Increlex AHM

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Increlex AHM

Clinical Indications

• Mecasermin (Increlex) and mecasermin rinfabate (Iplex) is considered medically necessary for the treatment of growth failure in children who meet 1 or more of the following criteria o Mecasermin (Increlex) and mecasermin rinfabate (Iplex) is considered medically necessary for the treatment of growth failure in children with severe primary insulin-like growth factor-1 deficiency (primary IGFD) who meet ALL of the following selection criteria [A] [B] . Basal insulin-like growth factor-1 (IGF-1) standard deviation score less than or equal to -3.0 for age and sex . Height standard deviation score less than or equal to -3.0 for age and sex . Normal or elevated growth hormone (GH) (defined as stimulated serum GH level (peak level) of greater than 10 nanograms per milliliter (ng/ml) or basal (unstimulated) serum GH level greater than 5 ng/ml) o Mecasermin (Increlex) and mecasermin rinfabate (Iplex) is considered medically necessary for treatment of growth failure in children with GH gene deletion who have developed neutralizing antibodies to GH • Mmecasermin (Increlex) and mecasermin rinfabate (Iplex) is considered investigational for any of the following (not an all inclusive list) o cardiovascular protection o prevention of hearing loss o prevention of retinopathy of prematurity o treatment of AIDS muscle wasting o treatment of amyotrophic lateral sclerosis o treatment of Alzheimer's disease o treatment of anorexia nervosa o treatment of burns o treatment of chronic liver disease o treatment of Crohn's disease o treatment of cystic fibrosis o treatment of extreme insulin resistance o treatment of HIV-associated adipose redistribution syndrome (HARS) o treatment of myotonic muscular dystrophy o treatment of osteoporosis o treatment of partial GH resistance

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o treatment of spinal cord injury o treatment of X-linked severe combined immunodeficiency o treatment of Werner syndrome o wound healing • Mecasermin rinfabate (Iplex) is currently not marketed because of a court order related to patent infringement • Contraindications to mecasermin (Increlex) and mecasermine rinfabate (Iplex) are presented in the background section • Subsequent Request o Patient is already on Increlex for one of the indications above AND the yearly review to assess medical appropriateness of continued treatment confirms ALL of the following documentation . Bone Age and Bone Mass evaluation- X-ray report confirms epiphyses have not yet closed (children age 10 years and older) . Linear Growth evaluation/growth velocity in past 12 months- Copy of updated growth chart shows growth rate remains > 2 cm/yr . Patient has not yet attained final height as growth plates not yet fused and height remains < 5th percentile of adult height (18 yr old on growth chart) for gender Absence of severe side effects

Indications considered Not Medically Necessary Return to top of Increlex AHM - AC

• Contraindications or indications to discontinue use include 1 or more of the following o Contraindications to Increlex include 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 o Therapy should be discontinued when 1 or more of the following are identified . Poor or no response . Attainment of final height and height reaches the 5th percentile for gender of adult height, i.e., 18- year-old on the growth chart . Growth Plates are closed . Renal transplantation and re-evaluate growth 1 year after transplantation to assess medical appropriateness (allow at least 1 year for catch-up growth)

Evidence Summary

• 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

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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

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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: active or suspected neoplasia, allergy to mecasermin (IGF-1) or any of the inactive ingredients in Increlex, chronic illness (e.g., diabetes, cystic fibrosis, etc.), growth failure associated with other identifiable causes (e.g., Prader-Willi syndrome, Russell-Silver syndrome, Turner syndrome, Noonan syndrome or chromosomal abnormality), and also patients with closed epiphyses (bone growth plates are closed). • 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.

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• 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. • 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. The authors 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 recombinant human IGF-1 (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, amyotrophic lateral sclerosis, hearing loss prevention, spinal cord injury, cardiovascular protection, and

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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, and 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 minutes 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 one 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 IGF deficiency 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 amyotrophic lateral sclerosis (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 1year, 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

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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

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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 ug/L at week 0 versus 453 +/- 212 ug/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. • 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 2 standard deviations (approximately 3rd percentile).

References

• Guler HP, Zapf J, Froesch ER. Short-term metabolic effects of recombinant human insulin-like growth factor I in healthy adults. N Engl J Med. 1987;317(3):137-140. • Malozowski S, Tanner LA, Wysowski D, Fleming GA. Growth hormone, insulin-like growth factor I, and benign intracranial hypertension [letter]. N Engl J Med. 1993;329(9):665-666. • Rosenfeld RG, Rosenbloom AL, Guevara-Aguirre J. Growth hormone (GH) insensitivity due to primary GH receptor deficiency. Endocr. 1994;15(3):369-390. AC-AEINC102011 Page 8 of 11 Copyright 2016 No part of this document may be reproduced without permission

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• Guevara-Aguirre J, Vasconez O, Martinez V, et al. A randomized, double blind, placebo-controlled trial on safety and efficacy of recombinant human insulin-like growth factor-I in children with growth hormone receptor deficiency. J Clin Endocrinol Metab. 1995;80(4):1393-1398. • Ranke MB, Savage MO, Chatelain PG, et al. Insulin-like growth factor I improves height in growth hormone insensitivity: Two years' results. Horm Res. 1995;44(6):253-264. • Backeljauw PF, Underwood LE. Prolonged treatment with recombinant insulin-like growth factor-I in children with growth hormone insensitivity syndrome--a clinical research center study. GHIS Collaborative Group. J Clin Endocrinol Metab. 1996;81(9):3312-3317. • Guevara-Aguirre J, Rosenbloom AL, Vasconez O, et al. Two-year treatment of growth hormone (GH) receptor deficiency with recombinant insulin-like growth factor I in 22 children: Comparison of two dosage levels and to GH-treated GH deficiency. J Clin Endocrinol Metab. 1997;82(2):629-633. • Azcona C, Preece MA, Rose SJ, et al. Growth response to rhIGF-I 80 microg/kg twice daily in children with growth hormone insensitivity syndrome: Relationship to severity of clinical phenotype. Clin Endocrinol (Oxf). 1999;51(6):787-792. • Underwood LE, Backeljauw P, Duncan V. Effects of insulin-like growth factor I treatment on statural growth, body composition and phenotype of children with growth hormone insensitivity syndrome. GHIS Collaborative Group. Acta Paediatr Suppl. 1999;88(428):182-184. • Backeljauw PF, Underwood LE; GHIS Collaborative Group. Growth hormone insensitivity syndrome. Therapy for 6.5-7.5 years with recombinant insulin-like growth factor I in children with growth hormone insensitivity syndrome: A clinical research center study. J Clin Endocrinol Metab. 2001;86(4):1504-1510. • Shaw NJ, Fraser NC, Rose S, et al. Bone density and body composition in children with growth hormone insensitivity syndrome receiving recombinant IGF-I. Clin Endocrinol (Oxf). 2003;59(4):487-491. • Clark RG. Recombinant human insulin-like growth factor I (IGF-I): Risks and benefits of normalizing blood IGF-I concentrations. Horm Res. 2004;62 Suppl 1:93-100. • Savage MO, Camacho-Hubner C, Dunger DB. Therapeutic applications of the insulin-like growth factors. Growth Horm IGF Res. 2004;14(4):301-308. • Ranke MB. Insulin-like growth factor-I treatment of growth disorders, diabetes mellitus and insulin resistance. Trends Endocrinol Metab. 2005;16(4):190-197. • U.S. National Institutes of Health (NIH), National Library of Medicine (NLM). Prepubertal children with growth failure associated with primary insulin-like growth factor-1 (IGF-1) deficiency. Clinical Trials Listing. Bethesda, MD: NIH; July 2005. Available at:http://www.clinicaltrials.gov/ct/gui/show/NCT00125164. Accessed September 2, 2005. • Tercica, Inc. FDA approves Tercica's Increlex for short stature caused by severe primary IGF-1 deficiency. Press Releases. Brisbane, CA: Tercica; August 31, 2005. Available at: http://trca.client.shareholder.com/ReleaseDetail.cfm?ReleaseID=171776. Accessed September 2, 2005. • Tercica, Inc. Increlex™ (mecasermin [rDNA origin] injection). Package Insert. NDA 21-839. Brisbane, CA: Tercica; August 2005. Available at: http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction= Search.Label_ApprovalHistory. Accessed September 16, 2005.

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• No authors listed. Mecasermin rinfabate: Insulin-like growth factor-I/insulin-like growth factor binding protein-3, mecaserimin rinfibate, rhIGF-I/rhIGFBP-3. Drugs R D. 2005;6(2):120-127. • Nichols Institute Diagnostics. Insulin-like growth factor I assay for the quantitative determination of insulin-like growth factor I in human serum. Products Listing. Rev. D. San Clemente, CA: Nichols Institute; revised December 2004. Available at: http://www.nicholsdiag.com/products/growth/di-igf-i.pdf. Accessed February 20, 2006. • Insmed, Inc. Iplex (mecasermin rinfabate). Proposed Package Insert. Glen Allen, VA: Insmed; December 2005. Available at: http://www.insmed.com/PDF/iPLEX_package_insert.pdf. Accessed June 5, 2006. • Kemp SF, Fowlkes JL, Thrailkill KM. Efficacy and safety of mecasermin rinfabate. Expert Opin Biol Ther. 2006;6(5):533-538. • Kemp SF, Thrailkill KM. Investigational agents for the treatment of growth hormone-insensitivity syndrome. Expert Opin Investig Drugs. 2006;15(4):409-415. • No authors listed. Mecasermin rinfabate: Insulin-like growth factor-I/insulin-like growth factor binding protein-3, mecaserimin rinfibate, rhIGF-I/rhIGFBP-3. Drugs R D. 2005;6(2):120-127. • Rosenbloom AL. Is there a role for recombinant insulin-like growth factor-I in the treatment of idiopathic short stature? Lancet. 2006;368(9535):612-616. • No authors listed. Insulin-like growth factor-1 for severe growth failure. Med Lett Drugs Ther. 2007;49(1261):43-44. • Rosenbloom AL. The role of recombinant insulin-like growth factor I in the treatment of the short child. Curr Opin Pediatr. 2007;19(4):458-464. • Mitchell JD, Wokke JHJ, Borasio GD. Recombinant human insulin-like growth factor I (rhIGF-I) for amyotrophic lateral sclerosis/motor neuron disease. Cochrane Database Syst Rev. 2007:(4):CD002064. • Keating GM. Mecasermin. BioDrugs. 2008;22(3):177-188. • Williams RM, McDonald A, O'Savage M, Dunger DB. Mecasermin rinfabate: rhIGF-I/rhIGFBP-3 complex: iPLEX. Expert Opin Drug Metab Toxicol. 2008;4(3):311-324. • Kemp SF. Insulin-like growth factor-I deficiency in children with growth hormone insensitivity: Current and future treatment options. BioDrugs. 2009;23(3):155-163. • U.S. Food and Drug Administration (FDA). Access to Iplex for patients with ALS. Information for Health Professionals (Drugs). Rockville, MD: FDA; July 27, 2009. Available at: http://www.fda.gov/Drugs/ResourcesForYou/HealthProfessionals/ucm118117.htm. Accessed September 15, 2009. • U.S. Food and Drug Administration (FDA). FDA position on allowing patients with ALS access to Iplex under an IND. Information for Health Professionals (Drugs). Rockville, MDL FDA; updated July 1, 2009. Available at: http://www.fda.gov/Drugs/ResourcesForYou/HealthProfessionals/ucm118121.htm. Accessed September 15, 2009. • No authors listed. Mecasermin: New drug. Insufficient improvement in statural growth. Prescrire Int. 2009;18(101):111-113. • Fintini D, Brufani C, Cappa M. Profile of mecasermin for the long-term treatment of growth failure in children and adolescents with severe primary IGF-1 deficiency. Ther Clin Risk Manag. 2009;5(3):553-559.

ActiveHealth Management Medical Management Guidelines

• No authors listed. Mecasermin: New drug. Insufficient improvement in statural growth. Prescrire Int. 2009;18(101):111-113. • Rosenbloom AL. Mecasermin (recombinant human insulin-like growth factor I). Adv Ther. 2009;26(1):40-54. • Midyett LK, Rogol AD, Van Meter QL, et al; MS301 Study Group. Recombinant insulin-like growth factor (IGF)-I treatment in short children with low IGF-I levels: First-year results from a randomized clinical trial. J Clin Endocrinol Metab. 2010;95(2):611-619. • Beohar N, Rapp J, Pandya S, Losordo DW. Rebuilding the damaged heart: The potential of cytokines and growth factors in the treatment of ischemic heart disease. J Am Coll Cardiol. 2010;56(16):1287-1297. • EFNS Task Force on Diagnosis and Management of Amyotrophic Lateral Sclerosis, Andersen PM, Abrahams S, Borasio GD, et al. EFNS guidelines on the clinical management of amyotrophic lateral sclerosis (MALS) -- revised report of an EFNS task force. Eur J Neurol. 2012;19(3):360-375. Available at: http://www.guideline.gov/content.aspx?id=38469&search=mecasermin. Accessed August 19, 2013. • Rinaldi C, Bott LC, Chen KL, et al. Insulinlike growth factor (IGF)-1 administration ameliorates disease manifestations in a mouse model of spinal and bulbar muscular atrophy. Mol Med. 2012;18:1261-1268. • Kim RJ, Vaghani S, Zifchak LM, et al. In vitro and in vivo effects of IGF-I on adiposity in HIV-associated metabolic disease: A pilot study. Arch Med Res. 2013 Jul 15. [Epub ahead of print]

Reviewed by a Board Certified Internist Reviewed by David Evans, MD, Medical Director, Active Health Management- Nov 2016 Copyright 2016 ACTIVEHEALTH MANAGEMENT No part of this document may be reproduced without permission.

Footnotes

[A] Note: Persons with severe primary IGFD include those with mutations in the GH receptor (GHR), post-GHR signaling pathway, and IGF-1 gene defects. [ A in Context Link 1 ]

[B] Note: IGF-1 analogue therapy is no longer considered medically necessary once fusion of the epiphysis has occurred. Treatment is also considered not medically necessary if there is evidence of neoplasia or intra-cranial hypertension. [ B in Context Link 1 ]

Codes

CPT® or HCPCS: 80428, 80429, 80430, 83003, 96372, 96379, 99506, J2170, J2170