Cigna Drug and Biologic Coverage Policy

Cigna Drug and Biologic Coverage Policy Subject Mecasermin Table of Contents Coverage Policy... 1 General Background... 3 Coding/Billing Information... 5 References... 5 Effective Date... 5/15/2017 Next Review Date... 4/15/2018 Coverage Policy Number... 6107 Related Coverage Resources Somatropin (Genotropin, Humatrope, Norditropin, Nutropin, Nutropin AQ, Omnitrope, Saizen, Serostim, Tev- Tropin, Zorbtive ) INSTRUCTIONS FOR USE The following Coverage Policy applies to health benefit plans administered by Cigna companies. Coverage Policies are intended to provide guidance in interpreting certain standard Cigna benefit plans. Please note, the terms of a customer s particular benefit plan document [Group Service Agreement, Evidence of Coverage, Certificate of Coverage, Summary Plan Description (SPD) or similar plan document] may differ significantly from the standard benefit plans upon which these Coverage Policies are based. For example, a customer s benefit plan document may contain a specific exclusion related to a topic addressed in a Coverage Policy. In the event of a conflict, a customer s benefit plan document always supersedes the information in the Coverage Policies. In the absence of a controlling federal or state coverage mandate, benefits are ultimately determined by the terms of the applicable benefit plan document. Coverage determinations in each specific instance require consideration of 1) the terms of the applicable benefit plan document in effect on the date of service; 2) any applicable laws/regulations; 3) any relevant collateral source materials including Coverage Policies and; 4) the specific facts of the particular situation. Coverage Policies relate exclusively to the administration of health benefit plans. Coverage Policies are not recommendations for treatment and should never be used as treatment guidelines. In certain markets, delegated vendor guidelines may be used to support medical necessity and other coverage determinations. Proprietary information of Cigna. Copyright 2017 Cigna Coverage Policy Cigna covers mecasermin (Increlex ) as medically necessary for the treatment of growth failure in children with severe primary insulin-like growth factor-1 (IGF-1) deficiency and ALL of the following: child is 2 years of age or older height standard deviation score less than or equal to 3.0 basal IGF-1 standard deviation score less than or equal to 3.0 normal or elevated growth hormone (GH) child is not concurrently treated for growth hormone deficiency (GHD) Note: Severe primary IGF-1 deficiency includes patients with mutations in the GH receptor (GHR), post- GHR signaling pathway, and IGF-1 gene defects. Cigna covers mecasermin (Increlex ) as medically necessary for the treatment of growth failure in children with growth hormone (GH) gene mutation with development of neutralizing antibodies to GH and ALL of the following: child is 2 years of age or older evidence of (GH1) gene mutation presence of GH neutralizing antibodies child is not concurrently treated for growth hormone deficiency (GHD) Page 1 of 5

initial criteria for growth hormone deficiency (GHD) in children were met, including BOTH of the following: o auxologic evaluation (stature and growth velocity data), including ONE of the following: individual s height is more than 2 standards of deviation (SD) below average for the population mean height for age and sex, AND a height velocity measured over one year is more than 1 SD below the mean for chronological age. individual s height velocity measured over one year is more than 2 SD below the mean for age and sex OR more than 1.5 SD below the mean sustained over two years o diagnostic evaluation, including BOTH of the following: growth hormone response of less than 10 ng/ml to at least two provocative stimuli of growth hormone release: clonidine, glucagon, insulin, L-arginine, levodopa, propranolol. One abnormal growth hormone stimulation test is sufficient for children with defined central nervous system (CNS) pathology (for example, empty sella syndrome, interruption of pituitary stalk, hypoplasia of the pituitary gland, craniofacial developmental defects, pituitary or hypothalamic tumors, etc.); multiple pituitary hormone deficiency (MPHD) (i.e., deficiency of two or more pituitary hormones) or a proven genetic defect affecting the growth hormone axis. other pituitary hormone deficiencies (for example, thyroid, cortisol or sex steroids) have been ruled out and/or corrected prior to time of testing Standard re-authorization criteria apply: Yearly reassessment for reauthorization of coverage is required. Coverage for continuation of therapy requires meeting current initial use criteria and evidence of a beneficial response as shown by growth curve chart. Coverage for growth promotion will cease when the bony epiphyses have closed. Child is not concurrently treated for growth hormone deficiency (GHD) Cigna does NOT cover mecasermin (Increlex ) for any other indication or for treatment of secondary forms of IGF-1 deficiency due to ANY of the following because it is considered experimental, investigational or unproven (this list may not be all-inclusive): GH deficiency malnutrition hypothyroidism chronic treatment with pharmacologic doses of anti-inflammatory drugs Cigna does NOT cover mecasermin (Increlex) for the diagnosis/treatment/management of the following conditions because they are considered not medically necessary (this list may not be all-inclusive): idiopathic (i.e. of unknown origin) short stature, also called non-growth hormone deficient short stature in children When coverage is available and medically necessary, the dosage, frequency, duration of therapy, and site of care should be reasonable, clinically appropriate, and supported by evidence-based literature and adjusted based upon severity, alternative available treatments, and previous response to mecasermin (Increlex ) therapy. Note: Receipt of sample product does not satisfy any criteria requirements for coverage FDA Approved Indications Severe Primary IGF-1 Deficiency (Primary IGFD) Page 2 of 5

Increlex is indicated for the treatment of growth failure in children, 2 years and older, with severe primary IGF-1 deficiency or growth hormone (GH) gene deletion who have developed neutralizing antibodies to GH. Severe Primary IGF-1 deficiency (IGFD) is defined by: height standard deviation score 3.0 and basal IGF-1 standard deviation score 3.0 and normal or elevated growth hormone (GH) Severe primary IGFD includes classical and other forms of growth hormone insensitivity. Patients with primary IGFD may have mutations in the GH receptor (GHR), post-ghr signaling pathway including the IGF-1 gene. They are not GH deficient, and therefore, they cannot be expected to respond adequately to exogenous GH treatment. Increlex 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 antiinflammatory steroids. Thyroid and nutritional deficiencies should be corrected before initiating Increlex treatment. Limitations of use: Increlex is not a substitute to GH for approved GH indications. (2016) FDA Recommended Dosing Preprandial glucose monitoring is recommended at treatment initiation and until a well-tolerated dose is established. If frequent symptoms of hypoglycemia or severe hypoglycemia occur, preprandial glucose monitoring should continue. The dosage of Increlex should be individualized for each patient. The recommended starting dose of Increlex is 0.04 to 0.08 mg/kg (40 to 80 micrograms/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 should be administered shortly before or after (± 20 minutes) a meal or snack. If the patient is unable to eat shortly before or after a dose for any reason, that dose of Increlex should be withheld. Subsequent doses of Increlex should never be increased to make up for one or more omitted doses. Drug Availability Increlex is supplied as a 10 mg per ml sterile solution in multiple dose glass vials (40 mg per vial). General Background Disease Overview IGF-I deficiency has also been called growth hormone insensitivity syndrome or growth hormone resistance syndrome. IGF-I deficiency was first described in a severe form, due to a block of growth hormone action at the level of the growth hormone receptor. As a consequence of this abnormal growth hormone receptor function, little IGF-I is produced. The ensuing severe IGF-I deficiency causes a type of growth failure that resembles the growth failure seen in patients with severe growth hormone deficiency. However, patients with severe IGF-I deficiency have normal concentrations of growth hormone. This primary form of severe IGF-I deficiency is differentiated from secondary forms of IGF-I deficiency or growth hormone insensitivity, caused by, for example, malnutrition, GH deficiency or hypothyroidism. (Backeljauw, 2014) Pharmacology Mecasermin contains recombinant deoxyribonucleic acid (DNA)-engineered human insulin-like growth factor-1 (rhigf-1). It is designed to replace natural IGF-1 in pediatric patients who are deficient, promoting normalized statural growth. Patients with severe primary IGF-1 deficiency (primary IGFD) fail to produce adequate levels of IGF-1, due to disruption of the growth hormone (GH) pathway used to promote IGF-1 release (possible GH pathway disruptions include mutations in the GH receptor [GHR], post-ghr signaling pathway, and IGF-1 gene defects). The active ingredient of mecasermin is identical to the natural hormone IGF-1, which the body normally produces in response to stimulation by GH. IGF-1 is the direct mediator of growth hormone's effect on statural growth and must be present in order for children's Page 3 of 5

bones, cartilage and organs to grow normally. Without adequate IGF-1, children cannot achieve a height within the normal range. (McEvoy, 2016) Severe primary IGFD can lead to a range of other metabolic disorders, including lipid abnormalities, decreased bone density, obesity, and insulin resistance. Mecasermin is the first product based on the IGF-1 protein approved by the FDA specifically indicated for the long-term treatment of growth failure in pediatric patients with Primary IGFD or with GH gene deletion who have developed neutralizing antibodies to GH. Mecasermin is not indicated to treat secondary IGFD resulting from GH deficiency, malnutrition, hypothyroidism or chronic treatment with pharmacologic doses of anti-inflammatory steroids. Thyroid and nutritional deficiencies should be corrected before initiating mecasermin treatment. Mecasermin is not a substitute for GH treatment. Mecasermin was 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. (McEvoy, 2016) Guidelines Pediatric Endocrine Society The Pediatric Endocrine Society provides guidance regarding the use of IGF-1 therapy to increase height in patients with severe Primary Insulin-like Growth Factor Deficiency and administering IGF-1 20 minutes after a carbohydrate-containing meal or snack. In addition, the guideline recommends a trial of GH therapy before initiating IGF-1 for patients with unexplained IGF-1 deficiency. This recommendation, however, is not supported by clinical trial evidence. Patients with hormone signaling defects known to be unresponsive to GH treatment can start directly on IGFI replacement; these include patients with very low or undetectable levels of GHBP and/or proven GHR gene mutations known to be associated with Laron syndrome/ GHIS, GH-neutralizing antibodies, STAT5b gene mutations, and IGF1 gene deletion or mutation. (Grimberg, 2016) Clinical Efficacy FDA Approved Indications Approval of mecasermin was based on five clinical trials of the drug: four were open-label studies, and one was double-blind and placebo-controlled. The studies enrolled a total of 71 children suffering from extreme short stature; all children exhibited symptoms of Primary IGFD, including slow growth rates, low IGF-1 serum concentrations and normal growth hormone secretion. Data from these 5 clinical studies were pooled for a global efficacy and safety analysis. Baseline characteristics for the patients evaluated in the primary and secondary efficacy analyses were (mean, SD): chronological age (years): 6.7 ± 3.8; height (cm): 84.8 ± 15.3 cm; height standard deviation score (SDS): -6.7 ± 1.8; height velocity (cm/yr): 2.8 ± 1.8; height velocity SDS: -3.3 ± 1.7; IGF-1 (ng/ml): 21.6 ± 20.6; IGF-1 SDS: -4.3 ± 1.6; and bone age (years): 4.2 ± 2.8. Sixty-one subjects had at least one year of treatment. Fifty-three (87%) had Laron Syndrome; 7 (11%) had GH gene deletion, and 1 (2%) had neutralizing antibodies to GH. Thirty-seven (61%) of the Reference ID: 3902304 subjects were male; forty-eight (79%) were Caucasian. Fifty-six (92%) of the subjects were prepubertal at baseline. Forty-nine subjects were included in an analysis of the effects of INCRELEX on bone age advancement. The mean ± SD change in chronological age was 4.9 ± 3.4 years and the mean ± SD change in bone age was 5.3 ± 3.4 years. An analysis of safety showed that long-term treatment with mecasermin has an acceptable safety profile and appears to be well tolerated. Side effects were mild to moderate in nature and included hypoglycemia (42%), tonsillar hypertrophy (15%) and intracranial hypertension (4%). Funduscopic examination is recommended at the initiation and periodically during the course of Increlex therapy. Experimental, Investigational, Unproven Uses Case series and randomized controlled trials have investigated mecasermin for several conditions, including the following: Autism Spectrum Disorder Bone loss associated with anorexia Phelan- McDermid syndrome Prevention of Retinopathy of Prematurity Page 4 of 5

Rett syndrome Amyotrophic Lateral Sclerosis (ALS) Coding/Billing Information Note: Increlex is typically covered under pharmacy benefit plans. Certain prescription drugs require an authorization for coverage to ensure that appropriate treatment regimens are followed. Medical drug coding and diagnosis codes, however, are generally not required for pharmacy claims submissions, therefore, this section is not in use. References 1. Backeljauw P, Dattani M, Cohen P, Rosenfeld R. Pediatric Endocrinology. 4th ed. Philadelphia, PA: Saunders Elsevier; 2014: 291-404 2. Grimberg A, DiVall S, Polychronakos C, et al. On behalf of the Drug and Therapeutics Committee and Ethics Committee of the Pediatric Endocrine Society. Guidelines for Growth Hormone and Insulin- Like Growth Factor-I Treatment in Children and Adolescents: Growth Hormone Deficiency, Idiopathic Short Stature, and Primary Insulin-Like Growth Factor-I Deficiency. Horm Res Paediatr Nov 2016; 86: 361 397. 3. Ipsen Biopharmaceuticals, Inc., Increlex (mecasermin [rdna origin] injection) Product Information. Basking Ridge, NJ: Ipsen Biopharmaceuticals. March 2016. 4. McEvoy GK, ed. AHFS 2016 Drug Information. Bethesda, MD: American Society of Health-Systems Pharmacists, Inc. 2016.. The registered marks "Cigna" and the "Tree of Life" logo are owned by Cigna Intellectual Property, Inc., licensed for use by Cigna Corporation and its operating subsidiaries. All products and services are provided by or through such operating subsidiaries and not by Cigna Corporation. Such operating subsidiaries include Connecticut General Life Insurance Company, Cigna Health and Life Insurance Company, Cigna Behavioral Health, Inc., Cigna Health Management, Inc., and HMO or service company subsidiaries of Cigna Health Corporation. Page 5 of 5