate pegvisomant to be the most potent medical treatment of acromegaly to date as serum IGF-I is normalized into the age-related reference range in 97% of patients treated with doses of up to 40 mg per day. Although a great deal more information is needed on the long-term effects of pegvisomant on both the metabolic consequences of acromegaly and pituitary adenoma tumor growth, it represents the most exciting development in the medical management of acromegaly for many years.