INCRELEX, Mecasermin Form

Mecasermin (Increlex®) is a human insulin-like growth factor-1 (IGF-1). FDA Approved Indication(s) Increlex is indicated for the treatment of growth failure (GF) in pediatric patients 2 years of age and older with: • Severe primary IGF-1 deficiency (IGFD) 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). • Growth hormone (GH) gene deletion who have developed neutralizing antibodies to GH Limitation(s) of use:
• • Increlex is not a substitute to GH for approved GH indications. Increlex is not indicated for use in patients with secondary forms of IGFD, such as GH deficiency, malnutrition, hypothyroidism, or chronic treatment with pharmacologic doses of anti-inflammatory corticosteroids. Policy/Criteria Provider must submit documentation (such as office chart notes, lab results or other clinical information) supporting that member has met all approval criteria.
It is the policy of health plans affiliated with Centene Corporation® that Increlex is medically necessary when the following criteria are met:
I. Initial Approval Criteria
A. Severe Primary IGF-1 Deficiency (must meet all):

1. Diagnosis of severe primary IGFD;
   2. Prescribed by or in consultation with a pediatric endocrinologist;
   3. Age ≥ 2 and < 18 years;
   4. If age > 10 years, open epiphysis on x-ray;
   5. IGF-1 serum level is ≥ 3 standard deviations (SD) below the mean;
   6. GH serum level is normal or elevated;
   7. Height is ≥ 3 SD below the mean for age and sex (SD, height, date, and age in months within the last 90 days are required);

2. Member does not have malignant neoplasia or a history of malignancy;

   9. Somatropin (recombinant human GH) is not prescribed concurrently with Increlex;
   10. Dose does not exceed 0.12 mg/kg twice daily. Page 1 of 8

   CLINICAL POLICY Mecasermin Approval duration: Medicaid/HIM – 12 months or up to age 18 years, whichever is shorter
   Commercial – 6 months or to the member’s renewal date, whichever is longer B. Growth Hormone Insensitivity (must meet all):

   1. Diagnosis of acquired GH insensitivity;
   2. Prescribed by or in consultation with a pediatric endocrinologist;
   3. Age ≥ 2 and < 18 years;
   4. If age > 10 years, open epiphysis on x-ray;
   5. Documentation of genetic GH deficiency due to a GH gene deletion;
   6. Documentation of neutralizing GH antibodies;
   7. Member meets (a or b): a. Short stature (SS): height is > 2 SD below the mean for age and sex (SD, height, date, and age in months within the last 90 days are required); b. GF: one of the following (i, ii, or iii): i. Height deceleration across two growth chart percentiles representing > 1 SD below the mean for age and sex (SD and 2 heights, dates, and ages in months at least 6 months apart within the last year are required); ii. Growth velocity > 2 SD below the mean for age and sex over 1 year (SD and 2 heights, dates, and ages in months at least 1 year apart within the last year are required); iii. Growth velocity > 1.5 SD below the mean for age and sex sustained over 2 years (SD and 2 heights, dates, and ages in months at least 2 years apart within the last two years are required);
3. Member does not have malignant neoplasia or a history of malignancy;
   9. Somatropin (recombinant human GH) is not prescribed concurrently with Increlex;
   10. Dose does not exceed 0.12 mg per kg twice daily. Approval duration: Medicaid/HIM – 6 months or up to age 18 years, whichever is shorter
       Commercial – 6 months or to the member’s renewal date, whichever is longer C. Other diagnoses/indications (must meet 1 or 2):
4. If this drug has recently (within the last 6 months) undergone a label change (e.g., newly approved indication, age expansion, new dosing regimen) that is not yet reflected in this policy, refer to one of the following policies (a or b): a. For drugs on the formulary (commercial, health insurance marketplace) or PDL (Medicaid), the no coverage criteria policy for the relevant line of business: CP.CPA.190 for commercial, HIM.PA.33 for health insurance marketplace, and CP.PMN.255 for Medicaid; or b. For drugs NOT on the formulary (commercial, health insurance marketplace) or PDL (Medicaid), the non-formulary policy for the relevant line of business: CP.CPA.190 for commercial, HIM.PA.103 for health insurance marketplace, and CP.PMN.16 for Medicaid; or

5. If the requested use (e.g., diagnosis, age, dosing regimen) is NOT specifically listed under section III (Diagnoses/Indications for which coverage is NOT authorized) AND criterion 1 above does not apply, refer to the off-label use policy for the relevant line Page 2 of 8

   CLINICAL POLICY Mecasermin of business: CP.CPA.09 for commercial, HIM.PA.154 for health insurance marketplace, and CP.PMN.53 for Medicaid.
   II. Continued Therapy A. All Indications in Section I (must meet all):

6. Member meets one of the following (a or b): a. Currently receiving medication via Centene benefit or member has previously met initial approval criteria; b. Member is currently receiving medication and is enrolled in a state and product with continuity of care regulations (refer to state specific addendums for CC.PHARM.03A and CC.PHARM.03B);
7. If member has received treatment for ≥ 1 year, height has increased ≥ 2 cm in the last year as documented by 2 height measurements taken no more than 1 year apart (dates and height measurements are required);
8. Member does not have malignant neoplasia or a history of malignancy;
   4. Somatropin (recombinant human GH) is not prescribed concurrently with Increlex;
   5. If request is for a dose increase, new dose does not exceed 0.12 mg per kg twice daily.
      Approval duration: Medicaid/HIM – 12 months or up to age 18 years, whichever is shorter Commercial – 6 months or to the member’s renewal date, whichever is longer B. Other diagnoses/indications (must meet 1 or 2):
9. If this drug has recently (within the last 6 months) undergone a label change (e.g., newly approved indication, age expansion, new dosing regimen) that is not yet reflected in this policy, refer to one of the following policies (a or b): a. For drugs on the formulary (commercial, health insurance marketplace) or PDL (Medicaid), the no coverage criteria policy for the relevant line of business: CP.CPA.190 for commercial, HIM.PA.33 for health insurance marketplace, and CP.PMN.255 for Medicaid; or b. For drugs NOT on the formulary (commercial, health insurance marketplace) or PDL (Medicaid), the non-formulary policy for the relevant line of business: CP.CPA.190 for commercial, HIM.PA.103 for health insurance marketplace, and CP.PMN.16 for Medicaid; or

10. If the requested use (e.g., diagnosis, age, dosing regimen) is NOT specifically listed under section III (Diagnoses/Indications for which coverage is NOT authorized) AND criterion 1 above does not apply, refer to the off-label use policy for the relevant line of business: CP.CPA.09 for commercial, HIM.PA.154 for health insurance marketplace, and CP.PMN.53 for Medicaid.
    III. Diagnoses/Indications for which coverage is NOT authorized:
    A. Non-FDA approved indications, which are not addressed in this policy, unless there is sufficient documentation of efficacy and safety according to the off label use policies – CP.CPA.09 for commercial, HIM.PA.154 for health insurance marketplace, and CP.PMN.53 for Medicaid or evidence of coverage documents;
    Page 3 of 8

    CLINICAL POLICY Mecasermin B. Secondary forms of IGF-1 deficiency, such as:

11. GH deficiency;

    2. Malnutrition;
    3. Hypothyroidism;
    4. Chronic treatment with pharmacologic doses of anti-inflammatory steroids. IV. Appendices/General Information Appendix A: Abbreviation/Acronym Key FDA: Food and Drug Administration GH: growth hormone IGF-1: insulin-like growth factor -1 Appendix B: Therapeutic Alternatives Not applicable IGFD: insulin-like growth factor deficiency SD: standard deviation Appendix C: Contraindications/Boxed Warnings • Contraindication(s): o In pediatric patients with malignant neoplasia or a history of malignancy o Known hypersensitivity to mecasermin o Intravenous administration o In patients with closed epiphyses for growth promotion • Boxed warning(s): none reported Appendix D: Primary IGF-1 Deficiency • Causes: o GH receptor mutations (known as Laron syndrome or the classical model of GH insufficiency)
       o Post-GH receptor mechanisms  GH receptor signal transduction    Defective stabilization of circulating IGF-I IGF-I gene mutations Impaired IGF-1 promoter function o IGF-1 receptor mutations Unlike the causes above, IGF-1 levels are normal or elevated in the case of IGF-1 receptor mutations which would render mecasermin therapy ineffective. ____ GH production and secretion is normal or above normal; therefore, exogenous GH treatment would be ineffective. Appendix E: General Information • Severe primary IGFD includes patients with mutations in the growth hormone receptor (GHR), post-GHR signaling pathway, and IGF-1 gene defects; 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 • Page 4 of 8

    CLINICAL POLICY Mecasermin pharmacologic doses of anti-inflammatory steroids. Thyroid and nutritional deficiencies should be corrected before initiating treatment. Increlex is not a substitute for GH treatment. • • Failure to increase height velocity during the first year of therapy by at least 2 cm/year suggests the need for assessment of compliance and evaluation of other causes of growth failure, such as hypothyroidism, under-nutrition, and advanced bone age. • CDC recommended growth charts, data tables, and related information that may be helpful in assessing length, height and growth are available at the following link: https://www.cdc.gov/growthcharts/index.htm.
    V. Dosage and Administration
    Indication Growth failure in children with severe primary IGFD or with GH gene deletion who have developed neutralizing antibodies to GH Dosing Regimen Initial dose: 0.04 mg/kg to 0.08 mg/kg (40 mcg/kg to 80 mcg/kg) SC BID. Maximum Dose 0.12 mg/kg per dose Dose may be increased by 0.04 mg/kg (40 mcg/kg) per dose up to 0.12 mg/kg (120 mcg/kg) SC BID VI. Product Availability
    Multi-dose vial: 40 mg/4 mL (10 mg/mL) VII.