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Background
Primary insulin growth factor deficiency (IGFD) afflicts an estimated 30,000 children evaluated for short stature in the United States. Primary IGFD is a growth hormone-resistant state characterized by lack of insulin-like growth factor-1 (IGF-1) production in the presence of normal or elevated levels of endogenous growth hormone. Approximately 6,000 children suffer from a more severe form of this condition, called severe primary IGFD (Tercica, Inc., 2005). Severe primary IGFD includes persons with mutations in the GH receptor (GHR), post-GHR signaling pathway, and IGF-1 gene defects; these persons are not GH deficient, and therefore, they cannot be expected to respond adequately to exogenous GH treatment.
The U.S. Food and Drug Administration (FDA) has approved two injectable drugs for the treatment of growth failure in children with severe primary IGFD or with GH gene deletion who have developed neutralizing antibodies to GH. Both mecasermin (Increlex) (Tercica, Inc., Brisbane, CA) and mecasermin rinfabate (Iplex) (Insmed, Inc., Glen Allen, VA) have been approved as part of the FDA’s orphan drug program in which drugs designed to treat rare conditions or those with few available therapies are given expedited approval. Both drugs contain recombinant human insulin-like growth factor-1 (rhIGF-1), which is identical to the natural hormone, IGF-1. In humans, IGF-1 is released in response to stimulation by GH, and has a broad range of activity central to growth and metabolism. Increlex and Iplex seek to replicate the naturally occurring form of IGF-1, providing patients who are IGF-1 deficient with a viable replacement source for the protein. Under normal circumstances, GH binds to its receptor in the liver and other tissues and stimulates the synthesis of IGF-1. In target tissues, the type 1 IGF-1 receptor, which is homologous to the insulin receptor, is activated by IGF-1, leading to intracellular signaling, thus stimulating statural growth. The metabolic actions of IGF-1 stimulate the uptake of glucose, fatty acids, and amino acids, which lead to cell, tissue, organ, and skeletal growth. In addition to having IGF-1 activity, Iplex contains a binding protein, binding protein-3 (rhIGFBP-3), which seeks to maintain equilibrium of these proteins in the blood.
The FDA’s approval of Increlex was based upon the results of five Phase III clinical studies (four open-label and one double-blind, placebo-controlled), with subcutaneous doses of Increlex generally ranging from 0.06 to 0.12 mg/kg administered twice daily for the treatment of short stature caused by severe primary IGFD (n = 71). Patients were enrolled in the trials on the basis of extreme short stature, slow growth rates, low IGF-1 serum concentrations, and normal GH secretion. In clinical studies, normal growth hormone was defined as serum GH level (peak level) of greater than 10 nanograms per milliliter (ng/ml) (20 mU/liter), after stimulation with insulin, levodopa, arginine, propranolol, clonidine, or glucagons, or an unstimulated (basal) serum GH level of greater than 5 ng/ml. Data from these five clinical studies were pooled for global efficacy and safety analysis. Of these children, 61 completed at least one year of rhIGF-1 replacement therapy, which is the generally accepted minimum length of time required to adequately measure growth responses to drug therapy. Fifty-three (87%) had Laron Syndrome; 7 (11%) had GH gene deletion, and 1 (2%) had neutralizing antibodies to GH. Data from the study, presented during the 86th Annual Meeting of The Endocrine Society (June 2004), demonstrated a statistically significant increase (p<0.001) in growth rate over an eight-year period in response to therapy. Compared to pre-treatment growth patterns, on average, children gained an additional inch per year for each year of therapy over the course of eight years. Patients were treated for an average of 3.9 years, with some patients being treated up to 11.5 years. An analysis of safety in the study concluded that long-term treatment with rhIGF-1 appears to be well tolerated. Side effects were mild to moderate in nature and included hypoglycemia (42%), injection site lipohypertrophy, and tonsillar hypertrophy (15%). Intracranial hypertension occurred in three subjects. Funduscopic examination is recommended at the initiation and periodically during the course of Increlex therapy. Symptomatic hypoglycemia was generally avoided when a meal or snack was consumed either shortly before (i.e., 20 minutes) or after the administration of Increlex.
According to the FDA-approved product labeling, Increlex is indicated for the long-term treatment of growth failure in children with severe primary IGF-1 deficiency (primary IGFD) or with GH gene deletion who have developed neutralizing antibodies to GH. Increlex is not intended for use in individuals with secondary forms of IGF-1 deficiency, such as GH deficiency, malnutrition, hypothyroidism, or chronic treatment with pharmacologic doses of anti-inflammatory steroids. Thyroid and nutritional deficiencies should be corrected before initiating Increlex treatment. Increlex is not a substitute for GH treatment (Tercica, Inc., 2005).
The recommended starting dose of Increlex is 0.04 to 0.08 mg/kg twice daily by subcutaneous injection. If well-tolerated for at least one week, the dose may be increased by 0.04 mg/kg per dose, to the maximum dose of 0.12 mg/kg given twice daily. Doses greater than 0.12 mg/kg given twice daily have not been evaluated in children with primary IGFD and due to potential hypoglycemic effects should not be used. Increlex must be stored in the refrigerator (Tercica, Inc., 2005).
Tercica, Inc. is currently conducting a broad-scale Phase IIIb clinical study to evaluate the safety and efficacy of Increlex in children with primary IGFD. These patients will have less severe disease than the patients in Tercica's Phase III studies included in the company's New Drug Application (NDA) to the FDA.
According to the FDA-approved labeling for Increlex, contraindications to Increlex include the following:
- Patients with closed epiphyses (bone growth plates are closed)
- Active or suspected neoplasia
- Allergy to mecasermin (IGF-1) or any of the inactive ingredients in Increlex
- Growth failure associated with other identifiable causes (e.g., Prader-Willi syndrome, Russell-Silver syndrome, Turner syndrome, Noonan syndrome or chromosomal abnormality)
- Chronic illness (e.g., diabetes, cystic fibrosis, etc.).
Iplex contains rhIGF-1 and insulin-like growth factor binding protein-3 (rhIGFBP-3). The primary effect of IGFBP-3 in humans is to regulate the release of IGF-1 to target tissues as needed. Iplex has a longer half-life than Increlex and seeks to reduce the risk of short and long-term adverse events that have been associated with unbound levels of free IGF-1.
The FDA's approval of Iplex was based upon two cohort studies in children and adolescents with primary IGF-1 deficiency (IGFD) who received up to 2 mg/kg mecasermin rinfabate administered once daily by subcutaneous injection. Subjects included primary IGFD due to GH receptor deficiency (Laron syndrome) (n = 32 or 89%), GH gene deletion with neutralizing antibodies to GH (n = 3 or 8%), and one primary IGFD of unknown etiology. In the first cohort, subjects (n = 16) received up to 1 mg/kg daily for the first 12 months. The mean height velocity reportedly increased from 3.4 cm/year pre-treatment to 6.4 cm/year at 12 months (p < 0.0001). In the second cohort (n = 9), doses were titrated up to 2 mg/kg daily for 6 months. The investigators reported that the mean height velocity increased from 2.0 cm/year pre-treatment to 8.3 cm/year at 6 months (p < 0.0001). Children with genetic and acquired forms of GH insensitivity or IGFD appeared to respond equally well to treatment. Patients were treated for an average of 10.4 months. Safety information beyond one year of treatment is limited. The most common treatment-related adverse advents were mild hypoglycemia (31%), headaches (22%), and tonsillar and/or adenoid hypertrophy (19%). As is common with protein therapeutics, antibodies to the protein complex were detected in most patients, but were not associated with growth attenuation or adverse effects.
According to the FDA-approved product labeling, Iplex is indicated for the treatment of growth failure in children with severe primary IGF-1 deficiency (primary IGFD) or with GH gene deletion who have developed neutralizing antibodies to GH. Iplex is not intended for use in subjects with secondary forms of IGF-1 deficiency, such as GH deficiency, malnutrition, hypothyroidism, or chronic treatment with pharmacologic doses of anti-inflammatory steroids. Thyroid and nutritional deficiencies should be corrected before initiating Iplex treatment. Iplex is not a substitute for GH treatment (Insmed, Inc., 2005).
The recommended starting dose of Iplex is 0.5 mg/kg, to be increased into the therapeutic dose range of 1 to 2 mg/kg, once daily by subcutaneous injection. Dosage should be adjusted downward in the event of adverse effects (including hypoglycemia) and/or IGF-1 levels that are greater than or equal to 3 standard deviations above the normal reference range for IGF-1. Iplex must be kept frozen and thawed at room temperature for approximately 45 minutes before use (Insmed, Inc., 2005).
Iplex is also being investigated for various other indications, including extreme insulin resistance, myotonic muscular dystrophy, HIV-associated adipose redistribution syndrome (HARS), and short stature in children with primary IGFD associated with Noonan syndrome.
Rosenbloom (2006) questioned the use of recombinant IGF-1 in the treatment of idiopathic short stature. The author noted that there is no evidence that a substantial number of children with this condition are GH-insensitive, or that those who have lower concentrations of IGF-1 or GH-binding protein are less responsive to treatment with recombinant human GH than those with more normal baseline values. A rationale for monotherapy with IGF-1 or IGF-1 plus IGF binding protein 3 (IGFBP3) for growth other than for the specific indications characterized by unquestioned GH unresponsiveness is lacking, and considerable evidence suggests that treatment with IGF-1 or IGF-1 plus IGFBP3 will be less effective than GH monotherapy in individuals with idiopathic short stature.
According to the FDA-approved labeling for Iplex, contraindications to Iplex include the following:
- Patients with closed epiphyses (bone growth plates are closed)
- Active or suspected neoplasia
- Allergy to mecasermin rinfabate (rhIGF-1/rhIGFBP-3) or any of the excipients in Iplex
- Intravenous administration of Iplex is contraindicated.
In summary, both Increlex and Iplex have been shown to be effective; however, there are no studies comparing the efficacy of Increlex with Iplex (Kemp and Thrailkill, 2006). In addition; Increlex requires twice daily injection, may cause hypoglycemia (42%) and requires product refrigeration until use. Iplex requires once daily injection, may cause hypoglycemia (31%), and must be kept frozen and thawed at room temperature for approximately 45 minutes before use.
Appendix
Basal serum IGF-1 reference ranges: Normal serum IGF-1 values vary by age, sex, and pubertal status. Reference ranges for serum IGF-1 vary among laboratories. The reference range for the laboratory performing the test should be used to determine whether the member’s basal serum IGF-1 level meets criteria.
Height standard deviation score: The following website includes growth charts for children indicating heights (lengths) with curves down to 3 standard deviations: http://www.humatrope.com/pediatric_patients/hcp_clinical_tools.jsp?reqNavId=3.2.
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