Drugs Approved by the FDA
Drug Name: Somavert (pegvisomant)
The following information is obtained from various newswires, published medical journal articles, and medical conference presentations.

General Information
Somavert is the first in a new class of medicines called growth hormone receptor antagonists and the only medicine designed to specifically block the effects of excess growth hormone in acromegaly.

Somavert (pegvisomant), an analog of human growth hormone, is an injectable medication that has been structurally altered to act as a growth hormone (GH) receptor antagonist. Over production of growth hormone leads to abnormally high insulin-like growth factors (IGF-I), which then cause acromegaly like symptoms.

Somavert is indicated for the treatment of acromegaly in patients who have had an inadequate response to surgery and/or radiation therapy and/or other medical therapies, or for whom these therapies are not appropriate. The goal of treatment is to normalize serum IGF-I levels.

Somavert is available in single-dose, sterile glass vials in 10, 15, or 20 mg strengths.

Clinical Results
FDA approval of Somavert was based on the data from a 12-week, randomized, double blind, placebo-controlled study enrolling 112 subjects with acromegaly previously treated with therapy. Results showed that after 12 weeks of treatment, serum IGF-I levels were normalized in 39%, 75%, and 82% of subjects treated with 10, 15, or 20 mg/day of Somavert, respectively, versus 10% of subjects treated with placebo. The three Somavert groups also showed dose-dependent reductions in serum levels of IGF-I and IGF binding proteins compared with placebo at all post-baseline visits.

Following withdrawal from previous medical therapy, the 80 patients randomized to treatment with Somavert received a subcutaneous (SC) loading dose, followed by 10, 15, or 20 mg/day SC. Each individual score (for soft-tissue swelling, arthralgia, headache, perspiration and fatigue) was based on a nine-point ordinal rating scale (0 = absent and 8 = severe and incapacitating), and the total score was derived from the sum of the individual scores.

In addition, subject's ring size at week 12 was smaller in the groups treated with Somavert (15 or 20 mg) of, compared with placebo. The mean total score for signs and symptoms at week 12 was lower in each of the groups treated with Somavert, compared with the group treated with placebo.

Side Effects
Adverse events associated with the use of Somavert may include (but are not limited to) the following:

• Infection
  
• Pain
  
• Back pain
  
• Flu syndrome
  
• Chest pain
  
• Diarrhea
  
• Nausea
  
• Peripheral edema

Mechanism of Action
Pegvisomant is a recombinant DNA protein containing 191 amino acid residues to which several polyethylene glycol (PEG) polymers are covalently bonded. It is synthesized by a specific strain of Escherichia coli bacteria that has been genetically modified by the addition of a plasmid that carries a gene for GH receptor antagonist. Pegvisomant selectively binds to growth hormone (GH) receptors on cell surfaces, where it blocks the binding of endogenous GH, and thus interferes with GH signal transduction. This inhibition of signal results in the decrease of insulin-like growth factor (IGF-I) and IGF binding proteins. High IGF-I levels lead to the numerous health complications associated with acromegaly.

Literature References
van der Lely AJ, Hutson RK, Trainer P, et al. Long-term treatment of acromegaly with pegvisomant, a growth hormone receptor antagonist. The Lancet 2001 ; 358: 1754-1759.

Molitch ME. Clinical manifestations of acromegaly. Endocrinol Metab Clin North Am. 1992;21:597-614.

Orme SM, McNally RJ, Cartwright RA, et al. Mortality and cancer incidence in acromegaly: a retrospective cohort study. United Kingdom Acromegaly Study Group. J Clin Endocrinol Metab. 1998;83:2730-2734.

Bates AS,Van't Hoff W, Jones JM, et al. An audit of outcome of treatment in acromegaly. Q J Med. 1993;86:293-299.

Ben-Shlomo A, Melmed S. Acromegaly. Endocrinol Metab Clin North Am. 2001;30:565-583.

Sheaves R. A history of acromegaly. Pituitary. 1999;2:7-28.

Additional Information
For additional information regarding Somavert or acromegaly, please contact The Somavert Web Site or The Pharmacia Web Site.

New Analysis in "The Lancet" Shows Promising Results with Investigational Drug in Treatment of Debilitating Hormone Disease

CHARLOTTESVILLE, Va., November 24 2002- Results of an analysis published in today's issue of The Lancet show that the investigational drug pegvisomant normalized concentrations of the hormone IGF-I in 97 percent of patients with acromegaly during 12 months of treatment in two open-label studies. IGF-I is a measure of the activity of the disease and of its debilitating effects.

Pegvisomant is the first in a new class of compounds called growth hormone receptor antagonists and is designed to block the effects of excessive growth hormone production by a tumor of the pituitary gland.
Acromegaly is a serious, life-shortening disease triggered by overproduction of growth hormone, most often caused by a pituitary tumor. This excess of growth hormone leads to overproduction of a second hormone, insulin-like growth factor-I (IGF-I).

"Pegvisomant lowered serum IGF-I levels to normal in more than 90 percent of patients during one year of treatment, according to our analysis," said Dr. Michael O. Thorner, Henry B. Mulholland professor of internal medicine and professor of neurosurgery, University of Virginia Health System and one of the lead investigators in the international study. "We find these results encouraging since there has been no significant advance in the medical management of acromegaly in the past decade."

The retrospective analysis of two open-label, dose titration studies was conducted by aninternational team of leading endocrinologists in the United States and Europe. The investigators examined the long-term efficacy of pegvisomant in the treatment of 152 patients with active acromegaly, for an average of 425 days.

Of the 90 patients who were treated for 12 months or longer with once-daily injections of pegvisomant, 87 patients (97 percent) achieved a normal serum IGF-I concentration. Pegvisomant was generally well tolerated in the study. Two patients experienced progressive growth of their pituitary tumors, and two other patients had elevations of aminotransferase (ALT) and aspartate transaminase (AST) requiring withdrawal from treatment.

"Pegvisomant has a novel mechanism of action," Thorner said. "It blocks the action of growth hormone at the tissue level rather than relying on inhibition of growth hormone secretion from the tumor."

Patients with acromegaly often suffer from headache, excessive sweating, soft-tissue swelling, joint disorders and, perhaps most striking, a progressive coarsening of facial features and enlargement of the hands, feet and jaw. According to the sixth edition of Basic & Clinical Endocrinology, untreated patients with acromegaly face a mortality rate two to four times higher than the average person due to such serious long-term complications as heart and respiratory diseases, diabetes and some forms of cancer.
Traditional treatments for acromegaly include surgery to remove the pituitary tumor, radiation therapy and pharmaceutical treatments.

The drug used in the study is Sensus Drug Development Corporation's SOMAVERT® brand of pegvisomant. Sensus was acquired by Pharmacia Corporation in March 2001. Pharmacia has prepared regulatory filings for approval of SOMAVERT in the U.S. and Europe.

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