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Children whose growth falls below the third percentile for their age and gender are said to have "short stature." A variety of factors—including genetics, constitutional delays, and medical conditions—may cause this delay in growth. Children genetically predisposed to short stature typically have a parent of short stature, while children with con-stitutional growth delay may initially exhibit slow growth patterns but experience a rapid growth phase during puberty.
Growth-hormone deficiency is also a potential cause for slow statural growth.
Short children with growth-hormone deficiency are typically treated with growth-hormone injections, such as Pfizer's Genotropin. Growth hormone, normally produced by the pituitary gland, signals the body to produce insulinlike growth factor-1 (IGF-1), an essential growth factor for the development of bones and organs. When insufficient amounts of IGF-1 are produced, growth delay results. Growth hormone injections are intended to sufficiently elevate growth hormone levels to stimulate the production of IGF-1.
However, IGF-1 levels in these children may be more than two standard deviations below normal despite adequate or elevated growth hormone levels. If this condition, known as primary IGF-1 deficiency, is left untreated, it can lead to lipid abnormalities, decreased bone density, obesity, and insulin resistance.
Armed with advances in the understanding of primary IGF-1 deficiency, scientists have developed a recombinant human IGF-1. The first such product, mecasermin, from Tercica Inc., was approved under orphan drug status by the Food & Drug Administration in August of 2005. Mecasermin, which will be marketed as Increlex beginning in January 2006, is indicated for the long-term treatment of growth failure in children with severe primary IGF-1 deficiency or with growth-hormone gene deletion accompanied by the development of neutralizing antibodies to growth hormone. Severe primary IGF-1 deficiency is identified by height and serum IGF-1 levels more than three standard deviations below normal. Estrada predicts, however, that less than 5% of children with idiopathic short stature will actually meet the criteria for severe primary IGF-1 deficiency.
The standard starting dose of mecasermin is 0.04 to 0.08 mg/kg subcutaneously twice daily. Doses can be titrated weekly by 0.04 mg/ kg to a maximum dose of 0.12 mg/ kg twice daily. The most common side effect is hypoglycemia, occurring in more than 40% of patients. Mecasermin should be administered within 20 minutes of a meal or snack to reduce the risk of hypoglycemia. The manufacturer recommends withholding the dose if the patient cannot eat within that time frame. The manufacturer also recommends preprandial glucose monitoring at treatment initiation until a well-tolerated, individualized dose of mecasermin is achieved. Hypoglycemia may necessitate reductions in dose.
As Tercica continues to conduct phase III clinical trials on patients with less severe primary IGF-1 deficiency, Insmed Corp. is performing phase II clinical trials involving the use of IGF-1 to treat diabetes, severe burns, and hip fractures.
Other companies are also investigating the use of IGF-1 for the treatment of short-bowel syndrome and post-poliomyelitis syndrome.
Insmed is investigating the use of IGF-1 binding protein as an antitumor agent. In early October, Insmed received tentative approval of its IGF-1 and IGF-1 binding protein combination product, known as iPlex. The FDA has granted it exclusivity for seven years.
THE AUTHOR is a medical writer based in Connecticut.