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 (GH)-resistant state characterized by lack of insulin-like growth factor-1 (IGF-1) production in the presence of normal or elevated levels of endogenous GH. 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 can not be expected to respond adequately to exogenous GH treatment.
The U.S. Food and Drug Administration (FDA) has approved 2 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 IGF-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 intra-cellular 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 5 phase III clinical studies (4 open-label and 1 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 GH 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 5 clinical studies were pooled for global efficacy and safety analysis. Of these children, 61 completed at least 1 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 8-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 8 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 %). Intra-cranial hypertension occurred in 3 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 mins) 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 1 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:
- Active or suspected neoplasia
- Allergy to mecasermin (IGF-1) or any of the inactive ingredients in Increlex
- Chronic illness (e.g., cystic fibrosis, diabetes, etc.)
- Growth failure associated with other identifiable causes (e.g., chromosomal abnormality, Noonan syndrome, Prader-Willi syndrome, Russell-Silver syndrome, or Turner syndrome)
- Patients with closed epiphyses (bone growth plates are closed)
Iplex contains rhIGF-1 and IGF 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 2 cohort studies in children and adolescents with primary 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 1 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 1 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 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 mins 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.
A Cochrane systematic evidence review of the effectiveness of recombinant IGF-1 in amyotrophic lateral sclerosis (ALS) found that the available randomized placebo controlled trials do not permit a definitive assessment of the clinical efficacy of recombinant IGF-1 on ALS (Mitchell et al, 2007). Two randomized controlled trials involving 449 patients measured disease progression on a clinical rating scale of disease severity in amyotrophic lateral sclerosis. The combined results showed a small significant benefit in favor of recombinant IGF-1, the clinical relevance of which is unclear. The authors concluded that more research is needed, noting that one trial is in progress. They recommended that future trials should include survival as an outcome measure.
Rosenbloom (2009) stated that although the insulin-sensitizing effect may benefit both type 1 and type 2 diabetes, there are no ongoing clinical trials because of concern about risk of retinopathy and other complications. Promotion of rhIGF-I for the treatment of idiopathic short stature has been intensive, with neither data nor rationale suggesting that there might be a better response than has been documented with rhGH. Other applications that have either been considered or are undergoing clinical trial are based on the ubiquitous tissue-building properties of IGF-I and include chronic liver disease, cystic fibrosis, wound healing, AIDS muscle wasting, burns, osteoporosis, Crohn's disease, anorexia nervosa, Werner syndrome, X-linked severe combined immunodeficiency, Alzheimer's disease, muscular dystrophy, ALS, hearing loss prevention, spinal cord injury, cardiovascular protection, and prevention of retinopathy of prematurity. The most frequent side effect is hypoglycemia, which is readily controlled by administration with meals. Other common adverse effects involve hyperplasia of lymphoid tissue, which may require tonsillectomy/adenoidectomy, accumulation of body fat, and coarsening of facies. The anti-apoptotic properties of IGF-I are implicated in cancer pathogenesis -- a concern for long-term therapy. It is unlikely that mecasermin will be useful beyond the orphan indications of severe insulin resistance and GH insensitivity.
According to the FDA-approved labeling for Iplex, contraindications to Iplex include the following:
- Active or suspected neoplasia
- Allergy to mecasermin rinfabate (rhIGF-1/rhIGFBP-3) or any of the excipients in Iplex
- Intravenous administration of Iplex
- Patients with closed epiphyses (bone growth plates are closed)
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 mins before use.
IGF-1 analogue therapy is no longer necessary once fusion of the epiphysis has occurred. If growth in height velocity does not increase by 2 cm after 1 year of therapy, the physician should re-evaluate the cause of growth failure.
Kemp (2009) noted that mecasermin is approved by the U.S. FDA and the European Medicines Agency for the treatment of patients with severe primary IGFD or for patients with GH1 gene deletion who have developed neutralizing antibodies to GH. Moreover, mecasermin rinfabate (Iplex), is not available in the U.S. or Europe for treating conditions involving short stature, because of a court order related to patent infringement. Mecasermin has been shown to be effective in increasing height velocity and adult height in patients with severe GH resistance and in IGF-1 gene deletion. There has been some interest in using mecasermin to treat patients with partial GH resistance or idiopathic short stature. At the present time, the data are insufficient to make this recommendation.
On July 27, 2009, Insmed Inc (manufacturer of Iplex) announced that the Company will cease the supply of Iplex to any new patients. In addition, the Company will not initiate further clinical trials with Iplex at this time. The Company has determined that its limited inventory on hand must be conserved for the treatment of existing patients. Furthermore, the FDA and Insmed have agreed that access to Iplex for investigational use in patients with ALS will occur in 2 ways under Investigational New Drug applications (INDs):
- Single-patient INDs requesting “compassionate use” of Iplex for treatment of named patients with ALS, received and date-stamped by FDA’s document room by close of business on March 6, 2009, will be allowed to proceed, and Insmed has agreed to supply Iplex to those patients; and
- The remaining supply of Iplex, which is very limited, will be used by Insmed to conduct a clinical trial under an IND in which other patients with ALS who are interested in receiving Iplex treatment will be randomly assigned to receive drug through a lottery system.
In a 1-year, randomized, open-label trial, Midyett et al (2010) examined the safety and effectiveness of rhIGF-I in short children with low IGF-I levels. A total of 136 short, pre-pubertal subjects with low IGF-I (height and IGF-I sd scores less than -2, stimulated GH greater than or equal to 7 ng/ml); 124 completed the study, and 6 withdrew for adverse events and 6 for other reasons. Recombinant human IGF-I was administered subcutaneously, twice-daily using weight-based dosing (40, 80, or 120 microg/kg; n = 111) or subjects were observed (n = 25). First-year height velocity (centimeters per year, cm/yr), height SD score, IGF-I, and adverse events were pre-specified outcomes. First-year height velocities for subjects completing the trial were increased for the 80- and 120-microg/kg twice-daily versus the untreated group (7.0 +/- 1.0, 7.9 +/- 1.4, and 5.2 +/- 1.0 cm/yr, respectively; all p < 0.0001) and for the 120- versus 80-microg/kg group (p = 0.0002) and were inversely related to age. They were not predicted by GH stimulation or IGF-I generation test results and were not correlated with IGF-I antibody status. The most commonly reported adverse events of special interest during treatment were headache (38 % of subjects), vomiting (25 %), and hypoglycemia (14 %). The authors concluded that rhIGF-I treatment was associated with age- and dose-dependent increases in first-year height velocity. Adverse events during treatment were less common than in previous studies and were generally transient, easily managed, and without known sequelae. However, the authors noted that it is premature to state whether or not rhIGF-I treatment may alter adult height. A long-term extension trial is currently underway, which may provide some insight on this issue.
In a review on the potential of cytokines and growth factors in the treatment of ischemic heart disease, Beohar et al (2010) stated that the effect of GH on myocardial growth, cardiac function, and IGF-1 levels in patients with non-ischemic as well as ischemic cardiomyopathy, and in mixed patient populations, has been examined in several small studies. The authors concluded that available evidence suggested that more investigations with GH or IGF-1 are needed, despite concerns regarding retinopathy and other potential long-term side effects.
The European Federation of Neurological Societies’ guidelines on “The clinical management of amyotrophic lateral sclerosis” (EFNS, 2012) noted that “Currently, there is insufficient evidence to recommend treatment with vitamins, testosterone, antioxidants such as co-enzyme Q-10 and gingko biloba, intravenous immunoglobulin therapy, cyclosporin, interferons, Copaxone, KDI tripeptide, neurotrophic factors (including brain-derived neurotrophic factor [BDNF], insulin-like growth factor-1 [IGF-1], and mecasermin rinfabate), ceftriaxone, creatine, gabapentin, minocycline, stem cells, or lithium”.
Rinaldi et al (2012) noted that spinal and bulbar muscular atrophy is an X-linked motor neuron disease caused by poly-glutamine expansion in the androgen receptor. Patients develop slowly progressive proximal muscle weakness, muscle atrophy and fasciculations. Affected individuals often show gynecomastia, testicular atrophy and reduced fertility as a result of mild androgen insensitivity. No effective disease-modifying therapy is currently available for this disease. Recent studies by these investigators have demonstrated that IGF-1 reduces the mutant androgen receptor toxicity through activation of Akt in-vitro, and spinal and bulbar muscular atrophy transgenic mice that also over-express a non-circulating muscle isoform of IGF-1 have a less severe phenotype. These researchers sought to establish the effectiveness of daily intra-peritoneal injections of mecasermin rinfabate, recombinant human IGF-1 and IGF-1 binding protein 3, in a transgenic mouse model expressing the mutant androgen receptor with an expanded 97 glutamine tract. The study was done in a controlled, randomized, blinded fashion, and, to reflect the clinical settings, the injections were started after the onset of disease manifestations. The treatment resulted in increased Akt phosphorylation and reduced mutant androgen receptor aggregation in muscle. In comparison to vehicle-treated controls, IGF-1-treated transgenic mice showed improved motor performance, attenuated weight loss and increased survival. The authors concluded that these findings suggested that peripheral tissue can be targeted to improve the spinal and bulbar muscular atrophy phenotype and indicated that IGF-1 warrants further investigation in clinical trials as a potential treatment for this disease.
Kim and colleagues (2013) examined the effects of recombinant IGF-I in an adipocyte model of HIV lipodystrophy and in an open label study on body composition and metabolism in patients with HIV-associated lipodystrophy. The effects of IGF-I on ritonavir-induced adipocyte cell death were studied in-vitro. These researchers assessed lipid accumulation, IGF signaling, apoptosis, and gene expression. They conducted a 24-week open label trial of recombinant IGF-I in 10 adults with HIV-associated lipoatrophy. Laboratory assessments included glucose, insulin, lipids, and IGF-I. At weeks 0 and 24, body composition studies were performed including skinfold measurement, dual-energy x-ray absorptiometry, and computed tomography of the abdomen and thigh. In-vitro, ritonavir increased delipidation and apoptosis of adipocytes, whereas co-treatment with IGF-I attenuated the effect. In the clinical study, subcutaneous adipose tissue did not increase in patients after treatment with IGF-I; however, there was a decrease in the proportion of abdominal fat (39.8 ± 7 % versus 34.6 ± 7 %, p = 0.007). IGF-I levels increased with treatment (143 ± 28 μg/L at week 0 versus 453 ± 212 μg/L at week 24, p = 0.002), whereas IGFBP-3 levels declined (3.554 ± 1.146 mg/L versus 3.235 ± 1.151 mg/L, p = 0.02). Insulin at week 12 week decreased significantly (90.1 ± 39.8 pmol/L versus 33.2 ± 19.6 pmol/L, p = 0.002). There was a non-significant decrease in visceral adipose tissue (155.2 ± 68 cm2 at week 0 versus 140.6 ± 70 cm2 at week 24, p = 0.08). The authors concluded that use of recombinant IGF-I may lower fasting insulin and abdominal fat in patients with lipoatrophy associated with HIV infection. Moreover, they stated that further evaluation of this agent for treatment of HIV-associated lipodystrophy may be warranted.
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 2 standard deviations (approximately 3rd percentile).
Centers for Disease Control and Prevention: http://www.cdc.gov/growthcharts/