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 AC-AEINC102011 Page 1 of 11 Copyright 2016 No part of this document may be reproduced without permission ActiveHealth Management Medical Management Guidelines 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 AC-AEINC102011 Page 2 of 11 Copyright 2016 No part of this document may be reproduced without permission ActiveHealth Management Medical Management Guidelines 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 AC-AEINC102011 Page 3 of 11 Copyright 2016 No part of this document may be reproduced without permission ActiveHealth Management Medical Management Guidelines 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.